Pesticide-Induced Diseases: Sexual and Reproductive Dysfunction
A robust body of literature details reproductive effects in fish, amphibians, and reptiles related to exposure to endocrine disruptors. Evidence of these effects has also been seen in wild mammals such as polar bears and seals. Environmental exposure assessments and wildlife, laboratory and epidemiologic studies show exposure to low-level environmental contaminants, such as pesticides and other chemicals, subtly undermines the ability to reproduce. The study of endocrine disruption is revealing mechanisms that show how specific environmental contaminants can alter fertility. Laboratory animal experiments have confirmed these wildlife findings.
- Absence of effects on the rat sperm quality after subacute exposure to low doses of fungicide prochloraz.
Prochloraz (PCZ) is a fungicide and androgen-receptor antagonist used worldwide in horticulture and agriculture. Pre- and perinatal exposure to this pesticide during sexual differentiation is deleterious for male offspring. Since data on the effects of PCZ on epididymal functions are scarce, and because sperm maturation occurs in this organ, the present investigation aimed to determine whether low PCZ doses administered to rats during the phase of sperm transit through the epididymis might affect the morphophysiology of this organ and sperm quality. Adult male Wistar rats were assigned to 4 different groups: 0 (control, vehicle) or 10, 15, or 30 mg/kg bw/d PCZ diluted in corn oil administered orally for 4 consecutive days. Morphofunctional parameters of the male reproductive tract, hormone concentrations, sperm evaluations, and fertility and histopathologic analysis of testis and epididymis were assessed. There were no statistically significant differences between treated and control groups in relation to all evaluated parameters. Data demonstrated show that PCZ exposure for a brief 4-d exposure and low doses did not produce reproductive toxicity or compromise sperm quality in adult rats.
[Sanabria M, Pessin A, Zanutto MR, et al. 2015. J Toxicol Environ Health A. 78(8):481-91.]
- Anti-Müllerian hormone and lifestyle, reproductive, and environmental factors among women in rural South Africa.
Few data exist regarding anti-Müllerian hormone, a marker of ovarian reserve, in relation to environmental factors with potential ovarian toxicity.This analysis included 420 women from Limpopo, South Africa studied in 2010-2011. Women were administered comprehensive questionnaires, and plasma concentrations of anti-Müllerian hormone and dichlorodiphenyltrichloroethane were determined. The median age of women was 24 years; the median anti-Müllerian hormone concentration was 3.1 ng/ml. Women who reported indoor residual spraying in homes with painted walls (indicative of exposure to pyrethroids) had 25% lower anti-Müllerian hormone concentrations compared with women who reported no spraying. Little evidence of decreased anti-Müllerian hormone concentrations was observed among women with the highest dichlorodiphenyltrichloroethane levels. These are among the first data regarding anti-Müllerian hormone concentrations relative to pesticides and indoor air pollution. Our results are suggestive of decreased ovarian reserve associated with exposure to pyrethroid pesticides, which is consistent with laboratory animal data.
[Whitworth KW, Baird DD, Steiner AZ, et al.2015. Epidemiology.26(3):429-35.]
- Combined effects of repeated administration of Bretmont Wipeout (glyphosate) and Ultrazin (atrazine) on testosterone, oxidative stress and sperm quality of Wistar rats.
The potential toxicity resulting from the possible interactions of the herbicides, Ultrazin (atrazine, ATZ) and Bretmont Wipeout (glyphosate, GLY) is not completely known. This study evaluated reproductive- and hepato-toxicity in rats co-exposed to ATZ and GLY.Six weeks old male rats were exposed by gavage three times per week to ATZ (12.5 mg/kg) or GLY (5 mg/kg) alone or in combination (12.5 mg/kg ATZ + 5 mg/kg GLY).ATZ and GLY impaired sperm quality but GLY has more adverse effect on sperm quality than ATZ. Testosterone level, sperm motility, sperm counts, live/dead ratio and the weight of the epididymis were lower in the GLY group compared to the ATZ group by 57%, 33%, 20%, 22% and 41% and higher by 109%, 76.7%, 39.6%, 32.3% and 100% respectively in the combine-exposure group (ATZ + GLY) compared to the GLY group. Oxidative stress and histopathological changes were also noticeable in the liver but not in the testis of GLY-treated animals, and the observed effects were more remarkable in the GLY group than the ATZ or the combined-exposure group. The combined effects of the active ingredients on testosterone level, sperm count and hepatic malondialdehyde (MDA) levels were also similar as when the commercial formulations were used. Study finds antagonistic interactions between the two toxicants on the toxicity endpoints investigated in this study and these effects are due to the active ingredients of both herbicides in the commercial formulations.
[Abarikwu SO, Akiri OF, et al. 2015. Toxicol Mech Methods.25(1):70-80.]
- Effects of a mixture of pesticides on the adult female reproductive system of Sprague-Dawley, Wistar, and Lewis rats
The current study investigated the effects of a mixture of pesticides (dichlorvos, dicofol, dieldrin, endosulfan, and permethrin) on the reproductive system of Sprague-Dawley (SD), Wistar (WT), and Lewis (LEW) rats. Decreased body weights gain (SD and WT) and increased liver weights (SD, WT, and LEW) were observed in each strain fed the pesticides mixture at higher levels. At that dose level, rat strains also varied in their responses regarding the estrous cycle, hormonal levels, and number of developing ovarian follicles. The studied mixture of pesticides was found to interfere with the female reproductive system when individual pesticides were mixed above a certain level, indicating a threshold exists for each of the strains studied.
[Pascotto VM, Guerra MT, Franci JA, et al. 2015. J Toxicol Environ Health A. 78(9):602-16]
- Leydig cell number and sperm production decrease induced by chronic ametryn exposure: a negative impact on animal reproductive health.
Ametryn is an herbicide used to control broadleaf and grass weeds and its acute and chronic toxicity is expected to be low. Since toxicological data on ametryn is scarce, the aim of this study was to evaluate rat reproductive toxicity. Thirty-six adult male Wistar rats (90 days) were divided into three groups: Co (control) and T1 and T2 exposed to 15 and 30 mg/kg/day of ametryn, respectively, for 56 days. Testicular analysis demonstrated that ametryn decreased sperm number per testis, daily sperm production, and Leydig cell number in both treated groups, although little perceptible morphological change has been observed in seminiferous tubule structure. Lipid peroxidation was higher in group T2, catalase activity decreased in T1 group, superoxide dismutase activity diminished, and a smaller number of sulphydryl groups of total proteins were verified in both exposed groups, suggesting oxidative stress. These results showed negative ametryn influence on the testes and can compromise animal reproductive performance and survival.
[Dantas TA, Cancian G, Neodini DN, et al. 2015. Environ Sci Pollut Res Int. 22(11):8526-35.]
- Prenatal exposure to PCB-153, p,p'-DDE and birth outcomes in 9000 mother-child pairs: exposure-response relationship and effect modifiers.
Low-level exposure to polychlorinated biphenyl-153 (PCB-153) and dichlorodiphenyldichloroethylene (p-p'-DDE) can impair fetal growth; however, the exposure-response relationship and effect modifiers of such association are not well established. This study is an extension of an earlier European meta-analysis. The aim was to explore exposure-response relationship between PCB-153 and p-p'-DDE and birth outcomes; to evaluate whether any no exposure-effect level and susceptible subgroups exist; and to assess the role of maternal gestational weight gain (GWG). A pooled dataset of 9377 mother-child pairs enrolled in 14 study populations from 11 European birth cohorts was used. Study found an inverse linear exposure-response relationship between prenatal exposure to PCB-153 and birth weight, and effects on birth weight over the entire exposure range, including at low levels. This reduction seems to be stronger among children of mothers who were non-Caucasian or had smoked during pregnancy. This study suggests that the association between low-level exposure to PCB-153 and birth weight exists and follows an inverse linear exposure-response relationship with effects even at low levels, and that maternal smoking and ethnicity modify this association.
[Casas M, Nieuwenhuijsen M, Martínez D, et al. 2015. Environ Int. 74:23-31]
- Impaired development of female mouse offspring maternally exposed to simazine
Authors evaluated the toxicity of simazine in female mouse offspring with in utero and lactational exposure. Pregnant mice were exposed to environmentally relevant doses (from 5 to 500μg/kg) of simazine via oral administration, and their female offspring were then analyzed. The female offspring showed shortened anogenital distance and decreased whole body, ovarian, and uterine weights. Their ovaries showed increased apoptotic granulosa cells. In addition, expression of critical genes involved in regulation of cellular apoptosis and proliferation was significantly downregulated in the ovaries of simazine-exposed mice. Moreover, in vitro exposure of human granulosa cell-derived KGN cells to simazine (0.003-1nM) resulted in decreased viability and proliferation. Thus, the present study demonstrates that maternal exposure to low doses of simazine impairs normal development of female offspring via disturbance of cellular apoptosis and proliferation.
[Park S, Kim S, et al. 2014. Environ Toxicol Pharmacol. 38(3):845-51]
- Methamidophos alters sperm function and DNA at different stages of spermatogenesis in mice.
Methamidophos (MET) is a highly toxic organophosphate (OP) pesticide that is widely used in developing countries. MET has male reproductive effects, including decreased fertility. We evaluated MET effects on sperm quality, fertilization and DNA integrity, exploring the sensitivity of different stages of spermatogenesis. Adult male mice were exposed to evaluate MET's effects on epididymal maturation, meiosis or mitosis, respectively. At 1-days post-treatment (dpt), MET inhibited AChE (43-57%) and increased abnormal cells (6%). While at 28- and 45-dpt, sperm motility and viability were significantly reduced, and abnormal morphology increased. MDA and mitochondrial activity were not affected at any dose or time. DNA damage (OTM and %DNA) was also observed. Sperm phosphorylation (at serine and tyrosine residues) was observed at all time points. Data suggest that meiosis and mitosis are the more sensitive stages of spermatogenesis for MET reproductive toxicity compared to epididymal maturation.
[Urióstegui-Acosta M, Hernández-Ochoa I, Sánchez-Gutiérrez M,et al. 2014. Toxicol Appl Pharmacol. 279(3):391-400]
- Persistent organochlorine pollutants and human reproductive health
Study focuses on the reproductive health effects in humans from four diverse populations: an Inuit population from Greenland, a Swedish population of fishermen and fishermen's wives, and urban populations from the cities of Warsaw in Poland and Kharkiv in Ukraine, representing populations with considerable variations in organochlorine exposure levels due to differences in the consumption of contaminated food items and the period since banning the use of the organochlorines selected in the present study. Time to pregnancy varied between the populations included, whereas semen quality was remarkably similar with only minor differences in motility between countries and within regions in Greenland. Sperm concentration and morphology were not associated with PCB-153 or DDE exposure, but sperm motility was consistently associated with PCB-153 exposure across populations. Xeno-estrogen, -androgen and dioxin-like activity in serum samples were not consistently associated with semen quality measures, indicating that the associations observed with sperm motility were not caused via direct effects on these receptors. Results suggest a higher probability of ever having a spontaneous abortion among women with high PCB-153 or DDE exposure levels. Overall, the results suggest that PCB-153, but probably not DDE, may affect aspects of male and female reproductive functioning in European and Arctic populations at the levels of exposure currently experienced in these populations, although the associations observed did not seem to be a major cause of reduced human fertility.
[Toft G. 2014. Dan Med J. 61(11):B4967.]
