Pesticide-Induced Diseases: Endocrine Disruption

Common household products –detergents, disinfectants, plastics, and pesticides– contain chemical ingredients that enter the body, disrupt hormones and cause adverse developmental, disease, and reproductive problems. Known as endocrine disruptors, these chemicals, which interact with the endocrine system, wreak havoc in humans and wildlife. The endocrine system consists of a set of glands (thyroid, gonads, adrenal and pituitary) and the hormones they produce (thyroxine, estrogen, testosterone and adrenaline), which help guide the development, growth, reproduction, and behavior of animals, including humans. Hormones are signaling molecules, which travel through the bloodstream and elicit responses in other parts of the body.

Download Beyond Pesticides' Endocrine Disruption brochure (bi-fold), or read Beyond Pesticides article, "Pesticides That Disrupt Endocrine System Still Unregulated by EPA."

Endocrine disruptors function by: (i) Mimicking the action of a naturally-produced hormone, such as estrogen or testosterone, thereby setting off similar chemical reactions in the body; (ii) Blocking hormone receptors in cells, thereby preventing the action of normal hormones; or (iii) Affecting the synthesis, transport, metabolism and excretion of hormones, thus altering the concentrations of natural hormones. Endocrine disruptors have been linked to attention deficit hyperactivity disorder (ADHD), Parkinson’s and Alzheimer’s diseases, diabetes, cardiovascular disease, obesity, early puberty, infertility and other reproductive disorders, and childhood and adult cancers.

More than 50 pesticide active ingredients have been identified as endocrine disruptors by the European Union and endocrine disruptor expert Theo Colborn, PhD. Endocrine disruption is the mechanism for several health effect endpoints. See the related sections (Cancer, Developmental and Learning Disorders, Parkinson’s disease, Reproductive Health) for more information.

  • Assessment of genetic effects and pesticide exposure of farmers in NW Greece
    The present study aims at evaluating potential genotoxic and cytotoxic effects caused by the occupational exposure of farmers to pesticide mixtures in the Aitoloakarnania Prefecture (Greece). The aforementioned assessment was conducted through in vivo Cytokinesis Block Micronucleus assay (CBMN assay) in peripheral blood lymphocytes, in relation to chemical analysis of pesticide residues in blood samples. The exposure of the farmers' population studied to different combinations of pesticides induced significant differences in the frequencies of micronuclei (MN) compared to those of the control group. Furthermore, our results indicated a possible clastogenic and aneugenic effect of pesticides on the genetic material of the farmers exposed. Five pesticides (trifluralin, chlorpyriphos methyl, metolachlor, fenthion and dimethoate) and three metabolites (fenthion sulfone, fenthion sulfoxide and 4,4′ DDE) were detected in the 62.5% of blood samples, with mean concentrations ranging from 0.4 ng/ml to 48 ng/ml. Since the farmers studied probably exhibit detectable levels of systematic exposure to the pesticides applied, continuous educational programs focused on the rational and safe use of pesticides, together with implementation of risk communication strategies among farmers are highly recommended.
    [Moshou, H., Karakitsou, A., Yfanti, F., Hela, D., Vlastos, D., Paschalidou, A.K., Kassomenos, P. and Petrou, I., 2020. Environmental Research, p.109558.]
  • Association of urinary metabolites of organophosphate and pyrethroid insecticides, and phenoxy herbicides with endometriosis
    Endometriosis is a hormone-responsive gynecologic disease, signifying its connotations across a woman’s life span. Previous studies suggested that endocrine disrupting chemicals were risk factors for endometriosis. Nevertheless, little is known on exposure to organophosphate, pyrethroid and phenoxy acid pesticides on endometriosis diagnosis. In this study, we determined the concentrations of 11 pesticides, metabolites of organophosphate and pyrethroid insecticides, and phenoxy herbicides, in urine collected from 619 reproductive-age women in Utah and California, using liquid chromatography-tandem mass spectrometry. The association of urinary concentrations of pesticides with an increase in the odds of endometriosis diagnosis was examined in 594 women who underwent laparoscopy/laparotomy (operative cohort: n = 471) or pelvic magnetic resonance imaging (population cohort: n = 123), during 2007–2009. 2-Isopropyl-4-methyl-6-hydroxypyrimidine (IMPY), malathion dicarboxylic acid (MDA), para-nitrophenol (PNP), 3,5,6-trichloro-2-pyridinol (TCPY), 3-phenoxybenzoic acid (3-PBA), and 2,4-dichlorophenoxyacetic acid (2,4-D) were detected in ≥95% of the urine samples analyzed. Urinary concentrations of IMPY, MDA, PNP, 3-PBA and 2,4-D tended to be higher in younger, non-Hispanic black, nulliparous and less affluent women. IMPY was the most dominant compound in urine followed by PNP and TCPY. When women in the 4th quartile of IMPY and the 2nd quartile of TCPY concentrations (μg/g creatinine) were compared with women in the 1st quartile, the odds ratios (ORs) for diagnosis of endometriosis increased significantly in unadjusted models (IMPY OR = 1.89, 95% confidence interval (Cl) = 1.12–3.20; TCPY OR = 1.65, 95% Cl = 1.02–2.69) for the operative (n = 471) and entire data set (n = 594), respectively. Our results suggest that exposure to elevated concentrations of diazinon (the parent compound of IMPY) and chlorpyrifos and chlorpyrifos-methyl (parent compounds of TCPY) may be associated with endometriosis.
    [Li, A.J., Chen, Z., Lin, T.C., Louis, G.M.B. and Kannan, K., 2020. Environment International, 136, p.105456.]
  • Effects of environmental pyrethroids exposure on semen quality in reproductive-age men in Shanghai, China
    Animal experiments have revealed that pyrethroids (PYRs) exposure could affect semen quality, however evidence on humans being is limited and controversial.To explore the potential effects of environmental PYRs exposure on semen quality in reproductive age men.We conducted a cross-sectional study of 346 men who planned to conceive and addressed to hospital for preconception examination. PYRs exposure was assessed by analyzing PYRs urinary metabolites [3-phenoxybenzoic acid (3PBA), trans- and cis-3-(2,2-Dichlorovinyl) −2,2-dimethylcy clopropane carboxylic acid (TDCCA and CDCCA)] levels using gas chromatography-mass spectrometry. Semen quality was assessed by a computer-aided semen analyzer.For a detection rate of 99.7%, 76.6%, and 22.0%, the median levels (μg/g creatinine) of PYRs metabolites were 0.46 for 3PBA, 0.38 for TDCCA and under detection limit for CDCCA. Linear regression models found negative associations between 3PBA and sperm morphology (β = −2.12, 95% CI: −4.02 to −0.22) as well as between TDCCA and log-transformed total sperm count (β = −0.09, 95% CI: −0.16 to −0.01). In logistic regression models, men with the highest quartile of 3PBA had higher risk of poor semen quality (having below-reference semen parameter, OR = 2.40, 95% CI: 1.26 to 4.54; having below-reference sperms morphology, OR = 3.08, 95% CI: 1.10 to 8.60) compared to men in the lowest quartile. Our study suggests that environmental PYRs exposure might adversely affect semen parameters of reproductive age men in Shanghai, China. Further studies are needed to confirm our findings and demonstrate a causal relationship between PYRs exposure and semen quality.
    [Hu, Y., Zhang, Y., Vinturache, A., Wang, Y., Shi, R., Chen, L., Qin, K., Tian, Y. and Gao, Y., 2020. Chemosphere, 245, p.125580.]
  • Incidence of male breast cancer in Scotland over a twenty-five-year period (1992–2017)
    Male breast cancer (MBC) accounts for around 1% of all breast cancers diagnosed. There are inconsistent reports on the incidence of MBC which some propose may be rising. Here, for the first time, the incidence of MBC in Scotland over 25 years from 1992 to 2017 was examined through interrogating the Information Services Division Scotland database. Results showed MBC incidence rose with age, peaking in the 65–70 and 75–79 age groups. Both the total number and the age-adjusted incidence of MBC increased in Scotland since 1992. This rising trend was most clear in the North of Scotland. Interestingly a higher MBC incidence in some rural areas was also observed. Our findings emphasise the need for a better understanding of MBC risk factors so that improved prevention policies can be applied for patient benefit.
    [Reddington, R., Galer, M., Hagedorn, A., Liu, P., Barrack, S., Husain, E., Sharma, R., Speirs, V. and Masannat, Y., 2020. European Journal of Surgical Oncology.]
  • Longitudinal association of biomarkers of pesticide exposure with cardiovascular disease risk factors in youth with diabetes
    Cardiovascular disease (CVD) is the leading cause of death among individuals with diabetes, but little is known about the role of exposures to environmental chemicals such as pesticides in the early development of CVD risk in this population. To describe changes over time in concentrations of pesticide biomarkers among youth with diabetes in the United States and to estimate the longitudinal association between these concentrations and established risk factors for CVD. Pesticide biomarkers were quantified in urine and serum samples from 87 youth with diabetes participating in the multi-center SEARCH cohort study. Samples were obtained around the time of diagnosis (baseline visit, between 2006 and 2010) and, on average, 5.4 years later (follow-up visit, between 2012 and 2015). We calculated geometric mean (95% CI) pesticide biomarker concentrations. Eight CVD risk factors were measured at these two time points: body mass index (BMI) z-score, HbA1c, insulin sensitivity, fasting C-peptide (FCP), LDL cholesterol, HDL cholesterol, total cholesterol, and triglycerides. Linear regression models were used to estimate the associations between each pesticide biomarker at baseline and each CVD risk factor at follow-up, adjusting for baseline health outcome, elapsed time between baseline and follow up, sex, age, race/ethnicity, and diabetes type. Participants were, on average, 14.2 years old at their baseline visit, and most were diagnosed with type 1 diabetes (57.5%). 4-nitrophenol, 3-phenoxybenzoic acid, 2,4-dichlorophenoxyacetic acid (2,4-D), 3,5,6-trichloro-2-pyridinol, 2,2-bis(4-chlorophenyl)-1,1-dichloroethene, and hexachlorobenzene were detected in a majority of participants at both time points. Participants in the highest quartile of 2,4-D and 4-nitrophenol at baseline had HbA1c levels at follow-up that were 1.05 percentage points (95% CI: −0.40, 2.51) and 1.27 percentage points (0.22, 2.75) higher, respectively, than participants in the lowest quartile of these pesticide biomarkers at baseline. These participants also had lower log FCP levels (indicating reduced beta-cell function) compared to participants in the lowest quartile at baseline: beta (95% CI) for log FCP of −0.64 (−1.17, −0.11) for 2,4-D and −0.39 (−0.96, 0.18) for 4-nitrophenol. In other words, participants in the highest quartile of 2,4-D had a 47.3% lower FCP level compared to participants in the lowest quartile, and those in the highest quartile of 4-nitrophenol had a 32.3% lower FCP level than those in the lowest quartile. Participants with trans-nonachlor concentrations in the highest quartile at baseline had HbA1c levels that were 1.45 percentage points (−0.11, 3.01) higher and log FCP levels that were −0.28 (−0.84, 0.28) lower than participants in the lowest quartile at baseline, that is to say, participants in the highest quartile of trans-nonachlor had a 24.4% lower FCP level than those in the lowest quartile. While not all of these results were statistically significant, potentially due to the small same size, clinically, there appears to be quantitative differences. No associations were observed between any pesticide biomarker at baseline with BMI z-score or insulin sensitivity at follow-up.Exposure to select pesticides may be associated with impaired beta-cell function and poorer glycemic control among youth with diabetes.
