Epigenetic Transgenerational Actions of Endocrine Disruptors and Male Fertility

Anway, Matthew D.; Cupp, Andrea S.; Uzumcu, Mehmet; Skinner, Michael K.

doi:10.1126/science.1108190

Cited by 2,300 publications

(2,137 citation statements)

References 26 publications

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“…This study raises the possibility that exposure to ATZ can directly alter the fetal developmental program and that ATZ-induced effects can be inherited across generations. Here we used an outbred CD1 mouse model because outbred mice are more sensitive to toxic exposure than inbred mice (11) and are considered to be better predictors of the human response (106). Pregnant dams (F0) carrying F1 offspring were exposed to the herbicide ATZ between embryonic (E) days E6.5 to E15.5.…”

Section: Discussionmentioning

confidence: 99%

“…Taken together, these findings raise the possibility that histone marks, which are retained in sperm, play a key role in safekeeping epigenetic information for subsequent generations. A groundbreaking work by Skinner laboratory showed that the fetus undergoing gonadal sex determination is particularly vulnerable to environmental exposure that engenders changes in DNA methylation (11). …”

Section: Introductionmentioning

confidence: 99%

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Exposure to the widely used herbicide atrazine results in deregulation of global tissue-specific RNA transcription in the third generation and is associated with a global decrease of histone trimethylation in mice

et al. 2016

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The epigenetic events imposed during germline reprogramming and affected by harmful exposure can be inherited and transferred to subsequent generations via gametes inheritance. In this study, we examine the transgenerational effects promoted by widely used herbicide atrazine (ATZ). We exposed pregnant outbred CD1 female mice and the male progeny was crossed for three generations with untreated females. We demonstrate here that exposure to ATZ affects meiosis, spermiogenesis and reduces the spermatozoa number in the third generation (F3) male mice. We suggest that changes in testis cell types originate from modified transcriptional network in undifferentiated spermatogonia. Importantly, exposure to ATZ dramatically increases the number of transcripts with novel transcription initiation sites, spliced variants and alternative polyadenylation sites. We found the global decrease in H3K4me3 occupancy in the third generation males. The regions with altered H3K4me3 occupancy in F3 ATZ-derived males correspond to altered H3K4me3 occupancy of F1 generation and 74% of changed peaks in F3 generation are associated with enhancers. The regions with altered H3K4me3 occupancy are enriched in SP family and WT1 transcription factor binding sites. Our data suggest that the embryonic exposure to ATZ affects the development and the changes induced by ATZ are transferred up to three generations.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Exposure to the widely used herbicide atrazine results in deregulation of global tissue-specific RNA transcription in the third generation and is associated with a global decrease of histone trimethylation in mice

et al. 2016

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“…This latter concept of the epigenetic transmission of a trait through the modification of the infant's genes by maternal behavior has been studied extensively in the area of stress regulation, stress responsiveness, and the hypothalamic-pituitary-adrenal axis, but is yet to be studied in any depth for the hypothalamicpituitary-gonadal axis. The former concept of germline transmission of an epigenetic trait has been most clearly demonstrated in the field of reproductive toxicology, in which Skinner et al showed that prenatal exposure to endocrine-disrupting chemicals causes changes in DNA methylation that were manifested as the latent development of male infertility, reproductive cancers, and other dyfunctions, and that this phenotype is transmitted through the male germline across multiple generations [5,6]. Furthermore, these animals were also behaviorally modified across generations.…”

Section: The Developmental Basis Of Adult Disease and Dysfunctionmentioning

confidence: 99%

Developmental programming and endocrine disruptor effects on reproductive neuroendocrine systems

Gore¹

2008

Frontiers in Neuroendocrinology

230

122

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The ability of a species to reproduce successfully requires the careful orchestration of developmental processes during critical time points, particularly the late embryonic and early postnatal periods. This article begins with a brief presentation of the evidence for how gonadal steroid hormones exert these imprinting effects upon the morphology of sexually differentiated hypothalamic brain regions, the mechanisms underlying these effects, and their implications in adulthood. Then, I review the evidence that aberrant exposure to hormonally-active substances such as exogenous endocrine-disrupting chemicals (EDCs), may result in improper hypothalamic programming, thereby decreasing reproductive success in adulthood. The field of endocrine disruption has shed new light on the discipline of basic reproductive neuroendocrinology through studies on how early life exposures to EDCs may alter gene expression via non-genomic, epigenetic mechanisms, including DNA methylation and histone acetylation. Importantly, these effects may be transmitted to future generations if the germline is affected via transgenerational, epigenetic actions. By understanding the mechanisms by which natural hormones and xenobiotics affect reproductive neuroendocrine systems, we will gain a better understanding of normal developmental processes, as well as to develop the potential ability to intervene when development is disrupted.

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“…Estrogen-like molecules could interfere with the physiologic function of endogenous hormones causing, among others, significant effects on the reproductive system both in females and males [102, 103]. This adverse effect is only in part understood, and the wide variability of the results found in the literature depends on the experimental approach, the concentrations tested, the time of exposure and the effects of confounding variables [104].…”

Section: Effects Of Phyto- and Xenoestrogens On Human Breast Tissuementioning

confidence: 99%

Combating Malaria with Plant Molecules: A Brief Update

Negi¹,

Gupta²,

Hamid

2013

CMC

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Observations on the role of ovarian hormones in breast cancer growth, as well as interest in contraception, stimulated research into the biology of estrogens. The identification of the classical receptors ERα and ERβ and the transmembrane receptor GPER and the resolution of the structure of the ligand bound to its receptor established the principal molecular mechanisms of estrogen action. The presence of estrogen-like compounds in many plants used in traditional medicine or ingested as food ingredients, phytoestrogens, as well as the estrogenic activities of many industrial pollutants and pesticides, xenoestrogens, have prompted investigations into their role in human health. Phyto- and xenoestrogens bind to the estrogen receptors with a lower affinity than the endogenous estrogens and can compete or substitute the hormone. Xenoestrogens, which accumulate in the body throughout life, are believed to increase breast cancer risk, especially in cases of prenatal and prepuberal exposure whereas the role of phytoestrogens is still a matter of debate. At present, the application of phytoestrogens appears to be limited to the treatment of post-menopausal symptoms in women where the production of endogenous estrogens has ceased. In this review we discuss chemistry, structure and classification, estrogen signaling and the consequences of the interactions of estrogens, phytoestrogens and xenoestrogens with their receptors, the complex interactions of endogenous and exogenous ligands, the evaluation of the health risks related to xenoestrogens, and the perspectives toward the synthesis of potent third generation selective estrogen receptor modulators (SERMs).

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Epigenetic Transgenerational Actions of Endocrine Disruptors and Male Fertility

Cited by 2,300 publications

References 26 publications

Exposure to the widely used herbicide atrazine results in deregulation of global tissue-specific RNA transcription in the third generation and is associated with a global decrease of histone trimethylation in mice

Exposure to the widely used herbicide atrazine results in deregulation of global tissue-specific RNA transcription in the third generation and is associated with a global decrease of histone trimethylation in mice

Developmental programming and endocrine disruptor effects on reproductive neuroendocrine systems

Combating Malaria with Plant Molecules: A Brief Update

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