- Pesticide methoxychlor promotes the epigenetic transgenerational inheritance of adult-onset disease through the female germline.
This study examined the actions of the pesticide methoxychlor to promote the epigenetic transgenerational inheritance of adult-onset disease and associated differential DNA methylation regions (i.e. epimutations) in sperm. Gestating F0 generation female rats were transiently exposed to methoxychlor during fetal gonadal development (gestation days 8 to 14) and then adult-onset disease was evaluated in adult F1 and F3 (great-grand offspring) generation progeny for control (vehicle exposed) and methoxychlor lineage offspring. There were increases in the incidence of kidney disease, ovary disease, and obesity in the methoxychlor lineage animals. In females and males the incidence of disease increased in both the F1 and the F3 generations and the incidence of multiple disease increased in the F3 generation. There was increased disease incidence in F4 generation reverse outcross (female) offspring indicating disease transmission was primarily transmitted through the female germline. Analysis of the F3 generation sperm epigenome of the methoxychlor lineage males identified differentially DNA methylated regions (DMR) termed epimutations in a genome-wide gene promoters analysis. These epimutations were found to be methoxychlor exposure specific in comparison with other exposure specific sperm epimutation signatures. Observations indicate that the pesticide methoxychlor has the potential to promote the epigenetic transgenerational inheritance of disease and the sperm epimutations appear to provide exposure specific epigenetic biomarkers for transgenerational disease and ancestral environmental exposures.
[Manikkam M, Haque MM, et al. 2014. PLoS One. 24;9(7):e102091.]
- Prepubertal organochlorine pesticide concentrations and age of pubertal onset among Russian boys.
In animal studies, organochlorine pesticide (OCP) exposure alters pubertal development; however, epidemiological data are limited and inconsistent. The aim of this study was to evaluate the associations of serum OCP concentrations [hexachlorobenzene (HCB), β-hexachlorocyclohexane (β-HCH), and p,p'-dichlorodiphenyldichloroethylene (p,p'-DDE)] with male pubertal onset. In Chapaevsk, Russia, a town environmentally contaminated with OCPs, 350 8-9year old boys with measured OCPs were enrolled during 2003-2005 and were followed annually for eight years. The authors evaluated three measures of pubertal onset: testicular volume (TV)>3mL in either testis, or stage 2 or greater for genitalia (G2+), or pubic hair (P2+). In adjusted models, boys with higher HCB concentrations had later mean ages of TV>3mL and P2+ (but not G2+). Mean age at attaining TV>3mL was delayed 3.6, 7.9, and 4.7months for HCB Q2, Q3, and Q4, respectively, compared to Q1. Boys with higher HCB concentrations reached P2+ 0.1months earlier for Q2, 4.7months later for Q3 and 4.6months later for Q4 compared to Q1. There were no associations of serum β-HCH and p,p'-DDE concentrations with age of pubertal onset. Higher prepubertal serum HCB concentrations were associated with later age of gonadarche and pubarche.
[Lam T, Williams PL, Lee MM, et al. 2014. Environ Int. 73C:135-142.]
- Reproductive toxicities of methoxychlor based on estrogenic properties of the compound and its estrogenic metabolite, hydroxyphenyltrichloroethane.
Methoxychlor is an organochlorine pesticide having a weak estrogenicity, which is estimated to be approximately 1000- to 14,000-fold less potent to a natural ligand, 17β-estradiol. However, its active metabolite, hydroxyphenyltrichloroethane, has much more potent estrogenic activity and probably acts in the target organs of animals exposed to methoxychlor at least 100 times stronger than the parent compound. A variety of in vivo reproductive toxicity studies have shown that treatment with methoxychlor exerts typical endocrine-disrupting effects manifest as estrogenic effects, such as formation of cystic ovaries resulting in ovulation failures, uterine hypertrophy, hormonal imbalances, atrophy of male sexual organs, and deteriorations of sperm production in rats and/or mice, through which it causes serious reproductive damages in both sexes of animals at sufficient dose levels. However, methoxychlor is not teratogenic. The no-observed-adverse-effect level of methoxychlor among reliable experimental animal studies in terms of the reproductive toxicity is 10ppm (equivalent to 0.600mg/kg/day) in a two-generation reproduction toxicity study.
[Aoyama H, Chapin RE. 2014. Vitam Horm.94:193-210.]
- Subacute toxicity assessment of diflubenzuron, an insect growth regulator, in adult male rats.
The objective of the present study was to evaluate the toxicological effects of subacute exposure to Diflubenzuron (DFB) insecticide in adult male rats. Adult male rats were exposed (gavage) to 0, 2, 4, or 8 mg/kg of DFB for 28 days. No clinical signs of toxicity were observed in the DFB-treated animals of the experimental groups. However, there was an increase in serum levels of alanine aminotransferase in the group that received 8 mg/kg/DFB/day and urea at doses of 4 and 8 mg/kg/DFB/day, without altering other biochemical or hematological parameters. The subacute exposure to the lowest dose of DFB caused significant decrease in testis weight, daily sperm production, and in number of sperm in the epididymis in relation to the control group. However, no alterations were observed in the sperm morphology, testicular, epididymis, liver and kidney histology, or testosterone levels. These findings unveiled the hazardous effects of DFB on male reproduction after the subacute exposure and special attention should be addressed to the effects of low doses of this pesticide.
[de Barros AL, Cavalheiro GF, de Souza AV, et al, 2014. Environ Toxicol. doi: 10.1002/tox.22054.]
- Ancestral dichlorodiphenyltrichloroethane (DDT) exposure promotes epigenetic transgenerational inheritance of obesity.
Ancestral environmental exposures to a variety of environmental factors and toxicants have been shown to promote the epigenetic transgenerational inheritance of adult onset disease. The present work examined the potential transgenerational actions of the insecticide dichlorodiphenyltrichloroethane (DDT) on obesity and associated disease. Outbred gestating female rats were transiently exposed to a vehicle control or DDT and the F3 generation male sperm were collected to investigate methylation between the control and DDT lineage male sperm.The F1 generation DDT lineage animals did develop kidney disease, prostate disease, ovary disease and tumor development as adults. The F3 generation (great grand-offspring) had over 50% of males and females develop obesity. Several transgenerational diseases previously shown to be associated with metabolic syndrome and obesity were observed in the testis, ovary and kidney. The transgenerational transmission of disease was through both female (egg) and male (sperm) germlines. F3 generation sperm epimutations, differential DNA methylation regions (DMR), induced by DDT were identified. A number of the genes associated with the DMR have previously been shown to be associated with obesity. Observations indicate ancestral exposure to DDT can promote obesity and associated disease transgenerationally. The etiology of disease such as obesity may be in part due to environmentally induced epigenetic transgenerational inheritance.
[Skinner MK, Manikkam M, Tracey R, et al.2013. BMC Med. 23;11:228.]
- Association between serum levels of organochlorine pesticides and sex hormones in adults living in a heavily contaminated area in Brazil.
The study examined the association between serum concentrations of organochlorine (OC) pesticides and levels of sex hormones in adult population in a rural area in Brazil heavily contaminated with these pesticides. A cross-sectional study with 304 men and 300 women was undertaken. Wet weight serum concentrations of 19 OC pesticides (dichloro-diphenyl-trichloroethane [DDT] and hexachlorocyclohexane [HCH], among others) were determined in all participants. Testosterone levels were obtained for men and estradiol, progesterone, prolactin, luteinizing hormone (LH) and follicle-stimulating hormone (FSH) for women. After adjusting for serum lipids and confounders, heptachlor and o,p'-DDT concentrations in men were associated with lower testosterone levels, while peri- and postmenopausal women showed inverse associations between LH and hexachlorobenzene (HCB), p,p'-DDT, p,p'-DDD (dichloro-diphenyl-dichloroethane), endosulfan 1 and 2, aldrin and mirex, as well as between FSH and p,p'-DDD, endosulfan 1 and aldrin. Premenopausal women did not show statistically significant associations between OC pesticides and sex hormones.Thus,inverse associations between OC pesticide concentrations and testosterone in men and LH and FSH in peri-/postmenopausal women, together with the high proportion of women with elevated prolactin, suggest that these OC compounds may have triggered anti-androgenic effects in men and estrogenic effects in women in this population.
[Freire C, Koifman RJ, Sarcinelli PN, et al. 2013. Int J Hyg Environ Health. pii: S1438-4639(13)00106-5]
- Cypermethrin induced pathological and biochemical changes in reproductive organs of female rats.
Cypermethrin, a synthetic pyrethroid, has broad spectrum use in domestic agriculture, and veterinary applications due to its high bioefficacy, enhanced stability and low mammalian toxicity. The present investigation was performed to investigate the sub acute effects of cypermethrin in female rats. Cypermethrin at a dose of 50 mg kg(-1) body weight (1/5th LD50) was orally given to female rats for 4 weeks. Control rats received similar amount of ground nut oil. Significant decrease in ovarian weight (15.4%) was observed after four weeks of cypermethrin administration while the uterine weight (68.2%) and thickness of myometrium increased at 2 and 4 weeks. Cypermethrin caused degenerative changes in ovary as evidenced by increased follicular atresia and decreased concentration of proteins (38%), lipids (20%), phospholipids (18%) and cholesterol (37%). Acid (49.2%) and alkaline phosphatase (41%) activities were increased while lactate dehydrogenase (37.9%) and 3beta-HSDH (31.3%) decreased in treated rat ovary.
[Sangha GK, Kaur K, Khera KS. 2013. J Environ Biol. 34(1):99-105]
- Do in utero events contribute to current health disparities in reproductive medicine?
Health disparities exist in reproductive medicine as discussed in detail in the subsequent articles of this issue; however, in most cases, the exact cause of these differences is unknown. Some of these disparities can be linked to environmental exposures such as alcohol and other hazardous toxic exposures (polycarbonate, pesticides, nicotine) in adults. In addition, low socioeconomic status, behavioral risk factors, and lack of education have been linked to poor obstetric and reproductive outcomes in minority groups. Aside from these various environmental exposures later in life, there is evidence that adverse events in utero could contribute to poor reproductive outcome in specific minority groups. We will focus on the developmental origins of health and disease as a possible causal mechanism for health disparities in reproductive diseases, as this perspective may suggest tractable solutions of how to address and eliminate these health disparities.
[Sauerbrun-Cutler MT, Segars JH. 2013. Semin Reprod Med. 31(5):325-32]
- Endocrine disrupting contaminant mixtures induce adverse developmental effects in pre-weaning rats.
Reproductive toxicity was investigated in rats after developmental exposure to a mixture of 13 endocrine disrupting contaminants, including pesticides, plastic- and cosmetic ingredients, and paracetamol. ll exposures and a vehicle were administered by oral gavage to time-mated Wistar dams rats throughout gestation and lactation, and their offspring were assessed for reproductive effects at birth and in prepuberty.The mixture doses which included the anti-androgenic compounds, affected the male offspring by causing decreased anogenital distance, increased nipple retention and reduced ventral prostate weights, at both medium and high doses. Additionally, the weights of the levator ani/bulbocavernosus muscle (LABC) were decreased at the high anti-androgen mixture dose. No effects were seen after exposure to the estrogenic chemicals alone, whereas males exposed solely to paracetamol showed decreased LABC weights and increased nipple retention. Thus adverse reproductive effects were observed at mixtures reflecting 200 times high end human exposure, which is relatively close to the safety margin covered by the regulatory uncertainty factor of 100. This suggests that highly exposed human population groups may not be sufficiently protected against mixtures of endocrine disrupting chemicals.
