In utero exposure to chlordecone affects histone modifications and activates LINE-1 in cord blood.

Environmental factors can induce detrimental consequences into adulthood life. In this study, we examined the epigenetic effects induced by in utero chlordecone (CD) exposure on human male cord blood as well as in blood-derived Ke-37 cell line. Genome-wide analysis of histone H3K4me3 distribution revealed that genes related to chromosome segregation, chromatin organization, and cell cycle have altered occupancy in their promoters. The affected regions were enriched in ESR1, SP family, and IKZF1 binding motifs. We also observed a global reduction in H3K9me3, markedly in repeated sequences of the genome. Decrease in H3K9me3 after CD exposure correlates with decreased methylation in LINE-1 promoters and telomere length extension. These observations on human cord blood were assessed in the Ke-37 human cell line. H3K4me3 and the expression of genes related to immune response, DNA repair, and chromatin organization, which were affected in human cord blood were also altered in CD-exposed Ke-37 cells. Our data suggest that developmental exposure to CD leads to profound changes in histone modification patterns and affects the processes controlled by them in human cord blood.

Endocrine disrupting-chemicals and biochemical recurrence of prostate cancer after prostatectomy: A cohort study in Guadeloupe (French West Indies).

Previous studies have suggested that exposure to environmental chemicals with hormonal properties, also called endocrine disrupting chemicals, may be involved in the occurrence of prostate cancer (PCa). Such exposure may also influence the treatment outcome as it is still present at the time of diagnosis, the beginning of therapy, and beyond. We followed 326 men in Guadeloupe (French West Indies) who underwent radical prostatectomy as primary treatment of localized PCa. We analyzed the relationship between exposure to the estrogenic chlordecone, the antiandrogenic dichlorodiphenyldichloroethylene (DDE, the main metabolite of the insecticide DDT), and the nondioxin-like polychlorinated biphenyl congener 153 (PCB-153) with mixed estrogenic/antiestrogenic properties and the risk of biochemical recurrence (BCR) after surgery. After a median follow-up of 6.1 years after surgery, we found a significant increase in the risk of BCR, with increasing plasma chlordecone concentration (adjusted hazard ratio = 2.51; 95% confidence interval: 1.39-4.56 for the highest vs. lowest quartile of exposure; p trend = 0.002). We found no associations for DDE or PCB-135. These results shown that exposure to environmental estrogens may negatively influence the outcome of PCa treatment.

Ovarian dysfunction following prenatal exposure to an insecticide, chlordecone, associates with altered epigenetic features.

Chlordecone (CD) is an insecticide that was used in the French West Indies for several years to control the banana root borer pest. Given its nonsignificant degradation, it persists in the environment. CD is a carcinogenic compound with reproductive and developmental toxicity and is a recognized endocrine-disrupting chemical. In this study, we examined the effects of CD on female reproductive system of mice with the focus on epigenetic features in ovary. Our data show that gestational exposure to low dose of CD affects meiotic double-strand breaks repair in female embryos. In adult mice derived from CD-treated pregnant females, we observed delayed puberty, decreased number of primordial and increased number of atretic follicles. Gene expression analysis revealed that Rcbtb2 and Rbpms genes were not expressed in embryonic gonads. Estrogen signaling- and oocyte maturation-associated genes were downregulated in adult ovaries. The morphological changes were associated with altered epigenetic features: increased H2Aub and increased H3K27me3 and decreased H4ac and H3K4me3 in embryonic oocytes. The DNA damage-associated, γH2AX marks were detected in the follicles of treated but not control adult ovaries. We also found reduced H3K4me3 and H4ac in fully grown oocytes of the treated ovaries. The ChIP-seq analysis of H3K4me3 in adult ovaries showed that target genes of ZFP57 and TRIM28, which regulate pluripotency and imprinting, were significantly enriched in altered regions. Our study clearly demonstrates that gestational exposure to a low dose of CD impairs the function of female reproductive system and the changes are associated with altered epigenetic features.

[Systematic review of the impact of chlordecone on human health in the French West Indies]. / Revue systématique de l'impact du chlordécone sur la santé humaine aux Antilles françaises.

