Developmental exposure to chlordecone induces transgenerational effects in somatic prostate tissue which are associated with epigenetic histone trimethylation changes

Legoff, Louis; D’Cruz, Shereen Cynthia; Lebosq, Morgane; Gély-Pernot, Aurore; Bouchekhchoukha, Katia; Monfort, Christine; Kernanec, Pierre-Yves; Tevosian, Sergei G.; Multigner, Luc; Smagulova, Fátima

doi:10.1016/j.envint.2021.106472

Cited by 17 publications

(9 citation statements)

References 79 publications

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“…In animal models, it has been shown that exposure to CD affects germ cells in both sexes (9,11) and causes global alterations in somatic tissues such as prostate and liver (40). This study is designed to evaluate the effects of CD on humans by using cord blood obtained from males.…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2021

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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.

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Section: Discussionmentioning

confidence: 99%

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

et al. 2021

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“…Fertility status in humans is correlated with histone H3 methylation changes in retained sperm histones [ 23 ]. Exposure to the organochlorine insecticide chlordecone increases prostatic epithelial neoplasia in F1 and F3 mice, associated with alterations in histone H3K4me3 [ 24 ]. Histone modifications are epigenetic marks that can be transmitted to the offspring [ 25 ].…”

Section: Introductionmentioning

confidence: 99%

Impact of Endocrine Disruptors upon Non-Genetic Inheritance

Montjean

Neyroud

Yéfimova

et al. 2022

IJMS

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Similar to environmental factors, EDCs (endocrine-disrupting chemicals) can influence gene expression without modifying the DNA sequence. It is commonly accepted that the transgenerational inheritance of parentally acquired traits is conveyed by epigenetic alterations also known as “epimutations”. DNA methylation, acetylation, histone modification, RNA-mediated effects and extracellular vesicle effects are the mechanisms that have been described so far to be responsible for these epimutations. They may lead to the transgenerational inheritance of diverse phenotypes in the progeny when they occur in the germ cells of an affected individual. While EDC-induced health effects have dramatically increased over the past decade, limited effects on sperm epigenetics have been described. However, there has been a gain of interest in this issue in recent years. The gametes (sperm and oocyte) represent targets for EDCs and thus a route for environmentally induced changes over several generations. This review aims at providing an overview of the epigenetic mechanisms that might be implicated in this transgenerational inheritance.

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“…In the FWI, the pesticide CD was used in banana farming from 1973 to 1993, resulting in permanently polluted soil and waterways. Recent epidemiological studies identified health effects resulting from environmental exposure (Legoff et al 2021b ; Multigner et al 2016 ). The chronic external TLV external for CD recently reassessed (Anses 2021 ) highlighted the difficulty of performing such assessments without a human PBPK model.…”

Section: Discussionmentioning

confidence: 99%

Chlordecone: development of a physiologically based pharmacokinetic tool to support human health risks assessments

Emond

Multigner

2022

Arch Toxicol

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Chlordecone (CD; Kepone™) is a carcinogenic organochlorine insecticide with neurological, reproductive, and developmental toxicity that was widely used in the French West Indies (FWI) from 1973 to 1993 to fight banana weevils. Although CD has not been used there for more than 25 years, it still persists in the environment and has polluted the waterways and soil of current and older banana fields. Today, human exposure to CD in the FWI mainly arises from consuming contaminated foodstuffs. The aims of this study were to develop a physiologically based pharmacokinetic (PBPK) model in the rat and extrapolate it to humans based on available pharmacokinetic data in the literature. A comparison of simulations using the rat model with published experimental datasets showed reasonable predictability for single and repetitive doses, and, thus, it was extrapolated to humans. The human PBPK model, which has seven compartments, is able to simulate the blood concentrations of CD in human populations and estimate the corresponding external dose using the reverse dosimetry approach. The human PBPK model will make it possible to improve quantitative health risk assessments for CD contamination and reassess the current chronic toxicological reference values to protect the FWI population.

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Developmental exposure to chlordecone induces transgenerational effects in somatic prostate tissue which are associated with epigenetic histone trimethylation changes

Cited by 17 publications

References 79 publications

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

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

Impact of Endocrine Disruptors upon Non-Genetic Inheritance

Chlordecone: development of a physiologically based pharmacokinetic tool to support human health risks assessments

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