[Axelstad M, Christiansen S, Boberg J,et al. 2013. Reproduction. doi: 10.1530/REP-13-0447]
- Environmental and occupational pesticide exposure and human sperm parameters: a systematic review.
Of continuing concern are the associations between environmental or occupational exposures to pesticides and semen quality parameters. Prior research has indicated that there may be associations between exposure to pesticides of a variety of classes and decreased sperm health. The intent of this review was to summarize the most recent evidence related to pesticide exposures and commonly used semen quality parameters, including concentration, motility and morphology. Included in the review are 17 studies, 15 of which reported significant associations between exposure to pesticides and semen quality indicators. Specific pesticides targeted for study included dichlorodiphenyltrichloroethane (DDT), hexachlorocyclohexane (HCH), and abamectin. Pyrethroids and organophosphates were analyzed as classes of pesticides rather than as individual compounds, primarily due to the limitations of exposure assessment techniques. Overall, a majority of the studies reported significant associations between pesticide exposure and sperm parameters. A decrease in sperm concentration was the most commonly reported finding among all of the pesticide classes investigated. Decreased motility was also associated with exposures to each of the pesticide classes, although these findings were less frequent across studies. The evidence presented in this review continues to support the hypothesis that exposures to pesticides at environmentally or occupationally relevant levels may be associated with decreased sperm health.
[Martenies SE, Perry MJ. 2013. Toxicology.307:66-73]
- Environmental contaminant exposures and preterm birth: a comprehensive review.
Preterm birth is a significant public health concern, as it is associated with high risk of infant mortality, various morbidities in both the neonatal period and later in life, and a significant societal economic burden. As many cases are of unknown etiology, identification of the contribution of environmental contaminant exposures is a priority in the study of preterm birth. This is a comprehensive review of all known studies published from 1992 through August 2012 linking maternal exposure to environmental chemicals during pregnancy with preterm birth. Using PubMed searches, studies were identified that examined associations between preterm birth and exposure to five categories of environmental toxicants, including persistent organic pollutants, drinking-water contaminants, atmospheric pollutants, metals and metalloids, and other environmental contaminants. Individual studies were summarized and specific suggestions were made for future work in regard to exposure and outcome assessment methods as well as study design, with the recommendation of focusing on potential mediating toxicological mechanisms. In conclusion, no consistent evidence was found for positive associations between individual chemical exposures and preterm birth. By identifying limitations and addressing the gaps that may have impeded the ability to identify true associations thus far, this review can guide future epidemiologic studies of environmental exposures and preterm birth.
[Ferguson KK, O'Neill MS, Meeker JD. 2013. J Toxicol Environ Health B Crit Rev. 16(2):69-113]
- Environmental exposure to pyrethroids and sperm sex chromosome disomy: a cross-sectional study.
This study investigated whether environmental exposure to pyrethroids was associated with altered frequency of sperm sex chromosome disomy in adult men. A sample of 75 subjects recruited through a Massachusetts infertility clinic provided urine and semen samples. Individual exposures were measured as urinary concentrations of three pyrethroid metabolites ((3-phenoxybenzoic acid (3PBA), cis- and trans- 3-(2,2-Dichlorovinyl)-1-methylcyclopropane-1,2-dicarboxylic acid (CDCCA and TDCCA)). Multiprobe fluorescence in situ hybridization for chromosomes X, Y, and 18 was used to determine XX, YY, XY, 1818, and total sex chromosome disomy in sperm nuclei. Poisson regression analysis was used to examine the association between aneuploidy rates and pyrethroid metabolites while adjusting for covariates. Between 25-56% of the sample were above the limit of detection (LOD) for the pyrethroid metabolites. All sex chromosome disomies were increased by 7-30% when comparing men with CDCCA and TDCCA levels above the LOD to those below the LOD. For 3PBA, compared to those below the LOD, those above the LOD had YY18 disomy rates 1.28 times higher whereas a reduced rate was seen for XY18 and total disomy, and no association was seen for XX18 and 1818. Findings suggest that urinary concentrations of CDCCA and TDCCA above the LOD were associated with increased rates of aneuploidy. However the findings for 3BPA were not consistent.
[Young HA, Meeker JD, Martenies SE, et al. 2013. Environ Health. 12(1):111]
- Environmental toxins: Alarming impacts of pesticides on male fertility.
This review comprehensively summarizes the effects of more than 15 mostly used pesticides on male reproductive physiology, as recent experimental and epidemiological research have indicated their alarming impact on overall human health. Mechanisms have described that pesticide exposure damages spermatozoa, alter Sertoli or Leydig cell function, both in vitro and in vivo and thus affects semen quality. But, the literature suggests a need for more intricate research in those pesticides that are defined as mutagens or carcinogens and directly affect the hypothalamic-pituitary-gonadal axis. This literature review also proposes specific solutions to overcome these health effects.
[Sengupta P, Banerjee R. 2013. Hum Exp Toxicol.[Epub ahead of print]
- Environmentally induced epigenetic transgenerational inheritance of altered Sertoli cell transcriptome and epigenome: molecular etiology of male infertility.
Environmental toxicants have been shown to induce the epigenetic transgenerational inheritance of adult onset disease, including testis disease and male infertility. The current study was designed to determine the impact of an altered sperm epigenome on the subsequent development of an adult somatic cell (Sertoli cell) that influences the onset of a specific disease (male infertility). A gestating female rat (F0 generation) was exposed to the agriculture fungicide vinclozolin during gonadal sex determination and then the subsequent F3 generation progeny used for the isolation of Sertoli cells and assessment of testis disease. As previously observed, enhanced spermatogenic cell apoptosis was observed. The Sertoli cells provide the physical and nutritional support for the spermatogenic cells. Over 400 genes were differentially expressed in the F3 generation control versus vinclozolin lineage Sertoli cells. A number of specific cellular pathways were identified to be transgenerationally altered. One of the key metabolic processes affected was pyruvate/lactate production that is directly linked to spermatogenic cell viability. The Sertoli cell epigenome was also altered with over 100 promoter differential DNA methylation regions (DMR) modified. The genomic features and overlap with the sperm DMR were investigated. Observations demonstrate that the transgenerational sperm epigenetic alterations subsequently alters the development of a specific somatic cell (Sertoli cell) epigenome and transcriptome that correlates with adult onset disease (male infertility). The environmentally induced epigenetic transgenerational inheritance of testis disease appears to be a component of the molecular etiology of male infertility.
[Guerrero-Bosagna C, Savenkova M, Haque MM, et al. 2013. PLoS One. 8(3):e59922]
- Female farmworkers' health during pregnancy: health care providers' perspectives.
Pregnant farmworkers and their fetuses are at increased risk of negative health outcomes due to environmental and occupational factors at their workplaces. Health care providers who serve farm communities can positively affect workers' health through the informed care they deliver. Yet, interviews with rural health care providers reveal limited knowledge about agricultural work or occupational and environmental health risks during pregnancy. Professional associations, government organizations, academic institutions, and practice settings must renew their efforts to ensure that environmental and occupational health education, especially as it relates to women and their children, is incorporated into academic and practice environments.
[Kelley MA, Flocks JD, Economos J, McCauley LA. 2013. Workplace Health Saf. 61(7):308-13]
- Impact of boric acid exposure at different concentrations on testicular DNA and male rats fertility.
The aim of this study was to investigate the consequences of exposure to three levels of boric acid (BA) on male rats reproduction, fertility and progeny outcome, with emphasis on testicular DNA level and quality. Adult male rats (12 weeks old) were treated orally with BA for 60 d. The results indicated that BA administration at 125 mg/kg bwt had no adverse effects on fertility, sperm characteristics or prenatal development of the impregnated females. However, at dose 250 mg, BA treatment significantly increased serum nitric oxide, testosterone, estradiol levels and testicular boron and calcium levels and also significantly reduced serum arginase activity, sperm quality and testicular DNA content with minor DNA fragmentation. The impact of BA exposure at dose 250 mg on male rats fertility was translated into increases in pre-implantation loss with a resulting decrease in the number of live fetuses/litter. In addition to the significant alteration of biochemical measurements, observed at dose 250 mg, administration of BA at 500 mg caused testicular atrophy, severe damage of spermatogenesis, spermiation failure and significant reduction of Mg and Zn testicular levels. None of the male rats, treated with 500 mg/kg bwt, could impregnate untreated females, suggesting the occurrence of definitive loss of fertility. In conclusion, BA impaired fertility, in a dose-dependant manner, by targeting the highly proliferative cells, the germ cells, through decreasing DNA synthetic rate rather than the induction of DNA damage.
[El-Dakdoky MH, Abd El-Wahab HM.2013. Toxicol Mech Methods. 23(5):360-7]
- In vitro-in vivo correlations for endocrine activity of a mixture of currently used pesticides.
Two pesticide mixtures were investigated for potential endocrine activity. Mix 3 consisted of bitertanol, propiconazole, and cypermethrin, and Mix 5 included malathion and terbuthylazine in addition to the three pesticides in Mix 3. All five single pesticides and the two mixtures were investigated for their ability to affect steroidogenesis in vitro in H295R cells. The pesticides alone and both mixtures affected steroidogenesis with both mixtures causing increase in progesterone and decrease in testosterone. For Mix 5 an increase in estradiol was seen as well, indicating increased aromatase activity. The two mixtures were also investigated in pregnant rats dosed from gestational day 7 to 21, followed by examination of dams and fetuses. Decreased estradiol and reduced placental testosterone were seen in dams exposed to Mix 5. Also a significant increase in aromatase mRNA-levels in female adrenal glands was found for Mix5. However, neither of the two mixtures showed any effects on fetal hormone levels in plasma or testis, or on anogenital distance. Overall, potential aromatase induction was found for Mix 5 both in vitro and in vivo, but not for Mix 3, an effect likely owed to terbuthylazine in Mix 5. However, the hormonal responses in vitro were only partly reflected in vivo, probably due to some toxicokinetic issues, as the pesticide levels in the amniotic fluid also were found to be negatively affected by the number of compounds present in the mixtures. Nonetheless, the H295R assay gives hints on conceivable interference with steroidogenesis, thus generating hypotheses on in vivo effects.
[Taxvig C, Hadrup N, Boberg J, et al. 2013. Toxicol Appl Pharmacol.272(3):757-66]
- Late life effects on rat reproductive system after developmental exposure to mixtures of endocrine disrupters
This study examined late life effects of perinatal exposure of rats to a mixture of endocrine disrupting contaminants. Four groups of 14 time-mated Wistar rats were exposed by gavage from gestation day 7 to pup day 22 to a mixture of 13 anti-androgenic and estrogenic chemicals including phthalates, pesticides, UV-filters, bisphenol A, parabens and the drug paracetamol.Onset of puberty and estrous cyclicity at 9 and 12 months of age was assessed. Significantly fewer females showed regular estrus cyclicity at 12 months of age in the 2 exposure groups compared to controls. In 19 months old male offspring, epididymal sperm counts were lower than controls and in ventral prostate, an over-representation of findings related to hyperplasia was observed in exposed groups compared to controls particularly in the group dosed with anti-androgens. A higher incidence of pituitary adenoma at 19 months of age was found in males and females in the high dose group. Developmental exposure of rats to the highest dose of a human relevant mixture of endocrine disrupters induced adverse effects late in life manifested as earlier female reproductive senescence, reduced sperm counts, higher score for prostate atypical hyperplasia and higher incidence of pituitary tumors. These delayed effects highlight the need for further studies on the role of endocrine disrupters in hormone-related disorders in aging humans.
