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Environ Health Perspect

Title:		Multi- and Transgenerational Outcomes of an Exposure to a Mixture of Endocrine-Disrupting Chemicals (EDCs) on Puberty and Maternal Behavior in the Female Rat
Author(s):		Lopez-Rodriguez D; Aylwin CF; Delli V; Sevrin E; Campanile M; Martin M; Franssen D; Gerard A; Blacher S; Tirelli E; Noel A; Lomniczi A; Parent AS;
Address:		"GIGA Neurosciences, Neuroendocrinology Unit, University of Liege, Liege, Belgium. Division of Neuroscience, Oregon National Primate Research Center, Oregon Health & Science University (OHSU), Portland, Oregon, USA. Lille Neuroscience & Cognition (LilNCog), Institut national de la sante et de la recherche medicale (Inserm), CHU Lille, Lille, France. Tumor and Development Biology, GIGA-Cancer, University of Liege, Liege, Belgium. Department of Psychology: Cognition and Behavior, University of Liege, Liege, Belgium. Department of Pediatrics, University Hospital Liege, Liege, Belgium"
Journal Title:		Environ Health Perspect
Year:		2021
Volume:		20210812
Issue:		8
Page Number:		87003 -
DOI:		10.1289/EHP8795
ISSN/ISBN:		1552-9924 (Electronic) 0091-6765 (Print) 0091-6765 (Linking)
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-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. https://doi.org/10.1289/EHP8795"
Keywords:		"Animals *Endocrine Disruptors/toxicity Epigenesis, Genetic Female Hypothalamus/*drug effects Maternal Behavior/*drug effects Pregnancy *Prenatal Exposure Delayed Effects/chemically induced Rats Rats, Wistar Sexual Maturation;neuroscience;"
Notes:		"MedlineLopez-Rodriguez, David Aylwin, Carlos Francisco Delli, Virginia Sevrin, Elena Campanile, Marzia Martin, Marion Franssen, Delphine Gerard, Arlette Blacher, Silvia Tirelli, Ezio Noel, Agnes Lomniczi, Alejandro Parent, Anne-Simone eng P51 OD011092/OD/NIH HHS/ R01 HD084542/HD/NICHD NIH HHS/ Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't 2021/08/13 Environ Health Perspect. 2021 Aug; 129(8):87003. doi: 10.1289/EHP8795. Epub 2021 Aug 12"