    [Kaur, N., Starling, A.P., Calafat, A.M., Sjodin, A., Clouet-Foraison, N., Dolan, L.M., Imperatore, G., Jensen, E.T., Lawrence, J.M., Ospina, M. and Pihoker, C., 2020. Environmental Research, 181, p.108916.]
  • Neonicotinoid insecticides exposure cause amino acid metabolism disorders, lipid accumulation and oxidative stress in ICR mice
    Neonicotinoids are increasingly being used for pest control, and their potential health risks are now receiving attention. In this study, the toxic effects of three neonicotinoids (dinotefuran, nitenpyram and acetamiprid) were evaluated in ICR mice. After 30 days of exposure to neonicotinoids (1/200 LD50), oxidative stress levels, biochemical parameters, free fatty acids contents, and 1H NMR-based hepatic metabolomics were tested. All treatment groups showed signs of amino acid metabolism disorders especially elevated branched chain amino acids and phenylalanine. Furthermore, animals exposed to neonicotinoids had elevated lipid levels, which induced oxidative stress. Overall, we found that oxidative stress is a common toxic effect of exposure to neonicotinoids. In addition, lipid accumulation induced by amino acid metabolism disorder may be the cause of oxidative stress. Our results further our understanding of the toxicological effects of neonicotinoids on mammals.
    [Yan, S., Meng, Z., Tian, S., Teng, M., Yan, J., Jia, M., Li, R., Zhou, Z. and Zhu, W., 2020. Chemosphere, 246, p.125661.]
  • Neuropathological Mechanisms Associated with Pesticides in Alzheimer’s Disease
    Environmental toxicants have been implicated in neurodegenerative diseases, and pesticide exposure is a suspected environmental risk factor for Alzheimer’s disease (AD). Several epidemiological analyses have affirmed a link between pesticides and incidence of sporadic AD. Meanwhile, in vitro and animal models of AD have shed light on potential neuropathological mechanisms. In this paper, a perspective on neuropathological mechanisms underlying pesticides’ induction of AD is provided. Proposed mechanisms range from generic oxidative stress induction in neurons to more AD-specific processes involving amyloid-beta (Aβ) and hyperphosphorylated tau (p-tau). Mechanisms that are more speculative or indirect in nature, including somatic mutation, epigenetic modulation, impairment of adult neurogenesis, and microbiota dysbiosis, are also discussed. Chronic toxicity mechanisms of environmental pesticide exposure crosstalks in complex ways and could potentially be mutually enhancing, thus making the deciphering of simplistic causal relationships difficult.
    [Tang, B.L., 2020. Toxics, 8(2), p.21.]
  • Neurotransmission dysfunction by mixture of pesticides and preventive effects of quercetin on brain, hippocampus and striatum in rats
    Epidemiological and toxicological studies in pesticide mixtures show that most neurodegenerative diseases are associated with chronic exposure to pesticides.In this study, we were interested in the evaluation of the neurotoxicity of two pesticides: deltamethrin, a pyrethroid, at a dose of 0.32 mg/kg/day; and acetamiprid, a neonicotinoid, at a dose of 3.14 mg/kg/day, administered chronically orally for 90 days on an animal model, the Wistar rats, as well as the evaluation of the preventive effect of quercetin against this toxicity. The fundamental principle of this experiment is the evaluation of total and regional cerebral neurotransmission (hippocampus and striatum) in control rats and pesticide-treated rats.The analysis of the results of this study shows a very clear perturbation of neurotransmitter levels either regionally or totally in rats exposed to pesticides. On the other hand, the use of quercetin at a dose of 10 mg/kg/day modifies and improves the harmful effects of treatment with both insecticides (AC and DM). These results demonstrated that quercetin corrects the neurotoxicity caused by the mixture of deltamethrin and acetamiprid.
    [Gasmi, S., 2020. Toxicology and Environmental Health Sciences, pp.1-10.]
  • Organochlorine pesticide levels in Greek patients with Parkinson’s Disease
    Parkinson’s disease (PD) is a neurodegenerative disease, mostly presenting with characteristic motor symptoms. Organochlorines (OC) are a class of widely-used pesticides that have been included among the list of environmental factors incriminated in PD pathogenesis. However, most studies reporting this association are based on questionnaires, and few have reported exposure data. To examine the relationship between OC blood concentrations and PD risk. In the present study, we studied the concentrations of 8 OC compounds (hexachlorobenzene, heptachlor, hepachlor epoxide, c-chlordane, a-chlordane, p,p’-DDE, DDD, DDT) in 104 Greek PD patients and 110 healthy controls. All substances studied were present in at least one sample. The most frequently detected (above the level of quantification) pesticides were p,p’-DDE (n = 214, 100% of both groups) and hexachlorobenzene, HCB (n = 189, cases 46.5%, controls 53.5%). Higher levels of DDE were detected among PD patients in comparison to controls by using logistic regression analysis to control for confounders [Odds Ratio, OR (95% confidence interval, C.I.)]: 2.592,(1.29-5.21)], whilst lower levels of HCB were detect among PD patients [OR,95%CI:0.176(0.09-0.35)]. Our data suggest that exposure to specific OCs is related to the risk of PD. Further studies, using real exposure data, are needed in order to confirm and extend these findings.
    [Dardiotis, E., Aloizou, A.M., Sakalakis, E., Siokas, V., Koureas, M., Xiromerisiou, G., Petinaki, E., Wilks, M., Tsatsakis, A., Hadjichristodoulou, C. and Stefanis, L., 2020. Toxicology Reports.]
  • Persistent organic pollutant exposure and celiac disease: A pilot study
    Celiac disease affects approximately 1% of the population worldwide. Little is known about environmental factors that may modulate risk in genetically susceptible populations. Persistent organic pollutants (POPs) are known endocrine disruptors and, given the interplay between the endocrine and immune systems, are plausible contributors to celiac disease. The current study aims to elucidate the association between POPs and celiac disease. We conducted a single-site pilot study of 88 patients recruited from NYU Langone's Hassenfeld Children's Hospital outpatient clinic, 30 of which were subsequently diagnosed with celiac disease using standard serology and duodenal biopsy examination. Polybrominated diphenyl ether (PBDEs), perfluoroalkyl substances (PFASs), and p,p’-dichlorodiphenyldichloroethylene (DDE) and HLA-DQ genotype category were measured in blood serum and whole blood, respectively. Multivariable logistic regressions were used to obtain odds ratios for celiac disease associated with serum POP concentrations. Controlling for sex, race, age, BMI, and genetic susceptibility score, patients with higher serum DDE concentrations had 2-fold higher odds of celiac disease (95% CI: 1.08, 3.84). After stratifying by sex, we found higher odds of celiac disease in females with serum concentrations of DDE (OR = 13.0, 95% CI = 1.54, 110), PFOS (OR = 12.8, 95% CI = 1.17, 141), perfluorooctanoic acid (OR = 20.6, 95% CI = 1.13, 375) and in males with serum BDE153, a PBDE congener (OR = 2.28, 95% CI = 1.01, 5.18). This is the first study to report on celiac disease with POP exposure in children. These findings raise further questions of how environmental chemicals may affect autoimmunity in genetically susceptible individuals.
    [Gaylord, A., Trasande, L., Kannan, K., Thomas, K.M., Lee, S., Liu, M. and Levine, J., 2020. Environmental Research, p.109439.]
  • Spatial distribution patterns and human exposure risks of polycyclic aromatic hydrocarbons, organochlorine pesticides and polychlorinated biphenyls in Nepal using tree bark as a passive air sampler
    Nepal is abutted between the populated Indo-Gangetic Plain (IGP) and Himalayan mountains. Currently, knowledge on the country-wide distribution and cancer risks of atmospheric organic toxicants in Nepal remains limited. In this study, the concentrations, sources, and distributions of polycyclic aromatic hydrocarbons (PAHs), organochlorine pesticides (OCPs), and polychlorinated biphenyls (PCBs), along with their cancer risks, were investigated in Nepal by using tree bark as a passive air sampler. After transferring by a bark/air partitioning model, the averaged concentrations of ∑PAHs, ∑DDTs, ∑HCHs, HCB, ∑Endo and ∑PCBs in the atmosphere of Nepal were 3.71 × 104 pg/m3, 1.10 × 103 pg/m3, 2.92 × 102 pg/m3, 4.38 × 102 pg/m3, 4.66 pg/m3 and 65.8 pg/m3, respectively. Source diagnosis suggested that biomass burning is the major source for PAHs, while local application and long-range transport jointly contribute to the high levels of DDT and HCH in the air. The ILCR (incremental lifetime cancer risk) value was used to assess the risks of various chemicals. Adults have a higher risk than other age groups; the major exposure pathway for risk is by inhalation; and PAHs and HCHs are the dominant chemical classes that lead to risk. It was also found that, in certain hotspots in south Nepal, the carcinogenic risks caused by DDT and HCH were particularly high (>1 × 10−4). Given that illegal and disordered use of legacy POPs in south Nepal and the IGP region is common, our results highlight an urgent need for voluntary regulation of the ongoing use of pesticides.