[Isling LK, Boberg J, Jacobsen PR, et al. 2013. Reproduction. doi: 10.1530/REP-13-0448]
- Male pubertal development: are endocrine-disrupting compounds shifting the norms?
Endocrine-disrupting compounds (EDCs) are synthetic or natural compounds that interfere with endogenous endocrine action. In humans, a growing number of epidemiological studies report an association with altered pubertal timing and progression. This review focuses on the small number of studies performed in males that report an association of polychlorinated biphenyls with earlier sexual maturity rating and confirm subtle effects of lead, dioxins, and endosulfan on delaying pubertal onset and progression in boys. Recent studies have also demonstrated that EDC exposure may affect pubertal testosterone production without having a noticeable effect on sexual maturity rating. A limitation to understand the effects of EDCs in humans is the potential for confounding due to the long temporal lag from early-life exposures to adult outcomes. The complex interplay of multiple environmental exposures over time also complicates the interpretation of human studies. These studies have identified critical windows of vulnerability during development when exposures to EDCs alter critical pathways and affect postnatal reproductive health. Contemporaneous exposures can also disrupt the hypothalamic-pituitary-gonadal axis. This paper reviews the normal process of puberty in males and summarize human data that suggest potential perturbations in pubertal onset and tempo with early-life exposures to EDCs.
[Zawatski W, Lee MM. 2013. J Endocrinol. 218(2):R1-12]
- Metabolomics tools for describing complex pesticide exposure in pregnant women in Brittany (France).
This study aims to answer to following questions: What is the influence of exposures to multiple pesticides on the metabolome? What mechanistic pathways could be involved in the metabolic changes observed? Based on the PELAGIE cohort (Brittany, France), 83 pregnant women who provided a urine sample in early pregnancy, were classified in 3 groups according to the surface of land dedicated to agricultural cereal activities in their town of residence. The 3 groups of exposure were correctly separated with a PLS-DA model after implementing an orthogonal signal correction with pareto standardizations (R2 = 90.7% and Q2 = 0.53). After adjusting for maternal age, parity, body mass index and smoking habits, the most statistically significant changes were observed for glycine, threonine, lactate and glycerophosphocholine (upward trend), and for citrate (downward trend). This work suggests that an exposure to complex pesticide mixtures induces modifications of metabolic fingerprints. It can be hypothesized from identified discriminating metabolites that the pesticide mixtures could increase oxidative stress and disturb energy metabolism.
[Bonvallot N, Tremblay-Franco M, Chevrier C. et al. 2013. PLoS One. 8(5):e64433]
- Occupational exposure to organophosphate and carbamate pesticides affects sperm chromatin integrity and reproductive hormone levels among Venezuelan farm workers.
Several reports suggest that chronic pesticide exposure may affect semen quality and male fertility in humans. The objective of this study was to evaluate the association between occupational exposure to organophosphate (OP) and carbamate (CB) pesticides and semen quality, as well as levels of reproductive and thyroid hormones of Venezuelan farm workers. Thirty-five healthy men (unexposed group) and 64 male agricultural workers (exposed group) were recruited for clinical evaluation of fertility status. Fresh semen samples were evaluated for sperm quality and analyzed for DNA fragmentation index (DFI) by flow cytometry. Pesticide exposure was assessed by measuring erythrocyte acetylcholinesterase (AChE) and plasma butyrylcholinesterase (BuChE) with a Test-mate ChE field kit. Serum levels of total testosterone (Tt), follicle-stimulating hormone (FSH), luteinizing hormone (LH), prolactin (PRL), thyroid stimulating hormone (TSH) and free thyroxine (FT4) were analyzed using enzyme immunoassay kits. Evidence of pesticide exposure was found in 87.5% of farmers based on AChE and BuChE inhibition. Significant increments were observed in sperm DFI with significant decreases in some semen parameters. DFI was negatively correlated with BuChE, sperm concentration, morphology and vitality in these workers. The levels of Tt, PRL, FT4 and TSH appeared to be normal; however, there was a tendency for increased LH and FSH levels in exposed workers. Results confirm the potential impact of chronic occupational exposure to OP/CB pesticides on male reproductive function, which may cause damage to sperm chromatin, decrease semen quality and produce alterations in reproductive hormones, leading to adverse reproductive health outcomes.
[Miranda-Contreras L, Gómez-Pérez R, Rojas G, et al. 2013. J Occup Health. 55(3):195-203]
- Organochlorine compound levels in fertile and infertile women from Rio de Janeiro, Brazil.
The aim of the study was quantify organochlorine compounds in women seeking infertility treatment and in spontaneously pregnant ones. From the pesticides studied, pp'DDE was detected in 100% of infertile women, at higher mean levels than in pregnant women, without correlation with the etiology of infertility. Levels of the polychlorinated biphenyls (PCBs) were low, with positive samples in 100% in the infertile women for PCBs 138, 153, 180, while in pregnant women, they were 85.7% for congeners 138 and 153. Only PCB180 showed significance, with frequency of 71.4%. The risk factors for female infertility were: age, consumption of untreated water and of canned foods. Exposure to the most prevalent organochlorine compounds described in literature was confirmed in the study, indicating that pp'DDE may adversely influence female fertility.
[Bastos AM, de Souza Mdo C, de Almeida Filho GL, et al. 2013. Arq Bras Endocrinol Metabol.57(5):346-53]
- Organochlorine Pesticides and Risk of Endometriosis: Findings from a Population-Based Case-Control Study.
Endometriosis is considered an estrogen-dependent disease. Persistent environmental chemicals that exhibit hormonal properties, such as organochlorine pesticides (OCPs), may affect endometriosis risk. Authors investigated endometriosis risk in relation to environmental exposure to OCPs. They conducted the present analyses using data from the Women's Risk of Endometriosis (WREN) study, a population-based case-control study of endometriosis conducted among 18- to 49-year-old female enrollees of a large health care system in western Washington State. OCP concentrations were measured in sera from surgically confirmed endometriosis cases first diagnosed between 1996 and 2001 and from population-based controls. Data suggested increased endometriosis risk associated with serum concentrations of β-hexachlorocyclohexane (HCH) and mirex. The association between serum β-HCH concentrations and endometriosis was stronger in analyses restricting cases to those with ovarian endometriosis.
[Upson K, De Roos AJ, Thompson ML,et al. 2013. Environ Health Perspect. 11-12;121(11-12):1319-1324]
- Paternal fenvalerate exposure influences reproductive functions in the offspring.
The aim of the present study was to elucidate whether adverse effects on male reproductive system are passed from exposed male mice to their offspring. Adult male mice received Fen (10 mg/kg) daily for 30 days and mated with untreated females to produce offspring. Fenvalerate significantly changed the methylation status of angiotensin I-converting enzyme (Ace), forkhead box O3 (Foxo3a), huntingtin-associated protein 1 (Hap1), nuclear receptor subfamily 3 (Nr3c2), promyelocytic leukemia (Pml), and Prostaglandin F2 receptor negative regulator (Ptgfrn) genes in paternal mice sperm genomic DNA. Further, Fen significantly increased sperm abnormalities; serum testosterone and estradiol-17ß level in adult male (F0) and their male offspring (F1). Further, paternal Fen treatment significantly increased the length of estrous cycle, serum estradiol-17ß concentration in estrus, and progesterone levels in diestrus in female offspring (F1). These findings suggest that adverse effects of paternal Fen exposure on reproductive functions can be seen not only in treated males (F0) but also in their offsprings.
[Xia D, Parvizi N, Zhou Y, et al. 2013. Reprod Sci. 20(11):1308-15.]
- Pre- and postnatal toxicity of diazinon induces disruption of spermatogenetic cell line evidenced by increased testicular marker enzymes activities in rat offspring.
The objective of this study was to study the possible reproductive adverse effects of the diazinon on rat offspring exposed in utero and during lactation. Dams were gavaged daily before mating, during mating, and during pregnancy and lactation in separate groups. Reproductive outcome data of dams were examined. Body weight, testis weight, testicular marker enzyme activities (alkaline phosphatase, acid phosphatase, lactate dehydrogenase, and glucose-6-phosphate dehydrogenase), qualitative and quantitative testicular and epididymal histology, and immunohistochemisty for 3-β-hydroxysteroid dehydrogenase (HSD) were examined in male offspring at puberty and adulthood. The 30-mg/kg dose induced significant adverse effects at both puberty and adulthood in offspring. At puberty the male offspring showed a decrease in testicular weight, degenerative changes, and 3-β-HSD. At adulthood, there was a decrease in testicular weight and 3-β-HSD with an increase in the levels of testicular marker enzyme. Most of the adverse effects were irreversible and were evident at both puberty and adulthood in offspring, although a few parameters reverted back to the normal growth pattern. Hence, diazinon is a reproductive toxicant in male offspring, which caused significant damage to the testes when exposed during prenatal and postnatal life.
[Jayachandra S, D'Souza UJ. 2013. J Environ Pathol Toxicol Oncol.32(1):73-90]
- Prenatal exposure to the pesticide DDT and hypertension diagnosed in women before age 50: a longitudinal birth cohort study.
Elevated levels of the pesticide DDT (dichlorodiphenyltrichloroethane) have been positively associated with blood pressure and hypertension in studies among adults. Accumulating epidemiologic and toxicologic evidence suggests that hypertension during adulthood may also be affected by earlier life and possibly the prenatal environment. Study assessed whether prenatal exposure to the pesticide DDT increases risk of adult hypertension. Authors examined concentrations of DDT (p,p´- and o,p´-) and its metabolite p,p´-DDE (dichlorodiphenyldichloroethylene) in prenatal serum samples from a subset of women who had participated in the prospective Child Health and Development Studies birth cohort in the San Francisco Bay area while they were pregnant between 1959 and 1967. Authors surveyed daughters 39-47 years of age. Prenatal p,p´-DDT exposure was associated with hypertension. These associations between p,p´-DDT and hypertension were robust to adjustment for independent hypertension risk factors as well as sensitivity analyses. These findings suggest that the association between DDT exposure and hypertension may have its origins early in development.
[La Merrill M, Cirillo PM, Terry MB, et al. 2013. Environ Health Perspect. 121(5):594-9]
- Reproductive effects of two neonicotinoid insecticides on mouse sperm function and early embryonic development in vitro.
Acetamiprid (ACE) and imidacloprid (IMI) are two major members in the family of neonicotinoid pesticides, which are synthesized with a higher selectivity to insects. The present study determined and compared in vitro effects of ACE, IMI and nicotine on mammalian reproduction by using an integrated testing strategy for reproductive toxicology, which covered sperm quality, sperm penetration into oocytes and preimplantation embryonic development. Direct chemical exposure on spermatozoa during capacitation was performed, and in vitro fertilization (IVF) process, zygotes and 2-cell embryos were respectively incubated with chemical-supplemented medium until blastocyst formation to evaluate the reproductive toxicity of these chemicals and monitor the stages mainly affected. Generally, treatment of 500 µM or 5 mM chemicals for 30 min did not change sperm motility and DNA integrity significantly but the fertilization ability in in-vitro fertilization (IVF) process, indicating that IVF process could detect and distinguish subtle effect of spermatozoa exposed to different chemicals. Culture experiment in the presence of chemicals in medium showed that fertilization process and zygotes are adversely affected by direct exposure of chemicals, in an order of nicotine>IMI>ACE, whereas developmental progression of 2-cell stage embryos was similar to controls. These findings unveiled the hazardous effects of neonicotinoid pesticides exposure on mammalian sperm fertilization ability as well as embryonic development, raising the concerns that neonicotinoid pesticides may pose reproductive risks on human reproductive health, especially in professional populations.
