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.

• 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.]
• 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.]
  
• 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]
  
• 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]
• 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.]
• 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]
• 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]
• 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]
• 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]
• 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 Less than or equal to 0.05) . Mixtures simulating groundwater contaminants, insecticide formulation, and lawn-care herbicides reduced development to blastocyst and mean cell number per embryo (p Less than or equal to 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. Environ Health Perspect 112(6): 703-709]
• 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]
• 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]
• 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]
• 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]
• 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]
• 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 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]