    [Wang, X., Gong, P., Wang, C., Wang, X., Pokhrel, B. and Dotel, J., 2020. Environmental Research, p.109510.]
  • Association Between Exposure to Pyrethroid Insecticides and Risk of All-Cause and Cause-Specific Mortality in the General US Adult Population
    Widespread exposure to pyrethroid insecticides has been reported among the general population in the United States and worldwide. However, little is known about the association of pyrethroid. To examine the association of pyrethroid exposure with all-cause and cause-specific mortality among adults in the United States.The nationally representative cohort included 2116 adults aged 20 years and older who participated in the US National Health and Nutrition Examination Survey conducted from 1999 to 2002 and provided urine samples for pyrethroid metabolite measurements. Participants were linked to mortality data from the survey date through December 31, 2015. Data were analyzed from May to August 2019. Urinary levels of 3-phenoxybenzoic acid, a general pyrethroid metabolite and commonly used biomarker for pyrethroid exposure, were determined by using high-performance liquid chromatography coupled with electrospray chemical ionization and tandem mass spectrometry. Mortality from all causes, cardiovascular disease, and cancer. This cohort study of 2116 adults comprised 1145 women (weighted proportion, 51.6%) and 971 men (weighted, 48.4%), with a weighted mean (SE) age of 42.6 (0.5) years; 958 participants (weighted, 68.4%) were of non-Hispanic white ancestry, 646 (weighted, 14.7%) of Hispanic ancestry, 419 (weighted, 11.3%) of non-Hispanic black ancestry, and 93 (weighted, 5.6%) of other ancestry. During a median of 14.4 years (range, 0.1-16.8 years) of observation, 246 deaths occurred, including 41 associated with cardiovascular disease and 52 associated with cancer. Participants with higher urinary 3-phenoxybenzoic acid levels were at a higher risk of death during the follow-up period, with death occurring in 8.5% (unweighted, 75 of 709), 10.2% (unweighted, 81 of 701), and 11.9% (unweighted, 90 of 706) of participants across increasing tertiles of urinary 3-phenoxybenzoic acid levels. After adjustment for age, sex, race/ethnicity, socioeconomic status, dietary and lifestyle factors, body mass index, and urinary creatinine levels, the hazard ratios for all-cause mortality, cardiovascular disease mortality, and cancer mortality among participants with the highest tertile compared with those with the lowest tertile of urinary 3-phenoxybenzoic acid levels were 1.56 (95% CI, 1.08-2.26), 3.00 (95% CI, 1.02-8.80), and 0.91 (95% CI, 0.31-2.72), respectively. In this nationally representative sample of US adults, environmental exposure to pyrethroid insecticides was associated with an increased risk of all-cause and cardiovascular disease mortality. Further studies are needed to replicate the findings and determine the underlying mechanisms.
    [Bao, W., Liu, B., Simonsen, D.W. and Lehmler, H.J., 2019. JAMA Internal Medicine. 180(3):367-374.]
  • Association Between Urinary Triclosan With Bone Mass Density and Osteoporosis in US Adult Women, 2005‒2010
    Laboratory studies have demonstrated that triclosan (TCS) can cause significant interstitial collagen accumulation and an increase in trabecular bone. However, little is known about the relationship between TCS exposure and human bone health. We used 2005 to 2010 National Health and Nutrition Examination Survey data to examine the association between urinary TCS concentration and bone mineral density (BMD) and osteoporosis in US adult women aged ≥20 years. After inclusion and exclusion, 1848 women were analyzed. After adjustment for other covariates, we observed significant associations between tertile 3 of TCS concentration and lower BMD in regions of the total femur (β = −0.016; 95% CI = −0.032, −0.000), intertrochanteric region (β = −0.022; 95% CI = −0.042, −0.002), and lumbar spine (β = −0.014; 95% CI = −0.029, 0.001), respectively, relative to tertile 1. Compared with women at tertile 1, those at tertile 3 were more likely to have increased prevalence of osteoporosis in the intertrochanteric region (OR = 2.464; 95% CI = 1.190, 5.105). This epidemiological study investigated the association between urinary TCS concentration and BMD and osteoporosis in US adult women. We found urinary TCS concentration was negatively associated with BMD and was positively associated with the prevalence of osteoporosis. The evidence was stronger in postmenopausal women than in premenopausal women. Future prospective studies are needed to validate these findings.
    [Cai, S., Zhu, J., Sun, L., Fan, C., Zhong, Y., Shen, Q. and Li, Y., 2019. The Journal of Clinical Endocrinology & Metabolism, 104(10), pp.4531-4538.]
  • DDT and Breast Cancer: Prospective Study of Induction Time and Susceptibility Windows
    In a previous Child Health and Development Studies report, p, p’-DDT was associated with a fivefold increased risk of premenopausal (before age 50 years) breast cancer for women first exposed before puberty. Here we extend our observation to breast cancer diagnosed during early postmenopause (ages 50–54 years) to determine whether age at diagnosis modifies the interaction of DDT with age at exposure. We conducted a second prospective, nested case-control study in the Child Health and Development Studies (153 incident breast cancer cases diagnosed at ages 50–54 years and 432 controls matched to cases on birth year). These were analyzed separately and pooled with our previous study (129 breast cancer cases diagnosed at ages 31–49 years and 129 controls matched on birth year). Blood samples were obtained during pregnancy (median age, 26 years), 1–3 days after delivery from 1959 to 1967 in Oakland, California. Serum was assayed for p, p’-DDT, o, p’-DDT, and p, p’-DDE. Odds ratios (ORs) below are given for doubling of serum p, p’-DDT. All statistical tests were two-sided. For early postmenopausal breast cancer, p, p’-DDT was associated with risk for all women (ORDDT 50–54 = 1.99, 95% CI = 1.48 to 2.67). This association was accounted for by women first exposed to DDT after infancy (ORDDT 50–54 for first exposure after infancy = 2.83, 95% CI = 1.96 to 4.10 vs ORDDT 50–54 for first exposure during infancy = 0.56, 95% CI = 0.26 to 1.19; Pinteraction DDT x age at first exposure = .01). In contrast, for premenopausal breast cancer, p, p’-DDT was associated with risk among women first exposed during infancy through puberty, but not after (ORDDT = 3.70, 95% CI = 1.22 to 11.26, Pinteraction DDT x age at first exposure x age at diagnosis = .03). p, p’-DDT was associated with breast cancer through age 54 years. Risk depended on timing of first exposure and diagnosis age, suggesting susceptibility windows and an induction period beginning in early life. DDT appears to be an endocrine disruptor with responsive breast targets from in utero to menopause.
    [Cohn, B.A., Cirillo, P.M. and Terry, M.B., 2019. 111(8), pp.803-810.]
  • One size does not fit all: Caste and sex differences in the response of bumblebees (Bombus impatiens) to chronic oral neonicotinoid exposure
    Neonicotinoid insecticides have been implicated in the rapid global decline of bumblebees over recent years, particularly in agricultural and urban areas. While there is much known about neonicotinoid toxicity effects at the colony stage of the bumblebee annual cycle, far less is known about such effects at other stages critical for the maintenance of wild populations. In the present work, individual-based feeding assays were used to show that chronic consumption of the widely used neonicotinoid clothianidin at a field-realistic average rate of 3.6 and 4.0 ng/g·bee/day reduces survival of queen and male bumblebees, respectively, within a 7-day period. In contrast, worker survival was unaffected at a similar consumption rate of 3.9 ng/g·bee/day. To test the hypothesis that males have a lower tolerance for oral clothianidin exposure than workers due to their haploid genetic status, RNAseq analysis was used to compare the transcriptomic responses of workers and males to chronic intake of clothianidin at a sub-lethal dose of 0.37ng/bee/day for 5 days. Surprisingly, clothianidin consumption only altered the expression of 19 putative detoxification genes in a sex-specific manner, with 11/19 genes showing increased expression in workers. Sub-lethal clothianidin exposure also altered the expression of 40 genes associated with other major biological functions, including locomotion, reproduction, and immunity. Collectively, these results suggest that chronic oral toxicity effects of neonicotinoids are greatest during mating and nest establishment phases of the bumblebee life cycle. Chronic oral toxicity testing on males and queens is therefore required in order to fully assess the impact of neonicotinoids on wild bumblebee populations.
    [Mobley, M.W. and Gegear, R.J., 2018. PloS one, 13(10).]
  • Chronic exposure to the fungicide propiconazole: Behavioral and reproductive evaluation of F1 and F2 generations of male rats.
    Several studies have suggested that propiconazole (PROP) may be an endocrine disruptor; possibly altering the activity of the CYP51 enzyme, which is part of the cholesterol biosynthesis pathway required for the production of sexual steroid hormones. Another PROP effect is inhibition of the aromatase enzyme that converts androgens into estrogens, which could lead to negative effects on reproductive parameters. Therefore, the present study evaluated the reproductive and developmental toxicity of PROP by exposing two generations (F1 and F2) of male rats to this fungicide, since a previous study from our lab reported that PROP has anti-estrogenic and anti-androgenic activities (Costa et al., 2015) in the male parental (P) generation. The F1 males were exposed to PROP (4 or 20mg/kg) through germ cells (via the P generation), intra uterus, and lactation, following treatment by gavage from post-natal day (PND) 21 to 120, while the F2 generation was exposed through germ cells, intra uterus, and lactation. The parameters observed in both F1 and F2 generations were: body weight, anogenital distance (PND 0 and 21), ontogenic reflex, testosterone plasmatic levels, testis weight, and testicular histomorphology (PND 21); and in the F1 generation only: preputial separation (PND 40), sexual behavior, organ weights, testosterone and estradiol plasmatic levels (PND 120), sperm count and morphology, and testicular histomorphology at adulthood. In the F1 and F2 generations, PROP (4mg/kg) presented a decrease in testosterone levels, and in the F1 decreases in the vas deferens weight, without hormonal and functional changes of the reproductive organs, either at 4mg/kg or at 20mg/kg, in adulthood. Based on the results of this work, PROP did not alter the gonadal-endocrine parameters under these exposure conditions in rats.
    [Vieira ML, Costa NO, Pereira MRF, et al. 2017. Toxicology. 389:85-93.]