[Gu YH, Li Y, Huang XF, et al. 2013. PLoS One. 8(7):e70112]
- Residential proximity to methyl bromide use and birth outcomes in an agricultural population in California.
Methyl bromide, a fungicide often used in strawberry cultivation, is of concern for residents who live near agricultural applications because of its toxicity and potential for drift. Little is known about the effects of methyl bromide exposure during pregnancy. The study investigated the relationship between residential proximity to methyl bromide use and birth outcomes. Participants were from the CHAMACOS (Center for the Health Assessment of Mothers and Children of Salinas) study. Using data from the California Pesticide Use Reporting system, authors employed a geographic information system to estimate the amount of methyl bromide applied within 5 km of a woman's residence during pregnancy. Multiple linear regression models were used to estimate associations between trimester-specific proximity to use and birth weight, length, head circumference, and gestational age. High methyl bromide use (vs. no use) within 5 km of the home during the second trimester was negatively associated with birth weight, birth length, and head circumference. These outcomes were also associated with moderate methyl bromide use during the second trimester. Negative associations with fetal growth parameters were stronger when larger (5 km and 8 km) versus smaller (1 km and 3 km) buffer zones were used to estimate exposure.
[Gemmill A, Gunier RB, Bradman A, et al. 2013. Environ Health Perspect. 121(6):737-43]
- Roundup disrupts male reproductive functions by triggering calcium-mediated cell death in rat testis and Sertoli cells.
The present results show that acute Roundup exposure at low doses (36ppm, 0.036g/L) for 30min induces oxidative stress and activates multiple stress-response pathways leading to Sertoli cell death in prepubertal rat testis. The pesticide increased intracellular Ca(2+) concentration by opening L-type voltage-dependent Ca(2+) channels as well as endoplasmic reticulum IP3 and ryanodine receptors, leading to Ca(2+) overload within the cells, which set off oxidative stress and necrotic cell death. Similarly, 30min incubation of testis with glyphosate alone (36ppm) also increased (45)Ca(2+) uptake. These events were prevented by the antioxidants Trolox and ascorbic acid. Activated protein kinase C, phosphatidylinositol 3-kinase, and the mitogen-activated protein kinases such as ERK1/2 and p38MAPK play a role in eliciting Ca(2+) influx and cell death. Roundup decreased the levels of reduced glutathione (GSH) and increased the amounts of thiobarbituric acid-reactive species (TBARS) and protein carbonyls. Also, exposure to glyphosate-Roundup stimulated the activity of glutathione peroxidase, glutathione reductase, glutathione S-transferase, γ-glutamyltransferase, catalase, superoxide dismutase, and glucose-6-phosphate dehydrogenase, supporting downregulated GSH levels. Glyphosate has been described as an endocrine disruptor affecting the male reproductive system; however, the molecular basis of its toxicity remains to be clarified. We propose that Roundup toxicity, implicated in Ca(2+) overload, cell signaling misregulation, stress response of the endoplasmic reticulum, and/or depleted antioxidant defenses, could contribute to Sertoli cell disruption in spermatogenesis that could have an impact on male fertility.
[de Liz Oliveira Cavalli VL, Cattani D, Heinz Rieg CE, et al. 2013. Free Radic Biol Med. 65:335-46]
- The effects of pyridaben pesticide on the histomorphometric, hormonal alternations and reproductive functions of BALB/c mice.
This study was designed to elucidate how pyridaben can effects the histomorphometric, hormonal alternations and reproductive functions of BALB/c mice. 80 adult and apparently healthy male BALB/c mice were received the toxin at doses of 53 mg/kg. BW, and 212 mg/kg. BW, respectively.The levels of FSH, LH and testosterone were significantly decreased on the dose and time dependant means. The levels of the ROS and NOS were significantly increased in all test groups. The percent body weight gains significantly reduced, whereas weights significantly increased in test groups in a dose and time dependant manner. The histomorphometric and stereologic findings, including diameters of somniferous tubules, thickness of somniferous tubules epithelium, the leydig's cell distribution, TDI, SI, RI revealed that, all these parameters are also significantly reduces in test groups in a dose and time dependant manner. Study concludes that pyridaben causes histomorphometric and stereologic changes in testis, as well as hormonal and reproductive functional alternations in BALB/c mice.
[Ebadi Manas G, Hasanzadeh S, Parivar K. 2013. Iran J Basic Med Sci.16(10):1055-64.]
- Adverse effects on sexual development in rat offspring after low dose exposure to a mixture of endocrine disrupting pesticides.
The present study investigated whether a mixture of low doses of five environmentally relevant endocrine disrupting pesticides, epoxiconazole, mancozeb, prochloraz, tebuconazole and procymidone, would cause adverse developmental toxicity effects in rats. In rat dams, a significant increase in gestation length was seen, while in male offspring increased nipple retention and increased incidence and severity of genital malformations were observed. Severe mixture effects on gestation length, nipple retention and genital malformations were seen at dose levels where the individual pesticides caused no or smaller effects when given alone. Generally, the mixture effect predictions based on dose-additivity were in good agreement with the observed effects. The results indicate that there is a need for modification of risk assessment procedures for pesticides, in order to take account of the mixture effects and cumulative intake, because of the potentially serious impact of mixed exposure on development and reproduction in humans.
[Hass U, Boberg J, Christiansen S, Jacobsen PR, et al. 2012. Reprod Toxicol.34(2):261-74]
- Characterization of endocrine-disrupting chemicals based on hormonal balance disruption in male and female adult rats.
Reproductive functions are controlled by a finely tuned balance between estrogens and androgens. To further characterize the gonadal pathways leading to hormonal balance disruption by atrazine, vinclozolin, methoxychlor, and bisphenol A in rat, study investigated their effects in male and female young adult animals. Specifically, reproductive tract alterations, sex hormone balance in serum and gonads, tissue dosimetry, and mRNA expression were assessed. Study observed different aromatase regulation profiles between animals with similar estrogen-to-androgen ratios but with different chemical treatments. For example, increased estrogen-to-androgen ratios in atrazine-treated females could be partly linked to aromatase upregulation, while in methoxychlor- and bisphenol A-treated females, peripheral mechanisms such as conjugation/deconjugation processes might be more likely to elevate estrogen levels. In vinclozolin-treated animals, the decreased estrogen-to-androgen ratios reported might be due to an increase of peripheral (adrenal) steroidogenesis. Thus, measurement of many endpoints is necessary for good risk assessment.
[Quignot N, Arnaud M, Robidel F, Lecomte A, et al. 2012. Reprod Toxicol. 33(3):339-52.]
- Dioxin (TCDD) induces epigenetic transgenerational inheritance of adult onset disease and sperm epimutations.
The current study examined the ability of dioxin (2,3,7,8-tetrachlorodibenzo[p]dioxin, TCDD) to promote epigenetic transgenerational inheritance of disease and DNA methylation epimutations in sperm. Gestating F0 generation females were exposed to dioxin during fetal day 8 to 14 and adult-onset disease was evaluated in F1 and F3 generation rats. The incidences of total disease and multiple disease increased in F1 and F3 generations. Prostate disease, ovarian primordial follicle loss and polycystic ovary disease were increased in F1 generation dioxin lineage. Kidney disease in males, pubertal abnormalities in females, ovarian primordial follicle loss and polycystic ovary disease were increased in F3 generation dioxin lineage animals. Analysis of the F3 generation sperm epigenome identified 50 differentially DNA methylated regions (DMR) in gene promoters. These DMR provide potential epigenetic biomarkers for transgenerational disease and ancestral environmental exposures. Observations demonstrate dioxin exposure of a gestating female promotes epigenetic transgenerational inheritance of adult onset disease and sperm epimutations.
[Manikkam M, Tracey R, Guerrero-Bosagna C, Skinner MK. 2012. PLoS One.7(9):e46249]
- Evidence for diazinon-mediated inhibition of cis-permethrin metabolism and its effects on reproductive toxicity in adult male mice.
The potential toxicity resulting from combinatorial effects of organophosphorus and pyrethroid insecticides are not completely known. We evaluated male reproductive toxicity in mice co-exposed to diazinon and cis-permethrin. Nine-week-old male mice were exposed to diazinon or cis-permethrin alone or in combination, or vehicle (corn oil), for 6 weeks. Diazinon and the diazinon-permethrin mixture inhibited plasma and liver carboxylesterase activities. In the mixture group, urinary excretion of cis-permethrin metabolite 3-phenoxybenzoic acid decreased along with increased plasma and testicular concentrations of cis-permethrin, while excretion of diazinon metabolites, diethylphosphate and diethylthiophosphate, did not change, versus mice exposed to each chemical alone, which suggested that inhibition of carboxylesterase decreased the metabolic capacity to cis-permethrin. Though the co-exposure decreased testosterone biosynthesis, increased degenerate germ cells in seminiferous tubule and sperm morphological abnormalities versus controls more clearly than exposure to cis-permethrin alone, the expected potentiation of toxicity was not evident.
[Wang D, Kamijima M, Okamura A, et al. 2012. Reprod Toxicol. 34(4):489-97]
- Glyphosate impairs male offspring reproductive development by disrupting gonadotropin expression.
Glyphosate has been shown to alter aromatase activity and decrease serum testosterone concentrations. The aim of this study was to investigate the effect of gestational maternal glyphosate exposure on the reproductive development of male offspring. Sixty-day-old male rat offspring were evaluated for sexual behavior and partner preference; serum testosterone concentrations, estradiol, FSH and LH; the mRNA and protein content of LH and FSH; sperm production and the morphology of the seminiferous epithelium; and the weight of the testes, epididymis and seminal vesicles. The growth, the weight and age at puberty of the animals were also recorded to evaluate the effect of the treatment. The most important findings were increases in sexual partner preference scores and the latency time to the first mount; testosterone and estradiol serum concentrations; the mRNA expression and protein content in the pituitary gland and the serum concentration of LH; sperm production and reserves; and the height of the germinal epithelium of seminiferous tubules. An early onset of puberty but no effect on the body growth in these animals was also observed. These results suggest that maternal exposure to glyphosate disturbed the masculinization process and promoted behavioral changes and histological and endocrine problems in reproductive parameters. These changes associated with the hypersecretion of androgens increased gonadal activity and sperm production.
[Romano MA, Romano RM, Santos LD, et al. 2012. Arch Toxicol. 86(4):663-73]
- Pesticide and insect repellent mixture (permethrin and DEET) induces epigenetic transgenerational inheritance of disease and sperm epimutations.
The current study was designed to determine if a "pesticide mixture" (pesticide permethrin and insect repellent N,N-diethyl-meta-toluamide, DEET) promotes epigenetic transgenerational inheritance of disease and associated DNA methylation epimutations in sperm. Gestating F0 generation female rats were exposed during fetal gonadal sex determination and the incidence of disease evaluated in F1 and F3 generations. There were significant increases in the incidence of total diseases in animals from pesticide lineage F1 and F3 generation animals. Pubertal abnormalities, testis disease, and ovarian disease (primordial follicle loss and polycystic ovarian disease) were increased in F3 generation animals. Analysis of the pesticide lineage F3 generation sperm epigenome identified 363 differential DNA methylation regions (DMR) termed epimutations. Observations demonstrate that a pesticide mixture (permethrin and DEET) can promote epigenetic transgenerational inheritance of adult onset disease and potential sperm epigenetic biomarkers for ancestral environmental exposures.