INTRODUCTION: Several publications have highlighted the adverse effects of chlordecone on human and animal species. The possible long-term consequences continue to be explored as chlordecone still contaminates Caribbean soils. The objective of this literature review is to determine the long-term effects of chlordecone on human health. MATERIAL AND METHOD: We searched for the keyword "chlordecone" on different scientific databases: Medline®, ISI Web of Knowledge, Google Scholar, EM Premium. We have enriched our research with first degree references, related articles on PubMed and grey literature. RESULTS: Of the 192 articles analyzed, 12 responded to the impact of chlordecone on human health in the French West Indies. In obstetrics, exposure to chlordecone was associated with a lower incidence of gestational hypertension. In pediatrics, these studies have shown an association between prenatal exposure to chlordecone and increased risk of prematurity, decreased birth weight (especially when the mother gained excessive weight during pregnancy), decreased fine cognitive and motor acquisition, and changes in circulating concentrations of certain thyroid hormones. In oncology, exposure was associated with an increased risk of prostate cancer, particularly if there was a family history of prostate cancer. CONCLUSION: While the effects of acute exposure to chlordecone at high doses are well described (Kepone Shake syndrome at the time of the Hopewell accident), the effects at environmental doses are becoming clearer even if they remain complex to identify.

Perinatal exposure to chlordecone and infant growth.

BACKGROUND: The intensive use of chlordecone (an organochlorine insecticide) in the French West Indies until 1993 resulted in a long-term soil and water contamination. Chlordecone has known hormonal properties and exposure through contaminated food during critical periods of development (gestation and early infancy) may affect growth. OBJECTIVES: We aimed to assess the impact of prenatal and postnatal exposure to chlordecone on the growth of children from the TIMOUN mother-child cohort. METHODS: Chlordecone was determined in cord plasma at birth (N=222) and in breast milk samples (at 3 months). Dietary chlordecone intake was estimated at 7 and 18 months, with food-frequency questionnaires and food-specific contamination data. Anthropometric measurements were taken at the 3-, 7- and 18-month visits and measurements reported in the infants' health records were noted. Structured Jenss-Bayley growth models were fitted to individual height and weight growth trajectories. The impact of exposure on growth curve parameters was estimated directly with adjusted mixed non-linear models. Weight, height and body mass index (BMI), and instantaneous height and weight growth velocities at specific ages were also analyzed relative to exposure. RESULTS: Chlordecone in cord blood was associated with a higher BMI in boys at 3 months, due to greater weight and lower height, and in girls at 8 and 18 months, mostly due to lower height. Postnatal exposure was associated with lower height, weight and BMI at 3, 8 and 18 months, particularly in girls. CONCLUSION: Chlordecone exposure may affect growth trajectories in children aged 0 to 18 months.

Hypertensive disorders of pregnancy and gestational diabetes mellitus among French Caribbean women chronically exposed to chlordecone.

Few studies have explored the consequences of environmental exposure to organochlorine pesticides for gestational hypertension (GH), preeclampsia (PE) and gestational diabetes mellitus (GDM). Chlordecone is a persistent organochlorine pesticide that was used intensively, and almost exclusively, in the French West Indies until 1993. We investigated the impact of prenatal exposure to chlordecone on the occurrence of GDM, GH and PE by studying 779 pregnant women enrolled in a prospective mother-child cohort (Timoun Study) in Guadeloupe between 2004 and 2007. Chlordecone exposure was determined by assaying maternal plasma and information about pregnancy complications was obtained from midwives, pediatricians and hospital medical records after delivery. The risks of GH (n=65), PE (n=31) and GDM (n=71) were estimated by multiple logistic regression including potential confounders. Levels of chlordecone plasma concentration in the third (OR=0.2; 95% confidence interval (CI): 0.1, 0.5) and fourth quartiles (OR=0.3; 95% CI: 0.2, 0.7) were associated with a statistically significant decrease in the risk of GH. A log10 increase in chlordecone concentration was significantly associated with lower risk of GH (OR=0.4; 95% CI: 0.2, 0.6). No significant associations were observed between the chlordecone exposure and the risk of PE or GDM. This study suggests an inverse association between chlordecone exposure during pregnancy and GH. Further studies are required to determine the underlying mechanism, or the potential unknown confounding factors, resulting in this association.

Invited commentary: interpreting associations between exposure biomarkers and pregnancy outcome.

Levels of exposure biomarkers vary among individuals because of differences in both environmental exposure and metabolism. However, the ultimate interest is in providing information about the impact of modifying environmental exposures through regulation or behavior change. Using these levels in studies of pregnancy outcomes, as nicely illustrated by the study of Kadhel et al. in this issue of the Journal (Am J Epidemiol. 2014;179(5):536-544), has the usual strength of being integrative across multiple pathways but may reflect reverse causality, in which the underlying disease alters biomarker levels or shared physiological determinants of the biomarker level and the health outcome. Specifically, biomarkers may vary because of spatial differences in exposure, behavioral differences affecting exposure, and metabolic differences across members of the study population. Proper interpretation of such studies calls for a clearer understanding the sources of variation in exposure to more fully consider confounding and reverse causality due to metabolic differences within the study population.