  • Computational study involving identification of endocrine disrupting potential of herbicides: Its implication in TDS and cancer progression in CRPC patients.
    Several environmental pollutants, including herbicides, act as endocrine disrupting chemicals (EDCs). They can cause cancer, diabetes, obesity, metabolic diseases and developmental problems. Present study was conducted to screen 608 herbicides for evaluating their endocrine disrupting potential. The screening was carried out with the help of endocrine disruptome docking program, http://endocrinedisruptome.ki.si (Kolsek et al., 2013). This program screens the binding affinity of test ligands to 12 major nuclear receptors. As high as 252 compounds were capable of binding to at least three receptors wherein 10 of them showed affinity with at-least six receptors based on this approach. The latter were ranked as potent EDCs. Majority of the screened herbicides were acting as antagonists of human androgen receptor (hAR). A homology modeling approach was used to construct the three dimensional structure of hAR to understand their binding mechanism. Docking results reveal that the most potent antiandrogenic herbicides would bind to hydrophobic cavity of modeled hAR and may lead to testicular dysgenesis syndrome (TDS) on fetal exposure. However, on binding to T877 mutant AR they seem to act as agonists in castration-resistant prostate cancer (CRPC) patients.
    [Ahmad MI, Usman A, Ahmad M. 2017. Chemosphere. 173:395-403.]
  • Disruption of aromatase homeostasis as the cause of a multiplicity of ailments: A comprehensive review.
    Human health is beset with a legion of ailments, which is exacerbated by lifestyle errors. Out of the numerous enzymes in human body, aromatase, a cytochrome P450 enzyme is particularly very critical. Occurring at the crossroads of multiple signalling pathways, its homeostasis is vital for optimal health. Unfortunately, medications, hormone therapy, chemical additives in food, and endocrine-disrupting personal care products are oscillating the aromatase concentration beyond the permissible level. As this enzyme converts androgens (C19) into estrogens (C18), its agitation has different outcomes in different genders and age groups. Some common pathologies associated with aromatase disruption include breast cancer, prostate cancer, polycystic ovary syndrome (PCOS), endometriosis, osteoporosis, ovarian cancer, gastric cancer, pituitary cancer, Alzheimer's disease, schizophrenia, male hypogonadism, and transgender issues. Several drugs, cosmetics and pesticides act as the activators and suppressors of this enzyme. This carefully-compiled critical review is expected to increase public awareness regarding the threats resultant of the perturbations of this enzyme and to motivate researchers for further investigation of this field.
    [Patel S. 2017. J Steroid Biochem Mol Biol.168:19-25]
  • Effect of exposure to p,p´-DDE during the first half of pregnancy in the maternal thyroid profile of female residents in a Mexican floriculture area.
    Dichlorodiphenyldichloroethene (p,p´-DDE), the main metabolite of dichlorodiphenyltrichloroethane (DDT), has been associated with changes in human thyroid hormone levels. Maternal thyroid hormones are essential for adequate fetal neurodevelopment during the first half of pregnancy. To evaluate the association between maternal p,p´-DDE concentration and the maternal thyroid profile during the first half of pregnancy we analyzed the information of 430 pregnant women from a Mexican floriculture area, with a gestational age ≤16 weeks. The association between p,p´-DDE and thyroid profile was assessed through linear and logistic regression models. Thirty eight percent of women had p,p´-DDE levels below the Limit of Detection and 12.3% below the Limit of Quantification. Within the quantifiable range, median was 53.03ng/g. TSH >2.5 mIU/L was present in 9.3% of women; 47.7% had isolated hypothyroxinemia; 3.5% had subclinical hypothyroidism, and 5.8% had overt hypothyroidism. We observed a significant positive association between quantifiable p,p´-DDE and total T3 serum levels in comparison with those with concentrations below the Limit of Detection (β=0.19; 95% CI=0.06, 0.34). There were no significant associations with other hormones of the thyroid profile or with clinical diagnosis.Our findings suggest that p,p´-DDE exposure, even at low concentrations, could disrupt thyroid homeostasis during pregnancy.
    [Hernández-Mariano JÁ, Torres-Sánchez L, Bassol-Mayagoitia S, et al. 2017. Environ Res. 156:597-604.]
  • Effects of Endocrine-Disrupting Chemicals and Epigenetic Modifications in Ovarian Cancer: A Review.
    Ovarian cancer (OC) is a relatively fatal female reproductive malignancy. Since the underlying causes are uncertain, it brings us to believe that both genetic and external factors contribute toward development of this lethal disorder. Exposure to endocrine-disrupting chemicals (EDCs) in the form of occupational usage of pesticides, fungicides, herbicides, plasticizers, cosmetics, and so on is potentially carcinogenic and their ability to cause epigenetic modifications has led us to hypothesize that they may play a catalytic role in OC progression. In response to synthetic chemicals, animal models have demonstrated disturbances in the development of ovaries and steroid hormonal levels but in humans, more research is required. The present review is an attempt to address the impact of EDCs on the hormonal system and gene methylation levels that may lead to malfunctioning of the ovaries which may consequently develop in the form of cancer. It can be concluded that endocrine disruptors do have a potential carcinogenicity and their high proportions in human body may cause epigenetic modifications, prompting ovarian surface epithelium to grow in an abnormal manner.
    [Samtani R, Sharma N, Garg D. 2017. Reprod Sci. 1933719117711261.]
  • Endocrine Disruptor Compounds (EDCs) and agriculture: The case of pesticides.
    A number of pesticides are suspected or proved to act as endocrine disruptor compounds (EDCs). In the present survey of the literature, we try to define the main issues to be considered to classify individual pesticides as EDC or not.
    [Combarnous Y]
  • Endocrine Disruptors and Obesity
    The purpose of this review was to summarise current evidence that some environmental chemicals may be able to interfere in the endocrine regulation of energy metabolism and adipose tissue structure.Recent findings demonstrate that such endocrine-disrupting chemicals, termed "obesogens", can promote adipogenesis and cause weight gain. This includes compounds to which the human population is exposed in daily life through their use in pesticides/herbicides, industrial and household products, plastics, detergents, flame retardants and as ingredients in personal care products. Animal models and epidemiological studies have shown that an especially sensitive time for exposure is in utero or the neonatal period. In summarising the actions of obesogens, it is noteworthy that as their structures are mainly lipophilic, their ability to increase fat deposition has the added consequence of increasing the capacity for their own retention. This has the potential for a vicious spiral not only of increasing obesity but also increasing the retention of other lipophilic pollutant chemicals with an even broader range of adverse actions. This might offer an explanation as to why obesity is an underlying risk factor for so many diseases including cancer.
    [Darbre PD. 2017. Curr Obes Rep. 6(1):18-27]
  • Environmental endocrine disruptors: New diabetogens?
    The prevalence of type-2 diabetes has dramatically increased worldwide during the last few decades. While lifestyle factors (sedentariness, noxious food), together with genetic susceptibility, are well-known actors, there is accumulating evidence suggesting that endocrine disrupting chemicals (EDCs) may also play a pathophysiological role in the occurrence of metabolic diseases. Both experimental and epidemiological evidence support a role for early and chronic exposure to low doses of chemical pollutants with endocrine and metabolic disrupting effects. Most are present in the food chain and accumulate in the fat mass after absorption. In rodents, bisphenol A stimulates synthesis and secretion of pancreatic β cells and disturbs insulin signaling in liver, muscle and adipose tissue through epigenetic changes leading to insulin resistance and β cell impairment. In humans, epidemiological reports show statistical link between exposure to pesticides, polychlorinated bisphenyls, bisphenol A, phthalates, dioxins or aromatic polycyclic hydrocarbides or heavy metals and DT2 after acute accidental releases or early in life and/or chronic, low doses exposure. More prospective, longitudinal studies are needed to determine the importance of such environmental risk factors.
    [Fénichel P, Chevalier N. 2017. C R Biol. pii: S1631-0691(17)30124-5]
  • Environmental pollutants, a possible etiology for premature ovarian insufficiency: a narrative review of animal and human data.
    Because only 25% of cases of premature ovarian insufficiency (POI) have a known etiology, the aim of this review was to summarize the associations and mechanisms of the impact of the environment on this pathology. Eligible studies were selected from an electronic literature search from the PUBMED database from January 2000 to February 2016 and associated references in published studies. The literature search was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Data have been grouped according to the studied pollutants in order to synthetize their impact on follicular development and follicular atresia and the molecular pathways involved. Ninety-seven studies appeared to be eligible and were included in the present study, even though few directly address POI. Phthalates, bisphenol A, pesticides and tobacco were the most reported substances having a negative impact on ovarian function with an increased follicular depletion leading to an earlier age of menopause onset. These effects were found when exposure occured at different times throughout the lifetime from the prenatal to the adult period, possibly due to different mechanisms. The main mechanism seemed to be an increase in atresia of pre-antral follicles. Environmental pollutants are probably a cause of POI. Health officials and the general public must be aware of this environmental effect in order to implement individual and global preventive actions.
    [Vabre P, Gatimel N, Moreau J, Gayrard V, et al. 2017. Environ Health. 16(1):37.]
  • Evaluation of estrogen receptor alpha activation by glyphosate-based herbicide constituents.
    The safety, including the endocrine disruptive capability, of glyphosate-based herbicides (GBHs) is a matter of intense debate. Authors evaluated the estrogenic potential of glyphosate, commercial GBHs and polyethoxylated tallowamine adjuvants present as co-formulants in GBHs. Glyphosate (≥10,000 μg/L or 59 μM) promoted proliferation of estrogen-dependent MCF-7 human breast cancer cells. Glyphosate also increased the expression of an estrogen response element-luciferase reporter gene (ERE-luc) in T47D-KBluc cells, which was blocked by the estrogen antagonist ICI 182,780. Commercial GBH formulations or their adjuvants alone did not exhibit estrogenic effects in either assay. Transcriptomics analysis of MCF-7 cells treated with glyphosate revealed changes in gene expression reflective of hormone-induced cell proliferation but did not overlap with an ERα gene expression biomarker. Calculation of glyphosate binding energy to ERα predicts a weak and unstable interaction (-4.10 kcal mol-1) compared to estradiol (-25.79 kcal mol-1), which suggests that activation of this receptor by glyphosate is via a ligand-independent mechanism. Induction of ERE-luc expression by the PKA signalling activator IBMX shows that ERE-luc is responsive to ligand-independent activation, suggesting a possible mechanism of glyphosate-mediated activation. Study reveals that glyphosate, but not other components present in GBHs, can activate ERα in vitro, albeit at relatively high concentrations.