[Manikkam M, Tracey R, Guerrero-Bosagna C, Skinner MK. 2012. Reprod Toxicol. 34(4):708-19]
- Transgenerational actions of environmental compounds on reproductive disease and identification of epigenetic biomarkers of ancestral exposures.
Environmental factors during fetal development can induce a permanent epigenetic change in the germ line (sperm) that then transmits epigenetic transgenerational inheritance of adult-onset disease in the absence of any subsequent exposure. The epigenetic transgenerational actions of various environmental compounds and relevant mixtures were investigated with the use of a pesticide mixture (permethrin and insect repellant DEET), a plastic mixture (bisphenol A and phthalates), dioxin (TCDD) and a hydrocarbon mixture (jet fuel, JP8). The effects on the F1, F2 and F3 generations pubertal onset and gonadal function were assessed. The plastics, dioxin and jet fuel were found to promote early-onset female puberty transgenerationally (F3 generation). Spermatogenic cell apoptosis was affected transgenerationally. Ovarian primordial follicle pool size was significantly decreased with all treatments transgenerationally. Differential DNA methylation of the F3 generation sperm promoter epigenome was examined. Differential DNA methylation regions (DMR) were identified in the sperm of all exposure lineage males and found to be consistent within a specific exposure lineage, but different between the exposures. Exposure-specific epigenetic biomarkers were identified that may allow for the assessment of ancestral environmental exposures associated with adult onset disease.
[Manikkam M, Guerrero-Bosagna C, et al. 2012.PLoS One. 7(2):e31901.]
- Two-generation reproduction toxicity study in rats with methoxychlor.
A two-generation reproduction toxicity study was conducted in rats with a reference estrogenic pesticide, methoxychlor, to validate the sensitivity and competency of current guidelines recommended by the United States Environmental Protection Agency; Japanese Ministry of Agriculture, Forestry and Fisheries; and Organisation for Economic Co-operation and Development for predicting reproductive toxicity of the test compound based on estrogenic endocrine disrupting effects. Both sexes of SD rats were exposed to methoxychlor in the diet at concentrations of 0, 10, 500 and 1500 ppm for two successive generations. The present study has successfully detected estrogenic activities and reproductive toxicities of methoxychlor, as well as its systemic toxicity. Body weights, body weight gains and food consumption of both sexes of animals were suppressed significantly in the 500 and 1500 ppm groups. Typical reproductive toxicities observed in females of these groups included, but were not limited to, prolonged estrous cycle, reduced fertility, decreased numbers of implantation sites and newborns, decreased ovary weights and/or increased incidences of cystic ovary. Uterine weights of weanlings increased significantly in these groups, suggesting that the sensitivity of this parameter for predicting estrogenic ability of the test compound is comparable to that of the uterotrophic assay. Reproductive toxicities of methoxychlor seemed less potent in males than in females. Methoxychlor delayed preputial separation and significantly reduced sperm counts and reproductive organ weights of males of the 500 and/or 1500 ppm groups; however, most males that failed to impregnate females in the same group showed normal fertility when they were re-mated with untreated females. Neither systemic nor reproductive toxicities appeared in the 10 ppm group.
[Aoyama H, Hojo H, Takahashi KL, et al. 2012. Congenit Anom (Kyoto). 52(1):28-41]
- Dioxin Exposure and Age of Pubertal Onset among Russian Boys
Authors investigated the association of dioxins, furans, PCBs, and corresponding toxic equivalent (TEQ) concentrations with pubertal onset among boys in a dioxin-contaminated region.499 boys 8–9 years of age were enrolled in a longitudinal study in Chapaevsk, Russia. Pubertal onset [stage 2 or higher for genitalia (G2+) or testicular volume (TV) > 3 mL] was assessed annually between ages 8 and 12 years. The median (range) total serum TEQ concentration was 21 pg/g lipid, approximately three times higher than values in European children. At enrollment, boys were generally healthy and normal weight, with 30% having entered puberty by G2+ and 14% by TV criteria. Higher dioxin TEQs were associated with later pubertal onset by TV. Findings support an association of higher peripubertal serum dioxin TEQs and concentrations with later male pubertal onset reflected in delayed testicular maturation.
[Korrick, S.A., Lee, M., Williams, P., et al. 2011. Environ Health Perspect. 119 (9):1339–1344.]
- Internal exposure to pollutants and sexual maturation in Flemish adolescents
Sexual maturation of adolescents (aged 14-15 years) was studied in relation to internal exposure to pollutants. Serum levels of pollutants and sex hormones were measured in 1679 participants selected as a random sample of the adolescents residing in the study areas. Data on sexual development were obtained from the medical school examination files. Self-assessment questionnaires provided information on health, use of medication and lifestyle factors. In boys, serum levels of hexachlorobenzene (HCB), p,p'-DDE and polychlorinated biphenyls (sum of marker PCB138, 153 and 180) were significantly and positively associated with pubertal staging (pubic hair and genital development). Higher levels of serum HCB and blood lead were associated with, respectively, a lower and a higher risk of gynecomastia. In girls, significant and negative associations were detected between blood lead and pubic hair development; higher exposure to PCBs was significantly associated with a delay in timing of menarche. Further understanding of toxic mode of action and sensitive windows of exposure is needed to explain the current findings.
[Den Hond, E., Dhooge, W., Bruckers,L., Schoeters,G., et al. 2011.J Expo Sci Environ Epidemiol.21(3): 224–233.]
- Synergistic effect of dichlorvos, dimethoate and malathion mixture on reproduction toxicity in male mice
To evaluate the reproduction toxicity of the mixture composed of dichlorvos, dimethoate and malathion synergistic effect on male mice, and further explore its possible mechanisms.The 105 male mice were divided into 7 groups, including control. The oral gavage was given for successive 35 days, and the mice were sacrificed on the 36(th) day. The levels of sexual hormone were measured, including testosterone (T), follicle stimulating hormone (FSH), luteinizing hormone (LH) and estradiol (E(2)). Pathological changes of testicle and epididymis were observed by morphology, pathology and electron microscope. After 14 days exposure, the body weights of the mice were lower in the mix-high dose group (than those in control group. After 28 days exposure, the body weights of the mice were also lower in the mix-medium dose group. The sperm counts and sperm motility decreased significantly as the toxic concentration arised. Comparing to control group, the spermatozoa count and sperm motility had decreased in mix-medium and mix-high dose groups, and the sperm abnormality rates were higher in mix-medium and mix-high groups. Compared to those in control group, the serum level of FSH, E(2) in mix-medium and mix-high dose group increased, while the level of LH and T decreased. The morphological and ultramicrostructure results of testicle and epididymis indicated that the mature sperm numbers were decreased, and the cacoplastic sperm head and the tail of spermatozoon were observed in mix-high dose groups. Thus, the dichlorvos, dimethoate and malathion mixture had synergistic reproductive toxicity to the testicle and epididymis structure and function, and thus leading to the process of generation cell cytopoiesis abnormalities, simultaneously the hypothalamus-pituitary-gonad axis were also affected and thus resulted in parasecretion.
[Yu Y, Yang AM, Zhang JH et al. 2011. Chinese Journal of Preventive Medicine. 45(9):810-4]
- The effects of prenatal exposure to atrazine on pubertal and postnatal reproductive indices in the female rat.
Atrazine (ATR) is an herbicide that exerts negative reproductive effects. Study examined the effects of vehicle or ATR (1, 5, 20 and 100mg/kg-d), administered to Sprague-Dawley rats on gestational days 14-21, once daily or divided into two doses per day, on female offspring reproductive indices. Offspring body weights at birth were reduced and mortality increased in the 100mg/kg-d group shortly after birth; by PND 21 there were no significant effects. Vaginal opening was delayed in this group, indicating delayed puberty. No significant differences in mammary gland development were apparent at PND 45, or estrous cyclicity through PND 272. There were no differences between dosing regimens. Lower ATR doses showed few effects in females prenatally exposed to ATR, while the high dose reduced offspring body weight and delayed vaginal opening. Nonetheless, it is unlikely that environmental exposure comparable to the high dose would be encountered.
[Davis LK, Murr AS, Best DS, Fraites MJ, et al. 2011. Reprod Toxicol. 32(1):43-51]
- Widely Used Pesticides with Previously Unknown Endocrine Activity Revealed as in Vitro Anti-Androgens
Researchers screened pesticides using in-vitro assays, which use human cells to check whether the pesticides activate or inhibit hormone receptors in cells that turn genes on and off. ScientistsThirty out of 37 pesticides tested by the researchers altered male hormones, including 16 that had no known hormonal activity until now. There was some previous evidence for the other 14 . The most potent in terms of blocking androgens was the insecticide fenitrothion, an organophosphate insecticide. Others with hormonal activity include fludioxonil, fenhexamid, dimethomorph and imazalil, which are all fungicides. Due to estimated anti-androgenic potency, current use, estimated exposure, and lack of previous data, authors strongly recommend that dimethomorph, fludioxonil, fenhexamid, imazalil, ortho-phenylphenol and pirimiphos-methyl be tested for anti-androgenic effects in vivo.
[Orton F, Rosivatz E, Scholze M, Kortenkamp A 2011. Environ Health Perspect. doi:10.1289/ehp.1002895]
- Effects of prenatal exposure to a low dose atrazine metabolite mixture on pubertal timing and prostate development of male Long-Evans rats
The incidence of prostate inflammation went from 48 percent in the control group to 81 percent in the male offspring who were exposed to a mixture of atrazine and its breakdown products prenatally. The severity of the inflammation increased with the strength of the doses. Puberty was also delayed in the animals who received atrazine. The doses of atrazine mixture given to the rats during the last five days of their pregnancy are close to the regulated levels in drinking water sources. The current maximum contamination level of atrazine allowed in drinking water is 3 parts per billion. The doses given to the animals were 0.09 (or 2.5 parts per million), 0.87 or 8.73 milligrams per kilogram body weight.
[Stanko JP, et al. 2010. Reprod Toxicol. Epub ahead of print. DOI:10.1016/j.reprotox.2010.07.006]
- Maternal pesticide use and birth weight in the Agricultural Health Study
Studies examining the association between maternal pesticide exposure and low birth weight yield conflicting results. The authors examined the association between maternal pesticide use and birth weight among women in the Agricultural Health Study, a large study of pesticide applicators and their spouses in Iowa and North Carolina. The authors evaluated self-reported pesticide use of 27 individual pesticides in relation to birth weight among 2246 farm women whose most recent singleton birth occurred within 5 years of enrollment (1993-1997). First-trimester pesticide-related tasks were not associated with birth weight. Ever use of the pesticide carbaryl was associated with decreased birth weight. This study thus provides limited evidence about pesticide use as a modulator of birth weight. Overall, the authors observed no associations between birth weight and pesticide-related activities during early pregnancy; however, the authors have no data on temporal specificity of individual pesticide exposures prior to or during pregnancy and therefore cannot draw conclusions related to these exposure windows. Given the widespread exposure to pesticide products, additional evaluation of maternal pregnancy exposures at specific time windows and subsequent birth outcomes is warranted.