Chlordecone exposure, length of gestation, and risk of preterm birth.

Persistent organic pollutants have not been conclusively associated with length of gestation or with preterm birth. Chlordecone is an organochlorine pesticide that has been extensively used to control the banana root borer population in the French West Indies. Data from the Timoun Mother-Child Cohort Study conducted in Guadeloupe between 2004 and 2007 were used to examine the associations of chlordecone concentrations in maternal plasma with the length of gestation and the rate preterm birth in 818 pregnant women. Data were analyzed using multivariate linear regression for length of gestation and a Cox model for preterm birth. The median plasma chlordecone concentration was 0.39 µg/L (interquartile range, 0.18-0.83). No correlation was observed with plasma concentrations of p,p'-dichlorodiphenyl dichloroethene (ρ = 0.017) or polychlorinated biphenyl 153 (ρ = -0.016), the other main organochlorine compounds detected. A 1-log10 increase in chlordecone concentration was associated with a decreased length of gestation (-0.27 weeks; 95% confidence interval: -0.50, -0.03) and an increased risk of preterm birth (60%; 95% confidence interval: 10, 130). These associations may result from the estrogen-like and progestin-like properties of chlordecone. These results are of public health relevance because of the prolonged persistence of chlordecone in the environment and the high background rate of preterm births in this population.

Exposure to an organochlorine pesticide (chlordecone) and development of 18-month-old infants.

Chlordecone is a persistent organochlorine pesticide that was used in the French West Indies until the early 1990s for banana weevil borer control. Human exposure to this chemical in this area still occurs nowadays due to consumption of contaminated food. Although adverse effects on neurodevelopment, including tremors and memory deficits, have been documented in experimental studies conducted with rodents exposed during the gestational and neonatal periods, no study has been conducted yet to determine if chlordecone alters child development. This study examines the relation of gestational and postnatal exposure to chlordecone to infant development at 18 months of age in a birth-cohort of Guadeloupean children. In a prospective longitudinal study conducted in Guadeloupe (Timoun mother-child cohort study), exposure to chlordecone was measured at birth from an umbilical cord blood sample (n=141) and from a breast milk sample collected at 3 months postpartum (n=75). Toddlers were assessed using an adapted version of the Ages and Stages Questionnaire. Higher chlordecone concentrations in cord blood were associated with poorer fine motor scores. When analyses were conducted separately for boys and girls, this effect was only observed among boys. These results suggest that prenatal exposure to chlordecone is associated with specific impairments in fine motor function in boys, and add to the growing evidence that exposure to organochlorine pesticides early in life impairs child development.

Kepone (chlordecone) disrupts adherens junctions in human breast epithelial cells cultured on matrigel.

Perturbations in cell-extracellular matrix (ECM) interactions are a consistent feature of mammary tumors and cells in culture. We have utilized MCF-10ATG3B human breast epithelial cells to examine whether the organochlorine Kepone induces alterations in cell adhesion molecules important to cell-cell and cell-ECM interactions. Kepone effects on the levels and association of proteins involved in adherens junctions or desmosomes were examined using immunoblot analysis and immunoprecipitation. MCF-10ATG3B cells cultured on an ECM of Matrigel form lattice-like structures that are disrupted with 0.1 and 1 microM Kepone. E-cadherin protein levels decreased significantly by approximately 23% and approximately 69% following treatment with 0.1 and 1.0 microM Kepone, respectively, relative to solvent-treated cells. Desmoglein and alpha- and gamma-catenin levels did not vary significantly with Kepone. Beta-catenin protein levels decreased significantly by approximately 37%, 36% and 53% at 0.01, 0.1 and 1.0 microM Kepone, respectively. E-cadherin-gamma-catenin association was disrupted with 0.1 and 1.0 microM Kepone. Thus, Kepone disrupts cellular architecture, specifically E-cadherin-gamma-catenin containing adherens junctions, which may ultimately affect cellular phenotype.

Salmonid sexual development is not consistently altered by embryonic exposure to endocrine-active chemicals.