    [Mesnage R, Phedonos A, Biserni M, et al. 2017. Food Chem Toxicol. 108(Pt A):30-42.]
  • Exposure to endocrine disruptors during adulthood: consequences for female fertility.
    Endocrine disrupting chemicals are ubiquitous chemicals that exhibit endocrine disrupting properties in both humans and animals. Female reproduction is an important process, which is regulated by hormones and is susceptible to the effects of exposure to endocrine disrupting chemicals. Disruptions in female reproductive functions by endocrine disrupting chemicals may result in subfertility, infertility, improper hormone production, estrous and menstrual cycle abnormalities, anovulation, and early reproductive senescence. This review summarizes the effects of a variety of synthetic endocrine disrupting chemicals during adult life. The chemicals covered in this review are pesticides (organochlorines, organophosphates, carbamates, pyrethroids, and triazines), heavy metals (arsenic, lead, and mercury), diethylstilbesterol, plasticizer alternatives (di-(2-ethylhexyl) phthalate and bisphenol A alternatives), 2,3,7,8-tetrachlorodibenzo-p-dioxin, nonylphenol, polychlorinated biphenyls, triclosan, and parabens. This review focuses on the hypothalamus, pituitary, ovary, and uterus because together they regulate normal female fertility and the onset of reproductive senescence. The literature shows that several endocrine disrupting chemicals have endocrine disrupting abilities in females during adult life, causing fertility abnormalities in both humans and animals.
    [Rattan S, Zhou C, Chiang C, Mahalingam S, Brehm E, Flaws J. J Endocrinol. pii: JOE-17-0023. ]
  • Human exposure to endocrine disrupting chemicals: effects on the male and female reproductive systems.
    Endocrine disrupting chemicals (EDCs) comprise a group of chemical compounds that have been examined extensively due to the potential harmful effects in the health of human populations. During the past decades, particular focus has been given to the harmful effects of EDCs to the reproductive system. The estimation of human exposure to EDCs can be broadly categorized into occupational and environmental exposure, and has been a major challenge due to the structural diversity of the chemicals that are derived by many different sources at doses below the limit of detection used by conventional methodologies. Animal and in vitro studies have supported the conclusion that endocrine disrupting chemicals affect the hormone dependent pathways responsible for male and female gonadal development, either through direct interaction with hormone receptors or via epigenetic and cell-cycle regulatory modes of action. In human populations, the majority of the studies point towards an association between exposure to EDCs and male and/or female reproduction system disorders, such as infertility, endometriosis, breast cancer, testicular cancer, poor sperm quality and/or function. Despite promising discoveries, a causal relationship between the reproductive disorders and exposure to specific toxicants is yet to be established, due to the complexity of the clinical protocols used, the degree of occupational or environmental exposure, the determination of the variables measured and the sample size of the subjects examined. Future studies should focus on a uniform system of examining human populations with regard to the exposure to specific EDCs and the direct effect on the reproductive system.
    [Sifakis S, Androutsopoulos VP, Tsatsakis AM, Spandidos DA. 2017. Environ Toxicol Pharmacol. 51:56-70.]
  • Investigation of Associations Between Exposures to Pesticides and Testosterone Levels in Thai Farmers
    We conducted a cross-sectional study to assess the relationship between pesticide exposures and testosterone levels in 133 male Thai farmers. Urine and serum samples were collected concurrently from participants. Urine was analyzed for levels of specific- and non-specific metabolites of organophosphates (OPs), pyrethroids, select herbicides, and fungicides. Serum was analyzed for total and free testosterone. Linear regression analyses revealed significant negative relationships between total testosterone and the herbicide 2,4-dichlorophenoxyacetic acid (2,4-D) after controlling for covariates (e.g., age, BMI, smoking status). Positive significant associations were found between some OP pesticides and total testosterone. Due to the small sample size and the observational nature of the study, future investigation is needed to confirm our results and to elucidate the biological mechanisms.
    [Panuwet P, Ladva C, Barr DB, Prapamontol T, et al. 2017. Arch Environ Occup Health. doi: 10.1080/19338244.2017.1378606]
  • Low doses of chlorpyrifos interfere with spermatogenesis of rats through reduction of sex hormones.
    Use of pesticides results in indirect effects on human health. We aimed to evaluate implications of toxicological effects of subchronic chlorpyrifos exposure on reproductive function in male rats. A total of 48 adult Wistar male rats were separated into four groups (n = 12). Animals were gavaged with 2.5 mg/kg (T1), 5 mg/kg (T2), or 10 mg/kg (T3) body weight of chlorpyrifos (CPF) or distilled water (control) daily for 30 days. Organ weights, epididymal sperm parameters, DNA integrity, sex hormonal (FHS and LH) levels, and alanine aminotransferase (ALT), aspartate aminotransferase (AST), gamma-glutamyl transferase (GGT), and creatinine concentrations were determined on day 31. Another two sets of (four groups/set; n = 10) animals were orally treated with the same doses of CPF, control animal groups were treated with distilled water only for 30 days, and fertility indices and blood plasma acetylcholine esterase (AchE) were determined on day 31. Exposure to CPF resulted in a significant (p < 0.05) decrease in weights of testis and epididymis. An increase in liver weight resulted in reduced sperm counts and sperm motility and an increase in sperm abnormalities. Significant reduction in serum testosterone (p < 0.01), luteinizing hormone (p < 0.05), and follicular stimulating hormone (p < 0.05) levels was evident in animals treated with the highest dose. A significant decrease in the number of viable implantation sites and pups was observed in female rats mated with the T3 (p < 0.01) and T2 (p < 0.05) males. The ALT, AST, GGT, and creatinine contents were significantly increased (p < 0.05 and p < 0.01, respectively) on CPF exposure. A significant (p < 0.01) reduction in blood plasma AchE enzyme was observed with the highest dose. Our results demonstrated that prolonged exposure of CPF induces spermatogenesis damage, possibly through interference with sex hormones and AchE enzyme resulting in reduction of fertility. Therefore, awareness programs on handling CPF (pesticides) to enhance safety warrant minimization of its hazards.
    [Peiris DC, Dhanushka T. 2017. Environ Sci Pollut Res Int. doi: 10.1007/s11356-017-9617-x.]
  • Maternal linuron exposure alters testicular development in male offspring rats at the whole genome level.
    Linuron is a widely used herbicide; its toxicity on the male reproductive system has been recognized. The current study was designed to explore the molecular mechanism underlying linuron-induced reproductive toxicity. Pregnant rats received daily oral gavage of linuron at the dose of 120mg/kg/d from gestation day (GD)12 to GD17. Tissues from male offspring rats were collected for pathological examination and microarray gene expression profiling. Changes in gene expression were further verified by quantitative real-time RT-PCR. Data showed that linuron-exposed offspring rats had a decreased sperm count (88% of controls) and disrupted acrosome formation. There were evident damages in seminiferous tubules and abnormal morphology in mesenchymal cells in samples from linuron-exposed animals. Microarray analysis indicated that the expressions of testosterone synthesis-associated genes, i.e., Star, P450scc, 3β-Hsd, Abp, Cox7a2, Pcna, p450c17and17β-Hsd were significantly altered by linuron exposure, along with other genes involving in cell proliferation and apoptosis, such as c-myc, S6K, Apaf1, and TSC1. These data indicate that linuron upon entering male offspring body can directly or indirectly interact with the androgen production and function; linuron-induced alteration in genes encoding testosterone synthesis is likely a major factor in linuron-induced male reproductive toxicity.
    [Bai J, Han H, Wang F, Su L, et al. 2017. Toxicology. 389:13-20]
  • Occupational pesticide exposure and subclinical hypothyroidism among male pesticide applicators.
    Animal studies suggest that exposure to pesticides may alter thyroid function; however, few epidemiologic studies have examined this association. Study evaluated the relationship between individual pesticides and thyroid function in 679 men enrolled in a substudy of the Agricultural Health Study, a cohort of licensed pesticide applicators. Self-reported lifetime pesticide use was obtained at cohort enrolment (1993-1997). Intensity-weighted lifetime days were computed for 33 pesticides, which adjusts cumulative days of pesticide use for factors that modify exposure (eg, use of personal protective equipment). Thyroid-stimulating hormone (TSH), thyroxine (T4), triiodothyronine (T3) and antithyroid peroxidase (anti-TPO) autoantibodies were measured in serum collected in 2010-2013. Higher exposure to the insecticide aldrin was positively associated with subclinical hypothyroidism (ORQ3=4.15, 95% CI 1.56 to 11.01, ORQ4=4.76, 95% CI 1.53 to 14.82, ptrend <0.01), higher TSH (ptrend=0.01) and lower T4 (ptrend=0.04). Higher exposure to the herbicide pendimethalin was associated with subclinical hypothyroidism (fourth quartile vs no exposure: ORQ4=2.78, 95% CI 1.30 to 5.95, ptrend=0.02), higher TSH (ptrend=0.04) and anti-TPO positivity (ptrend=0.01). The fumigant methyl bromide was inversely associated with TSH (ptrend=0.02) and positively associated with T4 (ptrend=0.01).Results suggest that long-term exposure to aldrin, pendimethalin and methyl bromide may alter thyroid function among male pesticide applicators..
    [Lerro CC, Beane Freeman LE, DellaValle CT. et al. 2017. Occup Environ Med. pii: oemed-2017-104431.]
  • Recent advances on bisphenol-A and endocrine disruptor effects on human prostate cancer
    Endocrine disrupting chemicals (EDCs) are man-made substances widespread in the environment that include, among many others, bisphenol A (BPA), organochlorinated pesticides and hormone derivatives detectable in meat from animals raised in concentrated animal feeding operations. Increasing evidence indicates that EDCs have a negative impact on human health as well as on male and female fertility. They may also be associated with some endocrine diseases and increased incidence of breast and prostate cancer. This review aims to summarize available data on the (potential) impact of some common EDCs, focusing particularly on BPA, prostate cancer and their mechanisms of action. These compounds interfere with normal hormone signal pathway transduction, resulting in prolonged exposure of receptors to stimuli or interference with cellular hormone signaling in target cells. Understanding the effects of BPA and other EDCs as well as their molecular mechanism(s) may be useful in sensitizing the scientific community and the manufacturing industry to the importance of finding alternatives to their indiscriminate use.