[Sathyanarayana S., O. Basso, C.J. Karr, P., et al. 2010. J Agromedicine.15 (2): 127-36]
- Fourth National Report on Human Exposure to Environmental Chemicals
Report found more than 90 percent of males in the U.S. population had urine samples with detectable levels of metabolites of chlorpyrifos (TCPY). Over 75% of U.S. males had detectable levels of metabolites of naphthalene (1N). Chlorpyrifos is a known cholinesterase inhibitor, which the researchers believe may affect the release of luteinizing hormone (LH), the hormone that triggers testosterone secretion from the Leydig cells.
[Centers for Disease Control and Prevention. 2009. Atlanta, GA.]
- Profiling the Reproductive Toxicity of Chemicals from Multigeneration Studies in the Toxicity Reference Database
Multigeneration reproduction studies are used to characterize parental and offspring systemic toxicity, as well as reproductive toxicity of pesticides, industrial chemicals and pharmaceuticals. Results from 329 multigeneration studies on 316 chemicals have been digitized into standardized and structured toxicity data within the Toxicity Reference Database (ToxRefDB). Comparative analysis across the 329 studies identified chemicals with sensitive reproductive effects, based on comparisons to chronic and subchronic toxicity studies, as did the cross-generational comparisons within the multigeneration study. The general pattern of toxicity across all chemicals and the more focused comparative analyses identified 19 parental, offspring and reproductive effects with a high enough incidence to serve as targets for predictive modeling that will eventually serve as a chemical prioritization tool spanning reproductive toxicities. These toxicity endpoints included specific reproductive performance indices, male and female reproductive organ pathologies, offspring viability, growth and maturation, and parental systemic toxicities. Capturing this reproductive toxicity data in ToxRefDB supports ongoing retrospective analyses, test guideline revisions, and computational toxicology research.
[Martin, M, Mendez, E et al. 2009. Toxicol. Sci. 110 (1): 181-190.]
- Statistical Modeling Suggests That Anti-Androgens in Wastewater Treatment Works Effluents Are Contributing Causes of Widespread Sexual Disruption in Fish Living in English Rivers
In addition to the estrogenic substances, antiandrogenic activity was prevalent in almost all treated sewage effluents tested. Further, the results of the modeling demonstrated that feminizing effects in wild fish could be best modeled as a function of their predicted exposure to both antiandrogens and estrogens or to antiandrogens alone. Results provide a strong argument for a multicausal etiology of widespread feminization of wild fish in U.K. rivers involving contributions from both steroidal estrogens and xenoestrogens and from other (as yet unknown) contaminants with antiandrogenic properties. These results may add further credence to the hypothesis that endocrine-disrupting effects seen in wild fish and in humans are caused by similar combinations of endocrine-disrupting chemical cocktails.
[Jobling, S. et al. 2009. Environ Health Perspect 117:797-802. doi:10.1289/ehp.0800197]
- Synergistic Disruption of External Male Sex Organ Development by a Mixture of Four Antiandrogens
Study found the effect of combined exposure to four selected chemicals on malformations of external sex organs was synergistic, and the observed responses were greater than would be predicted from the toxicities of the individual chemicals. In relation to other hallmarks of disrupted male sexual development, including changes in anogenital distance (AGD), retained nipples, and sex organ weights, the combined effects were dose additive. When the four chemicals were combined at doses equal to no observed adverse effect levels estimated for nipple retention, significant reductions in AGD were observed in male offspring.
[Christiansen, S. et al. 2009. Environ Health Perspect 117:1839-1846]
- Testicular toxicity of chlorpyrifos (an organophosphate pesticide) in albino rat
Present study was undertaken to assess the effects of chlorpyrifos on testes, the main organ of male reproduction. Chlorpyrifos at the dose levels of 7.5, 12.5 and 17.5 mg/kg b. wt./day was administered orally to male rats of Wistar strain for 30 days. A significant reduction in weight was observed in testes. Chlorpyrifos also brought about marked reduction in epididymal and testicular sperm counts in exposed males and a decrease in serum testosterone concentration. Histopathological examination of testes showed mild to severe degenerative changes in seminiferous tubules at various dose levels. Fertility test showed 85% negative results. A significant reduction in the sialic acid content of testes and testicular glycogen was noticed, whereas the protein and cholesterol content was raised at significant levels. All these toxic effects are moderate at low doses and become severe at higher dose levels. From the results of the present study it is concluded that chlorpyrifos induces severe testicular damage and results in reduction in sperm count and thus affect fertility. Small changes in sperm counts are known to have adverse affects on human fertility. Therefore, application of such insecticide should be limited to a designed program.
[Joshi, S, Mathur, R and Gulati, N. 2007. Toxicology and Industrial Health. 23: 439—444]
- Exposure to nonpersistent insecticides and male reproductive hormones.
Study found high levels of the urinary metabolites of chlorpyrifos (TCPY) and carbaryl and naphthalene (1N) correlate directly with low levels of testosterone in male subjects.
[Meeker JD, et al. 2006. Epidemiology;17(1):61-8]
- Impact of PCB and p, p'-DDE Contaminants on Human Sperm Y:X Chromosome Ratio: Studies in Three European Populations and the Inuit Population in Greenland
S emen and blood from 547 men from Sweden, Greenland, Poland (Warsaw), and Ukraine (Kharkiv), with regionally different levels of POP exposure were collected. Swedish and Greenlandic men had on average significantly higher proportions of Y sperm. Study indicates that POP exposure might be involved in changing the proportion of ejaculated Y-bearing spermatozoa in human populations. Intercountry differences, with different exposure situations and doses, may contribute to varying Y:X chromosome ratios.
[Tiido T, et al. 2006. Environ Health Perspect 114:718-724. doi:10.1289/ehp.8668]
- Epigenetic Transgenerational Actions of Endocrine Disruptors and Male Fertility
Transient exposure of a gestating female rat during the period of gonadal sex determination to the endocrine disruptors vinclozolin (an antiandrogenic compound) or methoxychlor (an estrogenic compound) induced an adult phenotype in the F1 generation of decreased spermatogenic capacity (cell number and viability) and increased incidence of male infertility. These effects were transferred through the male germ line to nearly all males of all subsequent generations examined (that is, F1 to F4). The effects on reproduction correlate with altered DNA methylation patterns in the germ line.
[Anway, M.D. et al. 2005. Science: 308(5727) pp. 1466 - 1469]
- Exposure to persistent organochlorine pollutants associates with human sperm Y:X chromosome ratio
A geographically based study investigates risks to human fertility from persistent environmental organochlorines and finds that they may contribute to changes in sex ratios. This is the first study to indicate that exposure to POPs may increase the proportion of ejaculated Y-bearing spermatozoa.
[Tiido T, et al. 2005. Hum Reprod:20(7)1903-9]
- Methoxychlor Disrupts Uterine Hoxa10 Gene Expression
Study demonstrates that a mechanism by which methoxychlor disrupts uterine function is by suppressing Hoxa10 expression. Neonatal methoxychlor treatment resulted in an immediate suppression and cellular restriction of Hoxa10 expression as well as a permanent generalized decrease in expression that persisted in the adult. methoxychlor inhibited the expression of Hoxa10, a gene necessary for uterine development and function. One common mechanism by which endocrine disrupting chemicals produce lasting reproductive tract defects is through permanent alteration of developmental gene expression.
[Fei, X. et al. 2005. Endocrinology 146(8): 3445-3451]
- Low-Dose Agrochemicals and Lawn-Care Pesticides Induce Developmental Toxicity in Murine Preimplantation Embryos
Mixtures simulating preemergent herbicides, postemergent herbicides, and fungicides increased the percentage of apoptosis in exposed embryos (p ≤ 0.05). Mixtures simulating groundwater contaminants, insecticide formulation, and lawn-care herbicides reduced development to blastocyst and mean cell number per embryo (p ≤ 0.05). Our data demonstrate that pesticide-induced injury can occur very early in development, with a variety of agents, and at concentrations assumed to be without adverse health consequences for humans.
[Greenlee, A., et al. 2004. Environmental Health Perspectives, 112(6): 703-709.]
- Effect of Endosulfan on Male Reproductive Development
Male school children exposed to the highly toxic insecticide endosulfan showed delayed sexual maturity compared with similar children who were not exposed. Endosulfan also appears to interfere with sex hormone synthesis in males aged 10-19 years in a community of cashew plantations in northern Kerala, India.
[Saiyed, H et al. 2003. Environ Health Perspect 111:1958-1962]
- Geographic differences in semen quality of fertile U.S. males.
F irst study in the United States to compare semen quality among study centers using standardized methods and strict quality control. Sperm concentration was significantly lower in Columbia, Missouri, than in New York, New York; Minneapolis, Minnesota; and Los Angeles, California. Data suggest that sperm concentration and motility may be reduced in semirural and agricultural areas relative to more urban and less agriculturally exposed areas.
[Swan, S. et al. 2003. Environ Health Perspect; 111(4): 414–420]
- Risk factors for female infertility in an agricultural region
Mixing and applying herbicides 2 years before attempting conception was more common among infertile women (odds ratio [OR] = 27; 95% confidence interval [CI] = 1.9-380), as was the use of fungicides (OR = 3.3; CI = 0.8-13). Residing on a farm, ranch or in a rural area during this time period was protective of female fertility. Households supplied with central Wisconsin groundwater were at less risk for infertility than households using municipal sources (OR = 0.6; CI = 0.4-0.9). These results suggest that certain agricultural, residential and lifestyle choices may modify the risk of female infertility.
[Greenlee AR, et al. 2003. Epidemiology;14(4):429-36]
- Semen quality in relation to biomarkers of pesticide exposure.
Study addresses the hypothesis that pesticides currently used in agriculture in the Midwest contributed to these differences in semen quality. Men from Missouri with high levels of alachlor or diazinon in thier urine were significantly more likely to have poor sperm quality than were men with low levels, as were men with atrazine levels higher than the limit of detection (OR = 11.3). The herbicides 2,4-D and metolachlor were associated with poor semen quality in some analyses, whereas acetochlor levels were lower in cases than in controls (p = 0.04). No significant associations were seen for any pesticides within Minnesota, where levels of agricultural pesticides were low, or for the insect repellent DEET or the malathion metabolite malathion dicarboxylic acid. These associations between current-use pesticides and reduced semen quality suggest that agricultural chemicals may have contributed to the reduction in semen quality in fertile men from mid-Missouri reported previously.
[Swan, S.H. et al. 2003. Environ Health Perspect; 111(12): 1478–1484]
- Developmental Toxicity of a Commercial Herbicide Mixture in Mice: I. Effects on Embryo Implantation and Litter Size
Developmental toxicity in mice of a common commercial formulation of herbicide containing a mixture of 2,4-dichlorophenoxyacetic acid (2,4-D) , mecoprop, dicamba, and inactive ingredients was investigated. The data, although apparently influenced by season, showed an inverted or U-shaped dose-response pattern for reduced litter size, with the low end of the dose range producing the greatest decrease in the number of live pups born. The decrease in litter size was associated with a decrease in the number of implantation sites, but only at very low and low environmentally relevant doses.
