Multi- and Transgenerational Outcomes of an Exposure to a Mixture of Endocrine-Disrupting Chemicals (EDCs) on Puberty and Maternal Behavior in the Female Rat

Overview

Journal Environ Health Perspect

Date 2021 Aug 12

PMID 34383603

Citations 22

Authors

David Lopez-Rodriguez

Carlos Francisco Aylwin

Virginia Delli

Elena Sevrin

Marzia Campanile

Marion Martin

Delphine Franssen

Arlette Gerard

Silvia Blacher

Ezio Tirelli

Agnes Noel

Alejandro Lomniczi

Anne-Simone Parent

Affiliations

Soon will be listed here.

Abstract

Background: The effects of endocrine-disrupting chemicals (EDCs) on fertility and reproductive development represent a rising concern in modern societies. Although the neuroendocrine control of sexual maturation is a major target of EDCs, little is known about the potential role of the hypothalamus in puberty and ovulation disruption transmitted across generations.

Objectives: We hypothesized that developmental exposure to an environmentally relevant dose of EDC mixture could induce multi- and/or transgenerational alterations of sexual maturation and maternal care in female rats through epigenetic reprograming of the hypothalamus. We investigated the transmission of a disrupted reproductive phenotype via the maternal germline or via nongenomic mechanisms involving maternal care.

Methods: Adult female Wistar rats were exposed prior to and during gestation and until the end of lactation to a mixture of the following 13 EDCs: di--butyl phthalate (DnBP), di(2-ethylhexyl) phthalate (DEHP), bisphenol A (BPA), vinclozolin, prochloraz, procymidone, linuron, epoxynaxole, dichlorodiphenyldichloroethylene, octyl methoxynimmate, 4-methylbenzylidene camphor (4-MBC), butylparaben, and acetaminophen. Perinatally exposed offspring (F1) were mated with unexposed males to generate germ cell (F2) and transgenerationally exposed (F3 and F4) females. Sexual maturation, maternal behavior, and hypothalamic targets of exposure were studied across generations.

Results: Germ cell (F2) and transgenerationally (F3) EDC-exposed females, but not F1, displayed delayed pubertal onset and altered folliculogenesis. We reported a transgenerational alteration of key hypothalamic genes controlling puberty and ovulation (, , and ), and we identified the hypothalamic polycomb group of epigenetic repressors as actors of this mechanism. Furthermore, we found a multigenerational reduction of maternal behavior (F1-F3) induced by a loss in hypothalamic dopaminergic signaling. Using a cross-fostering paradigm, we identified that the reduction in maternal phenotype was normalized in EDC-exposed pups raised by unexposed dams, but no reversal of the pubertal phenotype was achieved.

Discussion: Rats developmentally exposed to an EDC mixture exhibited multi- and transgenerational disruption of sexual maturation and maternal care via hypothalamic epigenetic reprogramming. These results raise concerns about the impact of EDC mixtures on future generations. https://doi.org/10.1289/EHP8795.

Citing Articles

Two Hits of EDCs Three Generations Apart: Evaluating Multigenerational Anxiety-Like Behavioral Phenotypes in Male Rats Exposed to Aroclor 1221 and Vinclozolin.

Hilz E, Gillette R, Thompson L, Crews D, Gore A Environ Health Perspect. 2024; 132(12):127006.

PMID: 39739410 PMC: 11687611. DOI: 10.1289/EHP15684.

Two Hits of EDCs Three Generations Apart: Evaluating Multigenerational Anxiety-Like Behavioral Phenotypes in Female Rats Exposed to Aroclor 1221 and Vinclozolin.

Hilz E, Gillette R, Thompson L, Ton L, Pham T, Kunkel M Environ Health Perspect. 2024; 132(12):127005.

PMID: 39739409 PMC: 11687612. DOI: 10.1289/EHP15621.

Mild Gestational Hypothyroidism in Mice Has Transient Developmental Effects and Long-Term Consequences on Neuroendocrine Systems.

Quignon C, Backer A, Kearney J, Bow H, Wray S Thyroid. 2024; 35(1):97-110.

PMID: 39728609 PMC: 11807895. DOI: 10.1089/thy.2024.0512.

Environmentally-relevant doses of bisphenol A and S exposure in utero disrupt germ cell programming across generations resolved by single nucleus multi-omics.

Zhao L, Shi M, Winuthayanon S, MacLean 2nd J, Hayashi K bioRxiv. 2024; .

PMID: 39713385 PMC: 11661074. DOI: 10.1101/2024.12.05.627072.

Maternal Bisphenol B Exposure and Mammary Gland Development of Offspring: A Time-Series Analysis.

Ji X, Jiang P, Li Y, Su L, Yue H, Sang N Environ Health (Wash). 2024; 1(4):278-290.

PMID: 39474496 PMC: 11504573. DOI: 10.1021/envhealth.3c00085.

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