    [Di Donato M, Cernera G, Giovannelli P, et al. 2017. Mol Cell Endocrinol. pii: S0303-7207(17)30158-2. ]
  • Recent advances on bisphenol-A and endocrine disruptor effects on human prostate cancer.
    Endocrine disrupting chemicals (EDCs) are man-made substances widespread in the environment that include, among many others, bisphenol A (BPA), organochlorinated pesticides and hormone derivatives detectable in meat from animals raised in concentrated animal feeding operations. Increasing evidence indicates that EDCs have a negative impact on human health as well as on male and female fertility. They may also be associated with some endocrine diseases and increased incidence of breast and prostate cancer. This review aims to summarize available data on the (potential) impact of some common EDCs, focusing particularly on BPA, prostate cancer and their mechanisms of action. These compounds interfere with normal hormone signal pathway transduction, resulting in prolonged exposure of receptors to stimuli or interference with cellular hormone signaling in target cells. Understanding the effects of BPA and other EDCs as well as their molecular mechanism(s) may be useful in sensitizing the scientific community and the manufacturing industry to the importance of finding alternatives to their indiscriminate use.
    [Di Donato M, Cernera G, Giovannelli P, et al. Mol Cell Endocrinol. pii: S0303-7207(17)30158-2. ]
  • Reproductive toxic impact of subchronic treatment with combined butylparaben and triclosan in weanling male rats.
    The effect of treatment with combined butylparaben and triclosan on male gonadal toxicity in weanling rats was investigated. All treated groups experienced atrophy in the ventral prostate and seminal vesicle, likewise significant depletion in the number and motility of sperm. Given individually or combined butylparaben and triclosan, significantly decreased testosterone, luteinizing hormone, and follicle‐stimulating hormone levels. Individual treatment with tested compounds caused significant elevation in the E2 level, whereas combined treatment did not alter the E2 level. Testicular DNA damage was recorded in all treated groups. Moreover, the testicular malondialdehyde level was significantly elevated, along with a significant decrease in catalase enzyme activity in all treated groups. Superoxide dismutase enzyme activity was significantly decreased in the butylparaben‐treated group, increased in the triclosan‐treated group, and nonsignificantly changed the butylparaben‐triclosan‐treated group. The combined treatment produced an endocrine disturbance with a concomitant induction of testicular oxidative stress, which may represent a common mechanism of endocrine disruptor‐mediated dysfunction.
    [Riad, M et al. 2017. J Biochem Mol Toxicol doi:10.1002/jbt.22037.]
  • Understanding Epigenetic Effects of Endocrine Disrupting Chemicals: from Mechanisms to Novel Test Methods.
    Endocrine disrupting chemicals (EDCs) are man-made chemicals that interfere with hormonal signalling pathways. They are used in, e.g., production of common household materials, in resin-based medical supplies, pesticides. Thus, they are environmentally ubiquitous and humans and wildlife are exposed to them on a daily basis. Early life exposure to EDCs has been associated with later life adversities such as obesity, diabetes and cancer. Mechanisms underlying such associations are unknown but are likely to be mediated by epigenetic changes induced by EDCs. Epigenetics is the study of changes in gene function that are heritable but do not entail a change in DNA sequence. EDCs have been shown to affect epigenetic marks such as DNA methylation and histone modifications. The scope of this article is to review today's knowledge about mechanisms involved in EDC-induced epigenetic changes and to discuss how this knowledge could be used for designing novel methods addressing epigenetic effects of EDCs.
    [Alavian-Ghavanini A, Rüegg J. 2017. Basic Clin Pharmacol Toxicol. doi: 10.1111/bcpt.12878.]
  • Effect of methomyl on the biochemical and reproductive parameters in pregnancy rats: the protective role of Pistacia Lentiscus oil

    Methomyl (MET) is a carbamate insecticide used worldwide to protect a wide variety of crops from insect nuisances. Besides this beneficial role, it is classified as highly toxic compound for humans and animals by the EPA. Pistacia Lentiscus (PL) is a shrub that grows in the Mediterranean region; plant parts and oil have a long history in folk medicine in healing several diseases by their antioxidant, anti-inflammatory, antimicrobial, antifungal, antiatherogenic and anticancer properties. Hence, this study was undertaken to assess the effect of MET on biochemical, histological and reproductive parameters as well as the possible protective role of Pistacia Lentiscus oil (PLO) against MET-induced toxicity in pregnant female rats. Thirty two pregnant female rats were randomly divided into four equal groups including control, MET group (10 mg/kg/bw), PLO group (0.5 ml/kg/bw) and MET+ PLO group, MET and PLO were administered by oral route. At the eighteenth day of gestation (GD18), the blood samples were taken from retro-orbital sinus to evaluate the biochemical parameters and progesterone level. Then after the parturition, the different reproductive parameters were measured and the ovary and adrenal glands were removed, weighed, fixed and used for histopathological examination.The results show that MET increased significantly the weight of liver and adrenal gland, the level of cholesterol, glucose, creatinin, urea, ASAT and ALAT, meanwhile the level of total protein was reduced. Likewise, MET induced reproductive toxicity pronounced by a decline in the level of progesterone, an alteration in the reproductive index and an increase in the number of ovary atretic follicles and degenerative corpus luteum. The supplementation of the PLO with MET reverses partially and/or completely all adverse effects noted on the biochemical and reproductive parameters as well as on the histopathological changes by their antioxidant activities. We recommended the use of PLO by oral and/or dermal application as protective agent against several diseases related to reproduction dysfunction.
    [Mosbah, R., Mokrani, N., Mosbahi, I., Rouabhi, S. and Mantovani, A., 2016. In 18th European Congress of Endocrinology (Vol. 41). BioScientifica.]

  • Endocrine-Disrupting Chemicals and Reproductive Health.
    This review discusses the evidence linking industrial chemicals to a variety of health and reproductive outcomes. Industrial chemical production has increased over the past 30 to 40 years. Basic science, animal models, and epidemiologic data suggest that certain chemicals may act as endocrine disruptors (substances that interfere with normal hormonal action) and may play an etiologic role in a number of conditions whose incidence has also increased during this same period. These include low birth weight, gestational diabetes, obesity, certain cancers, certain birth defects, and neurodevelopmental disorders such as attention deficit disorder and autism. In addition, some environmental chemicals may have epigenetic effects, resulting in transgenerational health impacts. The epidemiologic and experimental evidence that links chemicals such as plasticizers (eg, phthalates and phenols), flame retardants, perfluorinated compounds, and pesticides with adverse reproductive health outcomes is reviewed. Women's health care providers are the liaison between scientific research and their patients; they should educate themselves on the significance of environmental toxins to health. They are ideally positioned, not only to counsel and reassure pregnant women, but also to suggest practicable changes in dietary and lifestyle habits to improve their health. Furthermore, women's health care providers should advocate for regulatory changes that protect women and their families from the health effects of environmental toxins.
    [Zlatnik MG. 2016. J Midwifery Womens Health. 61(4):442-55.]
  • Epidemiological trends of hormone-related cancers in Slovenia.
    The incidence of hormone-related cancers tends to be higher in the developed world than in other countries. In Slovenia, six hormone-related cancers (breast, ovarian, endometrial, prostate, testicular, and thyroid) account for a quarter of all cancers. Their incidence goes up each year, breast and prostate cancer in particular. The age at diagnosis is not decreasing for any of the analysed cancer types. The risk of breast cancer is higher in the western part of the country, but no differences in geographical distribution have been observed for other hormone-related cancers. Furthermore, areas polluted with endocrine-disrupting chemicals that affect hormone balance such as PCBs, dioxins, heavy metals, and pesticides, do not seem to involve a greater cancer risk. We know little about how many cancers can be associated with endocrine disruptors, as there are too few reliable exposure studies to support an association.
    [Zadnik V, Krajc M. Arh Hig Rada Toksikol. 67(2):83-92. ]
  • Epidemiological trends of hormone-related cancers in Slovenia.
    The incidence of hormone-related cancers tends to be higher in the developed world than in other countries. In Slovenia, six hormone-related cancers (breast, ovarian, endometrial, prostate, testicular, and thyroid) account for a quarter of all cancers. Their incidence goes up each year, breast and prostate cancer in particular. The age at diagnosis is not decreasing for any of the analysed cancer types. The risk of breast cancer is higher in the western part of the country, but no differences in geographical distribution have been observed for other hormone-related cancers. Furthermore, areas polluted with endocrine-disrupting chemicals that affect hormone balance such as PCBs, dioxins, heavy metals, and pesticides, do not seem to involve a greater cancer risk. We know little about how many cancers can be associated with endocrine disruptors, as there are too few reliable exposure studies to support an association.
    [Zadnik V, Krajc M. 2016. Arh Hig Rada Toksikol. 67(2):83-92. ]
  • Exposure to endocrine-disrupting chemicals in the USA: a population-based disease burden and cost analysis.
    Endocrine-disrupting chemicals (EDCs) contribute to disease and dysfunction and incur high associated costs (>1% of the gross domestic product [GDP] in the European Union). Exposure to EDCs varies widely between the USA and Europe because of differences in regulations and, therefore, we aimed to quantify disease burdens and related economic costs to allow comparison.We used existing models for assessing epidemiological and toxicological studies to reach consensus on probabilities of causation for 15 exposure-response relations between substances and disorders. We used Monte Carlo methods to produce realistic probability ranges for costs across the exposure-response relation, taking into account uncertainties. Estimates were made based on population and costs in the USA in 2010. Costs for the European Union were converted to US$ (€1=$1·33).The disease costs of EDCs were much higher in the USA than in Europe ($340 billion [2·33% of GDP] vs $217 billion [1·28%]). The difference was driven mainly by intelligence quotient (IQ) points loss and intellectual disability due to polybrominated diphenyl ethers (11 million IQ points lost and 43 000 cases costing $266 billion in the USA vs 873 000 IQ points lost and 3290 cases costing $12·6 billion in the European Union). Accounting for probability of causation, in the European Union, organophosphate pesticides were the largest contributor to costs associated with EDC exposure ($121 billion), whereas in the USA costs due to pesticides were much lower ($42 billion).EDC exposure in the USA contributes to disease and dysfunction, with annual costs taking up more than 2% of the GDP. Differences from the European Union suggest the need for improved screening for chemical disruption to endocrine systems and proactive prevention.