[Cavieres, M., et al. 2002. Environ Health Perspect 110:1081-1085]
- Reproductive Toxicity of Carbofuran to the Female Mice: Effects on Estrous Cycle and Follicles
Carbofuran, a systemic N-methyl carbamate pesticide was orally administered with the doses of 0.4, 0.7, 1 and 1.3 mg/kg body weight/day to normal virgin female Swiss albino mice for 30 days. Estrous cycle was effected by showing a significant decrease in the number of estrous cycle and the duration of each phases of estrous cycle with concomitant significant increase in the diestrus phase in 1 and 1.3 mg/kg/d carbofuran treatment when compared with that of control mice. There was a significant decrease in the number of healthy follicles and a significant increase in the number of atretic follicles in 1 and 1.3 mg/kg/d treated groups when compared with the control. The histologic observations of the ovary revealed the presence of less number of healthy follicles and more number of atretic follicles in high dose of carbofuran treated mice. There was a dose dependent decrease in the body weight. The ovary weight was also decreased significantly in 1.3mg/kg/d carbofuran treatment. There were no significant change in the weight of the organs such as uterus, kidney, adrenal, liver, spleen, thymus and thyroid. These observed effects of carbofuran on the estrous cycle and follicles may be due to a direct effect on the ovary or the hypothalamo-hypophysial ovarian axis causing hormonal imbalance.
[BALIGAR, PN, KALIWAL, BB. 2002. Industrial Health. 40(4):345-352]
- An exploratory analysis of the effect of pesticide exposure on the risk of spontaneous abortion in an Ontario farm population.
The Ontario Farm Family Health Study collected data by questionnaire on the identity and timing of pesticide use on the farm, lifestyle factors, and a complete reproductive history from the farm operator and eligible couples living on the farm. A total of 2,110 women provided information on 3,936 pregnancies, including 395 spontaneous abortions. To explore critical windows of exposure and target sites for toxicity, authors examined exposures separately for preconception (3 months before and up to month of conception) and postconception (first trimester) windows and for early (< 12 weeks) and late (12-19 weeks) spontaneous abortions. They observed moderate increases in risk of early abortions for preconception exposures to phenoxy acetic acid herbicides, triazines, and any herbicide. For late abortions, preconception exposure to glyphosate, thiocarbamates, and the miscellaneous class of pesticides was associated with elevated risks. This study shows that timing of exposure and restricting analyses to more homogeneous endpoints are important in characterizing the reproductive toxicity of pesticides.
[Arbuckle,TE, Lin, Z and Mery, LS. 2001. Environ Health Perspect. 109(8): 851–857.]
- Contribution of environmental factors to the risk of male infertility
Study shows that environmental factors contribute to the severity of infertility, and that this may worsen the effects of pre-existing genetic or medical risk factors. Exposure to pesticides and solvents is significantly associated with sperm threshold values well below the limit for male fertility. Results found that men exposed to pesticides had higher serum oestradiol concentrations, and that men exposed to solvents had lower LH concentrations than non-exposed men. All of these effects were greater in men with primary infertility than in men with secondary infertility.
[Oliva A, et al. 2001. Hum Reprod;16(8):1768-76]
- Environmental risk factors and male fertility and reproduction
Several environmental substances and pesticides exert a direct, cytotoxic effect on male germ cells. However, an increasing concern has been raised by compounds that may act through more subtle mechanisms, for example, specific pesticides that are potentially capable of modulating or disrupting the endocrine system. Overall, exposure to pesticides with endocrine-disrupting potential raise a particular concern for male fertility because of the possible occurrence of both effects at low concentrations and additive interactions with other environmental risk factors. Delayed reproductive problems deserve special attention, since experimental data consistently indicate a high vulnerability in the developing male reproductive system. Epidemiologic studies have confirmed an increased risk of conception delay associated with occupational exposure to pesticides. Moreover, an increased risk of spontaneous abortion has been noted among wives of exposed workers.
[Petrelli, G and Mantovani, A. 2001. Contraception. 65(4):297–300]
- Evaluation of the Toxic Potentials of Cypermethrin Pesticide on Some Reproductive and Fertility Parameters in the Male Rats
Adult male Sprague-Dawley rats were exposed to tap water containing 0, 8,571, 17,143, or 34,286 ppm cypermethrin for 12 weeks. Fertility was significantly reduced in male rats ingesting cypermethrin at a concentration of 13.15 and 18.93 mg in that the number of females impregnated by them was significantly reduced. The number of implantation sites was significantly reduced in females mated with males that had ingested cypermethrin at a concentration of 39.66 mg. A significant reduction in the number of viable fetuses was observed in females impregnated by the exposed males at all three doses of cypermethrin. Epididymal and testicular sperm counts as well as daily sperm production were significantly decreased in exposed males. The serum levels of testosterone, follicle-stimulating hormone and luteinizing hormone were significantly reduced in males exposed to 39.66 mg per day. Ingestion of cypermethrin at 18.93 and 39.66 mg/animal/day also resulted in a significant decrease in the perimeter and number of cell layers of the seminiferous tubules. The testes of treated animals were infiltrated with congested blood vessels with marked hemorrhage and a significant accumulation of connective tissue surrounding the seminiferous tubules, which contained a large number of immature spermatids. These results clearly demonstrate the adverse effects of cypermethrin pesticide on fertility and reproduction in male rats.
[Elbetieha, A, Da'as, SI et al. 2001. Arch Environ Contamn Tox. 41(4):522-528]
- Reproductive toxicity of DDT in adult male rats
The reproductive toxicity of DDT was investigated in adult male rats. Administration of DDT led to a dose-dependent reduction of testicular weight and the number as well as the percentage of motile spermatozoa in the epididymis. Testicular histological observations revealed alsoamarkedloss of gametes in the lumen of seminiferous tubules. In DDT treated rats, the seminal vesicles weights dropped significantly, resulting from a decrease of testosterone production by testes, whereas serum LH and FSH increased after pesticide exposure. This increase of gonadotrophin levels may be related to an impairment of the negative feedback exerted by the steroid on the hypothalamic–pituitary axis. It is concluded that DDT induced adverse effects on male rat fertility by acting directly on the testes and altering the neuroendocrinefunction.
[Rhouma, KB, Tebourbi et al. 2001. Hum Exp Toxicol 20(8):393-397]
- Environmental antiandrogens: low doses of the fungicide vinclozolin alter sexual differentiation of the male rat.
Data demonstrate that vinclozolin produces subtle alterations in sexual differentiation of the external genitalia, ventral prostate, and nipple tissue in male rat offspring at dosage levels below the previously described no-observed-effect-level (NOEL). These effects occur at a dosage level an order of magnitude below that required to induce malformations and reduce fertility.
[Gray LE, et al. 1999. Toxicol Ind Health;15(1-2):48-64]
- Effects of Pesticides and Toxic Substances On Behavioral and Morphological Reproductive Development: Endocrine Versus Nonendocrine Mechanisms
Exposure to toxic substances or pesticides during critical perinatal developmental periods can alter reproductive and central nervous system (CNS)function in a manner that does not compromise the growth and viability of the fetus but causes functional alterations that become apparent later in life. While some "CNS/behavioral teratogens" are mutagenic or alter cell division, other chemicals produce alterations of CNS development via endocrine-mediated mechanisms. This discussion focuses on studies conducted primarily in our laboratory that describe how pesticides and toxic substances alter development of the reproductive and central nervous systems as a consequence of organizational or activational exposures. Abnormal behavior and morphology can result from exposure to endocrine-disrupting toxicants by altering organization of the CNS during critical stages of life or activation of behavior after puberty. Some of the toxicants that alter rodent sexual differentiation include xenoestrogens, antiandrogenic pesticides, and dioxin-like toxic substances. Chemicals that alter sex-linked nonreproductive and reproductive CNS development via nonhormonal mechanisms are also discussed in order to demonstrate that multiple mechanisms of action are involved in the development of behavioral abnormalities in pre- and perinatally exposed offspring. The fact that reproductive function (behavioral, biochemical, and morphological) can be altered via such a wide variety of mechanisms indicates that hazard identification in this area cannot rely solely on the detection of endocrine activity.
[Gray, LE and Ostby, J. 1998. Toxicol Ind Health 14(1-2): 159-184]
- Latent Effects of Pesticides and Toxic Substances On Sexual Differentiation of Rodents
The current discussion presents information on the effects of toxic chemicals and pesticides that act on reproductive development via novel mechanisms, including germ cell toxicity, antiandrogenicity, and Ah-receptor binding. Information will be presented that describes how exposure during critical stages of life to synthetic chemicals present in our environment, such as benzidine- based dyes, antiandrogenic fungicides, 2,3,7,8 tetrachlorodibenzo-p-dioxin (TCDD), and PCB congener 169, result in abnormal rodent sex differentiation. In rodents, perinatal exposure to fetal germ cell toxicants reduced the reproductive potential of female, and permanently reduced sperm production in male progeny. Phenotypic sex differentiation, however, was unaffected by these germ cell toxicants. In contrast, antiandrogenic drugs and fungicides induced profound alterations in phenotypic sex differentiation. Effects such as hypospadias, ectopic testes, vaginal pouches, agenesis of the ventral prostate, and nipple retention in male rats were observed commonly. Although these antiandrogens induced no permanent effects in female progeny, another class of chemicals, the Ah-receptor mediated toxicants, did reduce fertility in both male and female rat offspring. Other toxicants produced dramatic alterations of sex differentiation (uterus unicornis, agenesis of the vas and epididymis, and undescended testes), via mechanisms that have not been characterized yet. Since these adult/pubertal alterations resulted from gestational and/or neonatal exposures, future studies should include a comprehensive assessment of reproductive function after perinatal exposure because the developing animal is extremely sensitive to toxicants during sex differentiation, and many of the effects are difficult to detect until late in life.
[Gray, LE and Kelce, W. 1996. Toxicol Ind Health.12(3-4): 515-531]
- Developmental effects of endocrine-disrupting chemicals in wildlife and humans.
Large numbers and large quantities of endocrine-disrupting chemicals have been released into the environment since World War II. Many of these chemicals can disturb development of the endocrine system and of the organs that respond to endocrine signals in organisms indirectly exposed during prenatal and/or early postnatal life; effects of exposure during development are permanent and irreversible. The risk to the developing organism can also stem from direct exposure of the offspring after birth or hatching. In addition, transgenerational exposure can result from the exposure of the mother to a chemical at any time throughout her life before producing offspring due to persistence of endocrine-disrupting chemicals in body fat, which is mobilized during egg laying or pregnancy and lactation. Mechanisms underlying the disruption of the development of vital systems, such as the endocrine, reproductive, and immune systems, are discussed with reference to wildlife, laboratory animals, and humans.
[Colborn, T, vom Saal, FS, and Soto, AM. 1993. Environ Health Perspect. 101(5): 378–384]
- Prevalence of adverse reproductive outcomes in a population occupationally exposed to pesticides in Colombia
A prevalence survey of adverse reproductive outcomes was carried out in a population of 8867 persons (2951 men and 5916 women) who had been working in the floriculture industry in the Bogotá area of Colombia for at least six months. These workers were exposed to 127 different types of pesticides. The prevalence rates for abortion, prematurity, stillbirths, and malformations were estimated for pregnancies occurring among the female workers and the wives of the male workers before and after they started working in floriculture, and these rates were related to various degrees of exposure. A moderate increase in the prevalence of abortion, prematurity, and congenital malformations was detected for pregnancies occurring after the start of work in floriculture.
[Restrepo, M, Muñoz, N et al. 1990. Scandinavian Journal of Work, Environment & Health.16(4):232-238]