Multi- and transgenerational outcomes of an exposure to a mixture of endocrine-disrupting chemicals (EDCs) on puberty and maternal behavior in the female rat

David López-Rodríguez, Carlos Francisco Aylwin, Virginia Delli, Elena Sevrin, Marzia Campanile, Marion Martin, Delphine Franssen, Arlette Gérard, Silvia Blacher, Ezio Tirelli, Agnès Noël, Alejandro Lomniczi, Anne Simone Parent, David López-Rodríguez, Carlos Francisco Aylwin

    Research output: Contribution to journalArticlepeer-review

    13 Scopus citations


    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-n-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 (Kiss1, Esr1, and Oxt), 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.

    Original languageEnglish (US)
    Article number087003
    JournalEnvironmental health perspectives
    Issue number8
    StatePublished - Aug 2021

    ASJC Scopus subject areas

    • Public Health, Environmental and Occupational Health
    • Health, Toxicology and Mutagenesis


    Dive into the research topics of 'Multi- and transgenerational outcomes of an exposure to a mixture of endocrine-disrupting chemicals (EDCs) on puberty and maternal behavior in the female rat'. Together they form a unique fingerprint.

    Cite this