    [Attina TM, Hauser R, Sathyanarayana S, et al. Lancet Diabetes Endocrinol. 4(12):996-1003]
  • Exposure to pesticides and prostate cancer: systematic review of the literature
    Investigations about the association between prostate cancer and environmental and/or occupational pesticide exposure have evidenced a possible role of these chemical substances on tumor etiology, related to their action as endocrine disruptors.To assess the association between pesticide exposure and prostate cancer by conducting a systematic review of the scientific literature.The review included 49 studies published between 1993 and 2015. All studies were in English and analyzed exposure to pesticides and/or agricultural activities. Most studies (32 articles) found a positive association between prostate cancer and pesticides or agricultural occupations, with estimates ranging from 1.01 to 14.10.The evidence provided by the reviewed studies indicates a possible association between the development of prostate cancer and pesticide exposure and/or agricultural occupations.
    [Silva JF, Mattos IE, Luz LL, Carmo CN, Aydos RD. Rev Environ Health. 31(3):311-27. ]
  • Glyphosate pathways to modern diseases V: Amino acid analogue of glycine in diverse proteins
    Glyphosate, a synthetic amino acid and analogue of glycine, is the most widely used biocide on the planet. Its presence in food for human consumption and animal feed is ubiquitous. Epidemiological studies have revealed a strong correlation between the increasing incidence in the United States of a large number of chronic diseases and the increased use of glyphosate herbicide on corn, soy and wheat crops. Glyphosate, acting as a glycine analogue, may be mistakenly incorporated into peptides during protein synthesis. A deep search of the research literature has revealed a number of protein classes that depend on conserved glycine residues for proper function. Glycine, the smallest amino acid, has unique properties that support flexibility and the ability to anchor to the plasma membrane or the cytoskeleton. Glyphosate substitution for conserved glycines can easily explain a link with diabetes, obesity, asthma, chronic obstructive pulmonary disease (COPD), pulmonary edema, adrenal insufficiency, hypothyroidism, Alzheimer’s disease, amyotrophic lateral sclerosis (ALS), Parkinson’s disease, prion diseases, lupus, mitochondrial disease, nonHodgkin’s lymphoma, neural tube defects, infertility, hypertension, glaucoma, osteoporosis, fatty liver disease and kidney failure. The correlation data together with the direct biological evidence make a compelling case for glyphosate action as a glycine analogue to account for much of glyphosate’s toxicity. Glufosinate, an analogue of glutamate, likely exhibits an analogous toxicity mechanism. There is an urgent need to find an effective and economical way to grow crops without the use of glyphosate and glufosinate as herbicides.
    [Samsel, A. and Seneff, S., 2016. J Biol Phys Chem, 16(6), pp.9-46.]
  • Human exposure to endocrine disrupting compounds: Their role in reproductive systems, metabolic syndrome and breast cancer. A review
    Endocrine disrupting chemicals (EDCs) are released into the environment from different sources. They are mainly used in packaging industries, pesticides and food constituents. Clinical evidence, experimental models, and epidemiological studies suggest that EDCs have major risks for humans by targeting different organs and systems in the body (e.g. reproductive system, breast tissue, adipose tissue, pancreas, etc.). Due to the ubiquity of human exposure to these compounds the aim of this review is to describe the most recent data on the effects induced by phthalates, bisphenol A and parabens in a critical window of exposure: in utero, during pregnancy, infants, and children. The interactions and mechanisms of toxicity of EDCs in relation to human general health problems, especially those broadening the term of endocrine disruption to 'metabolic disruption', should be deeply investigated. These include endocrine disturbances, with particular reference to reproductive problems and breast, testicular and ovarian cancers, and metabolic diseases such as obesity or diabetes.
    [Giulivo M, Lopez de Alda M, Capri E, Barceló D. 2016. Environ Res. 151:251-264.]
  • Human exposure to endocrine disrupting compounds: Their role in reproductive systems, metabolic syndrome and breast cancer. A review.
    Endocrine disrupting chemicals (EDCs) are released into the environment from different sources. They are mainly used in packaging industries, pesticides and food constituents. Clinical evidence, experimental models, and epidemiological studies suggest that EDCs have major risks for humans by targeting different organs and systems in the body (e.g. reproductive system, breast tissue, adipose tissue, pancreas, etc.). Due to the ubiquity of human exposure to these compounds the aim of this review is to describe the most recent data on the effects induced by phthalates, bisphenol A and parabens in a critical window of exposure: in utero, during pregnancy, infants, and children. The interactions and mechanisms of toxicity of EDCs in relation to human general health problems, especially those broadening the term of endocrine disruption to 'metabolic disruption', should be deeply investigated. These include endocrine disturbances, with particular reference to reproductive problems and breast, testicular and ovarian cancers, and metabolic diseases such as obesity or diabetes.
    [Giulivo M, Lopez de Alda M, Capri E, Barceló D. 2016. Environ Res. 151:251-264]
  • Individual and combined effect of chlorpyrifos and cypermethrin on reproductive system of adult male albino rats.
    Commercial mixtures of chlorpyrifos and cypermethrin pesticides are widely used to enhance the toxic effects of cypermethrin on target insects. So, the purpose of the current study was to evaluate the individual and combined toxic effects of chlorpyrifos (CPF) and cypermethrin (CYP) on reproductive system of adult male albino rats. Forty adult male albino rats were randomized into main four groups.  All treatments were given by oral gavage for 12 weeks. Single CPF and CYP exposures significantly have adverse effects on reproductive function of adult male albino rats manifested by reduced testicular weight, decreased sperm count, motility and viability, significantly increased percent of morphologically abnormal spermatozoa, and significant increments in sperm DNA fragmentation index (DFI) with respect to control group. Furthermore, serum follicle stimulating hormone, luteinizing hormone, and testosterone levels were decreased significantly compared to control group. This was accompanied with histopathological changes in the testis of rats such as necrosis, degeneration, decreasing number of spermatogenic cells in some seminiferous tubules, edema, congested blood vessels, and exudate in interstitial tissue of the testis. Notably, all these changes were exaggerated in rats treated concomitantly with chlorpyrifos and cypermethrin rendering the mixture more toxic than the additive effects of each compound and causing greater damage on the reproductive system of male albino rats than the individual pesticides.
    [Alaa-Eldin EA, El-Shafei DA, Abouhashem NS. 2016. Environ Sci Pollut Res. doi:10.1007/s11356-016-7912-6]
  • Lambda-cyhalothrin disrupts the up-regulation effect of 17β-estradiol on post-synaptic density 95 protein expression via estrogen receptor α-dependent Akt pathway.
    Lambda-cyhalothrin (LCT), one of the type II pyrethroids, has been widely used throughout the world. The estrogenic effect of LCT to increase cell proliferation has been well established. However, whether the estrogenic effect of LCT will influence neurodevelopment has not been investigated. In addition, 17β-Estradiol (E2) plays a crucial role in neurodevelopment and induces an increase in synaptic proteins. The post-synaptic density 95 (PSD95) protein, which is involved in the development of the structure and function of new spines and localized with estrogen receptor α (ERα) at the post-synaptic density (PSD), was detected in our study by using hippocampal neuron cell line HT22. We found that LCT up-regulated PSD95 and ERα expression, estrogen receptor (ER) antagonist ICI182,780 and phosphatidylinositol-4; 5-bisphosphate 3-kinase (PI3K) inhibitor LY294,002 blocked this effect. In addition, LCT disrupted the promotion effect of E2 on PSD95. To investigate whether the observed changes are caused by ERα-dependent signaling activation, we next detected the effects of LCT on the ERα-mediated PI3K-Protein kinase B (PKB/Akt)-eukaryotic initiation factor (eIF) 4E-binding protein 1 (4E-BP1) pathway. There existed an activation of Akt and the downstream factor 4E-BP1 after LCT treatment. In addition, LCT could disrupt the activation effect of E2 on the Akt pathway. However, no changes in cAMP response element-binding protein (CREB) activation and PSD95 messenger ribonucleic acid (mRNA) were observed. Our findings demonstrated that LCT could increase the PSD95 protein level via the ERα-dependent Akt pathway, and LCT might disrupt the up-regulation effect of E2 on PSD95 protein expression via this signaling pathway.
    [Wang Q, Xia X, Deng X, Li N, et al. 2016. J Environ Sci (China). 41:252-60.]
  • Negative Role of the Environmental Endocrine Disruptors in the Human Neurodevelopment
    The endocrine disruptors (EDs) are able to influence the endocrine system, mimicking or antagonizing hormonal molecules. They are bio-persistent for their degradation resistance in the environment. Our research group has investigated by gas chromatography-mass spectrometry (GC-MS) the EDs presence in 35 brain samples, coming from 27 cases of sudden intrauterine unexplained death syndrome (SIUDS) and 8 cases of sudden infant death syndrome (SIDS), collected by centralization in the last year (2015). More in detail, a mixture of 25 EDs has been subjected to analytical procedure, following standard protocols. Among the target analytes, some organochlorine pesticides, that is α-chlordane, γ-chlordane, heptachlor, p,p-DDE, p,p-DDT, and the two most commonly used organophosphorus pesticides (OPPs), chlorpyrifos and chlorfenvinfos, have been found in seven and three samples, respectively. The analytical procedure used to detect the presence of environmental EDs in cortex samples has been successfully implemented on SIUDS and SIDS victims. The environmental EDs have been found to be able to overcome the placental barrier, reaching also the basal ganglia assigned to the control of the vital functions. This finding, related to the OPPs bio-persistence, implies a conceptual redefinition of the fetal-placental and fetal blood-brain barriers: not real safety barriers but simply time-deferral mechanisms of absorption.
    [Roncati L, Termopoli V, Pusiol T. 2016. Front Neurol. 7:143.]
