Impact of Endocrine Disruptors upon Non-Genetic Inheritance

Montjean, Debbie; Neyroud, Anne-Sophie; Yéfimova, Marina; Benkhalifa, Moncef; Cabry, Rosalie; Ravel, Célia

doi:10.3390/ijms23063350

Cited by 31 publications

(36 citation statements)

References 156 publications

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“…( 39 ) on the multi-generational and very probably trans-generational impact of DES on neurodevelopment. This strengthens the hypothesis that in-utero exposure to DES (and to other endocrine disruptors) contributes to the pathogenesis of psychiatric disorders, particularly autistic disorders ( 47 , 48 ). According to the theory proposed by Nilsson and Skinner ( 49 ), epigenetic alterations (epimutations) induced by environmental insults (e.g.…”

Section: Methodssupporting

confidence: 85%

“…The F3 generation may exhibit transgenerational inheritance of disease susceptibility. Several epimutations can be implicated in this non-genetic inheritance ( 48 ): DNA and RNA methylation changes, histone modification alterations, non-coding RNAs and extracellular vesicles. It has been already shown that upon DES exposure, the ZFP57 and ADAMTS9 genes become hypermethylated.…”

Section: Methodsmentioning

confidence: 99%

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Diethylstilbestrol and autism

et al. 2022

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It is acknowledged that diethylstilbestrol (DES), a synthetic diphenol with powerful estrogenic properties, causes structural anomalies of the reproductive tract and increases the risk of cancer and genital malformations in children and grandchildren of mothers treated during pregnancy. Conversely, data on DES effects on neurodevelopment and psychiatric disorders in in-utero exposed children and their descendants are rare, especially concerning Autism Spectrum Disorders (ASD). Recent studies presented in this review strengthen the hypothesis that in-utero exposure to DES and also other synthetic estrogens and progestogens, which all are endocrine disruptors, contributes to the pathogenesis of psychiatric disorders, especially ASD. A large epidemiological study in the USA in 2010 reported severe depression in in-utero exposed children (n=1,612), and a French cohort study (n=1,002 in-utero DES exposed children) in 2016 found mainly bipolar disorders, schizophrenia, major depression, suicide attempts, and suicide. Few publications described ASD in in-utero exposed children, mainly a Danish cohort study and a large Chinese epidemiological study. Molecular studies on endocrine disruptors demonstrated the transgenerational induction of diseases and DES epigenetic impact (DNA methylation changes) at two genes implicated in neurodevelopment (ZFP57 and ADAM TS9). We recently described in an informative family, somatic and psychiatric disorders in four generations, particularly ASD in boys of the third and fourth generation. These data show that the principle of precaution must be retained for the protection of future generations: women (pregnant or not) should be extremely vigilant about synthetic hormones.

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Section: Methodssupporting

confidence: 85%

Section: Methodsmentioning

confidence: 99%

Diethylstilbestrol and autism

et al. 2022

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“…It is not clear if EVs directly control gene expression, but they may participate in the epigenetic regulation of gene expression by transporting and delivering specific molecules potentially implicated in epigenetic inheritance. This mechanism might be of relevance in the genital tract with the modification of the gamete environment [ 30 ].…”

Section: Discussionmentioning

confidence: 99%

Diversity of Extracellular Vesicles in Human Follicular Fluid: Morphological Analysis and Quantification

Neyroud

Chiechio

Moulin

et al. 2022

IJMS

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The oocyte microenvironment constituted by the follicular fluid (FF) is a key for the optimal development of female gametes. Its composition reflects the physiological state of the ovarian follicle. The particularity of FF is to contain a huge diversity of extracellular vesicles specific to women, in the same way as seminal plasma in men. Here, we described and compared morphological aspects of broad subcategories of human FF-related Extracellular Vesicles (EVs). EVs participate in physiological and pathological processes and have potential applications in diagnostics or therapeutics. EVs isolated from FF are involved in different biological functions related to follicular growth, oocyte maturation, and embryo development. However, knowledge on the morphology of FF-derived EVs is limited, mainly due to their sub-micrometer size and to intrinsic limitations in methods applied for their characterization. The aim of this study was to provide a comprehensive morphological description of EVs from FF of healthy subjects and quantification. EVs separation was realized by centrifugation, with comparison of the EV yield obtained from differential centrifugation and one-step ultracentrifugation. Cryo-Transmission Electron Microscopy was used to reveal the morphology, size, and phenotype of EVs. Dynamic Light Scattering (DLS) and Nanoparticle Tracking Analysis (NTA) were used to quantify and analyze the size distribution for each centrifugation step. We performed a comprehensive inventory of human follicular fluid EVs. We show that human FF contains a huge diversity of EVs. This study brings novel insights on EVs from normal FF and provides a reference for further studies of EVs in ovarian diseases.

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“…While life-style factors such as obesity have been shown to alter sperm non-coding RNAs in men,(53) no human studies have directly investigated the link between environmental toxicants such as DDT and germline RNA changes to the best of our knowledge; though several reports in animal models exist. (54–56) Nonetheless, a number of epidemiological studies link parental environmental toxins and cancer in the progeny. For instance, an association between paternal exposure to pesticides and a number of childhood cancers in offspring has been reported.…”

Section: Discussionmentioning

confidence: 99%

Environmentally Induced Sperm RNAs Transmit Cancer Susceptibility to Offspring in a Mouse Model

Nasir

et al. 2020

Preprint

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BackgroundDNA sequence accounts for the majority of disease heritability, including cancer. However, it is becoming clear that environmentally-induced epigenetic inheritance can also occur. Epidemiological studies have shown that maternal exposure to the pesticide DDT in pregnancy is associated with increased breast cancer risk in women. Yet, the effects of paternal exposure to this and other pesticides on the progeny’s breast cancer development has not been investigated.MethodsMale mice (c57bl/6) were exposed to DDT or to a control-vehicle (CO) solution and used for sperm collection or mating with unexposed females to produce the DDT or CO daughters. In another experiment, normal mouse embryos (zygote stage) were injected with miRNA-10b and implanted into surrogate mothers to produce miR-10b offspring. DDT daughters or miRNA-10b females were used to study breast cancer development and metabolic parameters. Paternal sperm was used for RNA-seq analysis and miRNA expression levels.ResultsPre-conception paternal DDT exposure altered the sperm small non-coding RNA load, with an increase in miRNAs and a specific surge in miRNA-10b levels. DDT offspring weighed less at birth and at weaning, but became overweight and showed metabolic dysfunction in adulthood compared to CO. DDT daughters also showed increased mammary tumorigenesis, developing more aggressive tumors that grew faster than in CO. This tumor phenotype was linked to suppression of the AMPK energy sensing pathway and mTOR activation in mammary tissues. Remarkably, embryonic injection of miRNA-10b recapitulated the mammary gland and tumor phenotypes observed in DDT daughters.ConclusionsTo our knowledge, this is the first report of an association between paternal DDT exposure and breast cancer in offspring. Paternal DDT-induced programming of breast cancer development in daughters is mechanistically linked to sperm miRNA-10b. The impact of DDT and other endocrine disrupting chemicals on sperm and programming of breast and other cancers in offspring needs to be evaluated in humans.

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Impact of Endocrine Disruptors upon Non-Genetic Inheritance

Cited by 31 publications

References 156 publications

Diethylstilbestrol and autism

Diethylstilbestrol and autism

Diversity of Extracellular Vesicles in Human Follicular Fluid: Morphological Analysis and Quantification

Environmentally Induced Sperm RNAs Transmit Cancer Susceptibility to Offspring in a Mouse Model

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