Fish sexual development is sensitive to exogenous hormone manipulation, and salmonids have been used extensively as environmental sentinels and models for biomedical research. We simulated maternal transfer of contaminants by microinjecting rainbow trout (Oncorhynchus mykiss) and chinook salmon (Oncorhynchus tshawytscha) embryos. Fish were reared for 6 months and sexed, and gonads were removed for histology and measurement of in vitro steroid production. Analysis of fat samples showed that dichlorodiphenylethylene (DDE) levels, o, p'M-DDE and p,o, p'-DDE isomers, were elevated 6 months after treatment. A preliminary study showed an increased ratio of males to females after treatment with 80 mg/kg and 160 mg/kg of the xenoestrogen o,o, p'-DDE. One fish treated with 160 mg/kg o,o, p'-DDE had gonads with cells typical of both males and females. A follow-up study, using more fish and excluding the highly toxic 160 mg/kg o,o, p'-DDE dose, showed no effect on sex ratio or gonadal histology. Embryonic exposure of monosex male trout, monosex female trout, and mixed sex salmon to o, o, p'-DDE, p,o, p'-DDE, mixtures of DDE isomers, and octylphenol failed to alter sexual development. We observed no treatment-dependent changes in in vitro gonadal steroid production in any experiments. Trout exposed in ovo and reared to maturity spawned successfully. These results suggest that mortality attributable to the xenoestrogens o,o, p'-DDE, chlordecone, and octylphenol, and the antiandrogen p,o, p'-DDE, is likely to occur before the appearance of subtle changes in sexual development. Because trout appeared to be sensitive to endocrine disruption, we cannot dismiss the threat of heavily contaminated sites or complex mixtures to normal sexual development of salmonids or other aquatic organisms.

Pesticides: an important but underused model for the environmental health sciences.

Pesticides are high-volume, widely used, environmental chemicals and there is continuous debate concerning their possible role in many chronic human health effects. Because of their known structures, known rates of application, and the presence of a large occupationally exposed population, they are not only important in their own right but are ideal models for the effects of environmental chemicals on the population in general. For reasons that are not always clear, this potential has not been realized. These exposed populations represent an underused asset in the study of the human health effects of environmental contaminants. Chronic effects thought to involve pesticides include carcinogenesis, neurotoxicity, and reproductive and development effects. In this paper we attempt to summarize this concern and, relying to a large extent on studies in our own laboratory, to indicate the importance and present status of studies of the mammalian metabolism of pesticides and indicate the need for further use of this model. Aspects considered include the role of pesticides as substrates for xenobiotic-metabolizing enzymes such as cytochrome P450 and the flavin-containing monooxygenase and their role as inducers or inhibitors of metabolic enzymes. The interaction of pesticides with complex multienzyme pathways, the role of biological characteristics, particularly gender, in pesticide metabolism, and the special role of pesticides at portals of entry and in target tissues are also considered.

ATSDR evaluation of health effects of chemicals. II. Mirex and chlordecone: health effects, toxicokinetics, human exposure, and environmental fate.

This document provides public health officials, physicians, toxicologists, and other interested individuals and groups with an overall perspective of the toxicology of mirex and chlordecone. It contains descriptions and evaluations of toxicological studies and epidemiological investigations and provides conclusions, where possible, on the relevance of toxicity and toxicokinetic data to public health. Additional substances will be profiled in a series of manuscripts to follow.

Prevention of toxic environmental illness in the twenty-first century.

Previous introductions of new technologies have frequently resulted in unanticipated occupational and environmental illness. Prevention of such illness in the twenty-first century requires stringent application of two fundamental principles of public health: evaluation of new technologies before their introduction, and surveillance of exposed persons after the introduction of new technologies. Failure to establish these basic preventive mechanisms in advance will inevitably result in the development of new toxic diseases in the twenty-first century.

Clinical evaluation of liver structure and function in humans exposed to halogenated hydrocarbons.

An unresolved question is whether humans exposed to comparatively low doses of persistent environmental chemicals such as polyhalogenated biphenyls or organochlorine pesticides are at risk for injury to the liver. Cross-sectional epidemiologic studies suggest that these chemicals may produce statistically significant but clinically mild abnormalities in the commonly employed chemical tests of liver function. The few reports of human liver morphology reveal nonspecific changes reflecting effects of lipophilic chemicals. There is evidence that chemicals of this category in at least some doses cause induction of liver microsomal enzymes involved in biotransformation of foreign substances. This finding has been documented by measurements of the clearance of model drugs or the appearance in the urine of steroid metabolites or glucaric acid. Although a positive statistical correlation between the concentrations of these chemicals in serum and the serum gamma-glutamyltranspeptidase activity has been reported, the non-specificity of the latter enzyme precludes conclusion that this change is indicative of induction of liver microsomal enzymes. Although the effects of this type of environmental chemical are not indicative of progressive liver disease, only prospective clinical trials can resolve the issue of the risk for future development of liver malignancy.

Neurological manifestations in humans exposed to chlordecone: follow-up results.

Twenty-three workers chronically exposed to chlordecone developed overt neurologic manifestations. These included postural and intention tremor, gait difficulty and opsoclonus. Blood levels of chlordecone ranged from 2.0 to 33.0 ppm. The manifestations slowly cleared in all but one worker.