  • The Increasing Prevalence in Intersex Variation from Toxicological Dysregulation in Fetal Reproductive Tissue Differentiation and Development by Endocrine-Disrupting Chemicals
    An increasing number of children are born with intersex variation (IV; ambiguous genitalia/hermaphrodite, pseudohermaphroditism, etc.). Evidence shows that endocrine-disrupting chemicals (EDCs) in the environment can cause reproductive variation through dysregulation of normal reproductive tissue differentiation, growth, and maturation if the fetus is exposed to EDCs during critical developmental times in utero. Animal studies support fish and reptile embryos exhibited IV and sex reversal when exposed to EDCs. Occupational studies verified higher prevalence of offspring with IV in chemically exposed workers (male and female). Chemicals associated with endocrine-disrupting ability in humans include organochlorine pesticides, poly-chlorinated biphenyls, bisphenol A, phthalates, dioxins, and furans. Intersex individuals may have concurrent physical disorders requiring lifelong medical intervention and experience gender dysphoria. An urgent need exists to determine which chemicals possess the greatest risk for IV and the mechanisms by which these chemicals are capable of interfering with normal physiological development in children.
    [Rich AL, Phipps LM, Tiwari S, et al. 2016. Environ Health Insights. 10:163-71. ]
  • EDC-2: The Endocrine Society's Second Scientific Statement on Endocrine-Disrupting Chemicals.
    The Endocrine Society's first Scientific Statement in 2009 provided a wake-up call to the scientific community about how environmental endocrine-disrupting chemicals (EDCs) affect health and disease. Five years later, a substantially larger body of literature has solidified our understanding of plausible mechanisms underlying EDC actions and how exposures in animals and humans-especially during development-may lay the foundations for disease later in life. At this point in history, we have much stronger knowledge about how EDCs alter gene-environment interactions via physiological, cellular, molecular, and epigenetic changes, thereby producing effects in exposed individuals as well as their descendants. Causal links between exposure and manifestation of disease are substantiated by experimental animal models and are consistent with correlative epidemiological data in humans. There are several caveats because differences in how experimental animal work is conducted can lead to difficulties in drawing broad conclusions, and we must continue to be cautious about inferring causality in humans. In this second Scientific Statement, we reviewed the literature on a subset of topics for which the translational evidence is strongest: 1) obesity and diabetes; 2) female reproduction; 3) male reproduction; 4) hormone-sensitive cancers in females; 5) prostate; 6) thyroid; and 7) neurodevelopment and neuroendocrine systems. Our inclusion criteria for studies were those conducted predominantly in the past 5 years deemed to be of high quality based on appropriate negative and positive control groups or populations, adequate sample size and experimental design, and mammalian animal studies with exposure levels in a range that was relevant to humans. We also focused on studies using the developmental origins of health and disease model. No report was excluded based on a positive or negative effect of the EDC exposure. The bulk of the results across the board strengthen the evidence for endocrine health-related actions of EDCs. Based on this much more complete understanding of the endocrine principles by which EDCs act, including nonmonotonic dose-responses, low-dose effects, and developmental vulnerability, these findings can be much better translated to human health. Armed with this information, researchers, physicians, and other healthcare providers can guide regulators and policymakers as they make responsible decisions.
    [Gore AC, Chappell VA, Fenton SE, Flaws JA, et al. 2015. Endocr Rev. 36(6):E1-E150.]
  • Gestational exposure to endocrine-disrupting chemicals and reciprocal social, repetitive, and stereotypic behaviors in 4- and 5-year-old children: the HOME study.
    Endocrine-disrupting chemicals (EDCs) may be involved in the etiology of autism spectrum disorders, but identifying relevant chemicals within mixtures of EDCs is difficult. Our goal was to identify gestational EDC exposures associated with autistic behaviors. We measured the concentrations of 8 phthalate metabolites, bisphenol A, 25 polychlorinated biphenyls (PCBs), 6 organochlorine pesticides, 8 brominated flame retardants, and 4 perfluoroalkyl substances in blood or urine samples from 175 pregnant women in the HOME (Health Outcomes and Measures of the Environment) Study (Cincinnati, OH). When children were 4 and 5 years old, mothers completed the Social Responsiveness Scale (SRS), a measure of autistic behaviors. We examined confounder-adjusted associations between 52 EDCs and SRS scores using a two-stage hierarchical analysis to account for repeated measures and confounding by correlated EDCs.Most of the EDCs were associated with negligible absolute differences in SRS scores (≤ 1.5). Each 2-SD increase in serum concentrations of polybrominated diphenyl ether-28 (PBDE-28) (β = 2.5; 95% CI: -0.6, 5.6) or trans-nonachlor (β = 4.1; 95% CI: 0.8-7.3) was associated with more autistic behaviors. In contrast, fewer autistic behaviors were observed among children born to women with detectable versus nondetectable concentrations of PCB-178 (β = -3.0; 95% CI: -6.3, 0.2), β-hexachlorocyclohexane (β = -3.3; 95% CI: -6.1, -0.5), or PBDE-85 (β = -3.2; 95% CI: -5.9, -0.5). Increasing perfluorooctanoate (PFOA) concentrations were also associated with fewer autistic behaviors (β = -2.0; 95% CI: -4.4, 0.4).Some EDCs were associated with autistic behaviors in this cohort, but our modest sample size precludes us from dismissing chemicals with null associations. PFOA, β-hexachlorocyclohexane, PCB-178, PBDE-28, PBDE-85, and trans-nonachlor deserve additional scrutiny as factors that may be associated with childhood autistic behaviors.
    [Braun JM, Kalkbrenner AE, Just AC, Yolton K, et al. 2014. Environ Health Perspect. 122(5):513-20.]
  • Sex-specific enhanced behavioral toxicity induced by maternal exposure to a mixture of low dose endocrine-disrupting chemicals
    Humans are increasingly and consistently exposed to a variety of endocrine disrupting chemicals (EDCs), chemicals that have been linked to neurobehavioral disorders such as ADHD and autism. Many of such EDCs have been shown to adversely influence brain mesocorticolimbic systems raising the potential for cumulative toxicity. As such, understanding the effects of developmental exposure to mixtures of EDCs is critical to public health protection. Consequently, this study compared the effects of a mixture of four EDCs to their effects alone to examine potential for enhanced toxicity, using behavioral domains and paradigms known to be mediated by mesocorticolimbic circuits (fixed interval (FI) schedule controlled behavior, novel object recognition memory and locomotor activity) in offspring of pregnant mice that had been exposed to vehicle or relatively low doses of four EDCs, atrazine (ATR - 10mg/kg), perfluorooctanoic acid (PFOA - 0.1mg/kg), bisphenol-A (BPA - 50 μg/kg), 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD - 0.25 μg/kg) alone or combined in a mixture (MIX), from gestational day 7 until weaning. EDC-treated males maintained significantly higher horizontal activity levels across three testing sessions, indicative of delayed habituation, whereas no effects were found in females. Statistically significant effects of MIX were seen in males, but not females, in the form of increased FI response rates, in contrast to reductions in response rate with ATR, BPA and TCDD, and reduced short term memory in the novel object recognition paradigm. MIX also reversed the typically lower neophobia levels of males compared to females. With respect to individual EDCs, TCDD produced notable increases in FI response rates in females, and PFOA significantly increased ambulatory locomotor activity in males. Collectively, these findings show the potential for enhanced behavioral effects of EDC mixtures in males and underscore the need for animal studies to fully investigate mixtures, including chemicals that converge on common physiological substrates to examine potential mechanisms of toxicity with full dose effect curves to assist in interpretations of relevant mechanisms.
    [Sobolewski M, Conrad K, Allen JL, Weston H, et al. 2014. Neurotoxicology. 45:121-30]
  • Impact of endocrine-disrupting chemicals on neural development and the onset of neurological disorders
    Even though high doses of organic pollutants are toxic, relatively low concentrations have been reported to cause long-term alterations in functioning of individual organisms, populations and even next generations. Among these pollutants are dioxins, polychlorinated biphenyls, pesticides, brominated flame retardants, plasticizers (bisphenol A, nonylphenol, and phthalates) as well as personal care products and drugs. In addition to toxic effects, they are able to interfere with hormone receptors, hormone synthesis or hormone conversion. Because these chemicals alter hormone-dependent processes and disrupt functioning of the endocrine glands, they have been classified as endocrine-disrupting chemicals (EDCs). Because certain EDCs are able to alter neural transmission and the formation of neural networks, the term neural-disrupting chemicals has been introduced, thus implicating EDCs in the etiology of neurological disorders. Recently, public concern has been focused on the effects of EDCs on brain function, concomitantly with an increase in neuropsychiatric disorders, including autism, attention deficit and hyperactivity disorder as well as learning disabilities and aggressiveness. Several lines of evidence suggest that exposure to EDCs is associated with depression and could result in neural degeneration. EDCs act via several classes of receptors with the best documented mechanisms being reported for nuclear steroid and xenobiotic receptors. Low doses of EDCs have been postulated to cause incomplete methylation of specific gene regions in the young brain and to impair neural development and brain functions across generations. Efforts are needed to develop systematic epidemiological studies and to investigate the mechanisms of action of EDCs in order to fully understand their effects on wildlife and humans.
    [Kajta M, Wójtowicz AK. 2013. Pharmacol Rep. 65(6):1632-9.]
  • Hormones and endocrine-disrupting chemicals: low-dose effects and nonmonotonic dose responses
    Here, a team of researchers review two major concepts in EDC studies: low dose and nonmonotonicity. Low-dose effects were defined by the National Toxicology Program as those that occur in the range of human exposures or effects observed at doses below those used for traditional toxicological studies. They review the mechanistic data for low-dose effects and use a weight-of-evidence approach to analyze five examples from the EDC literature. Additionally, they explore nonmonotonic dose-response curves, defined as a nonlinear relationship between dose and effect where the slope of the curve changes sign somewhere within the range of doses examined. Authors illustrate that nonmonotonic responses and low-dose effects are remarkably common in studies of natural hormones and EDCs. Whether low doses of EDCs influence certain human disorders is no longer conjecture, because epidemiological studies show that environmental exposures to EDCs are associated with human diseases and disabilities. Authors conclude that when nonmonotonic dose-response curves occur, the effects of low doses cannot be predicted by the effects observed at high doses. Thus, fundamental changes in chemical testing and safety determination are needed to protect human health.
    [Vandenberg LN, Colborn T, Hayes TB, Heindel JJ, Jacobs DR Jr, et al. 2012. Endocr Rev.33(3):378-455.]