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

Published on Aug 12, 2021in Environmental Health Perspectives8.382
· DOI :10.1289/EHP8795
David Lopez-Rodriguez2
Estimated H-index: 2
(University of Liège),
Carlos F. Aylwin5
Estimated H-index: 5
(Oregon National Primate Research Center)
+ 10 AuthorsEzio Tirelli23
Estimated H-index: 23
(University of Liège)
Sources
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.
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#1David Lopez-Rodriguez (University of Liège)H-Index: 2
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Abstract Plasticiser di-(2-ethylhexyl) phthalate (DEHP) is associated with female reproductive endocrine toxicity. Our previous study found that mono-(2-ethylhexyl) phthalate (MEHP), the metabolite of DEHP, can interfere with ovarian function via dysregulation of 17β-hydroxysteroid dehydrogenase (17β-HSD) in vitro. The aim of this study was to verify this hypothesis in vivo. The present study tested the hypothesis that subacute exposure to DEHP induced ovarian dysfunction by dysregulating 17β-HS...
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Di-(2-ethylhexyl) phthalate (DEHP) is ubiquitous in the environment and has been proposed to lead to reproductive disruption. In this study, we systematically investigated the effects of different doses of DEHP exposure on female hypothalamic–pituitary–gonadal axis development. Female Sprague–Dawley rats were gavaged with vehicle (corn oil) or DEHP (5 or 500mgkg–1 day–1) during postnatal Days (PNDs) 22–28 or PNDs 22–70. Results demonstrated that the low and high doses of DEHP exerted opposite ef...
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Abstracts This study was conducted to investigate the effects of maternal exposure bisphenol A (BPA) on ovaries development of F1 female mice. The BPA exposure model of pregnant mice was prepared by intragastric administration of BPA at the doses of 0, 2.5, 5, 10, 20, 40 mg kg−1 d−1 at gestation day (GD) 0.5–17.5. The ovarian index of the offspring mice was calculated at postnatal day (PND) 21 and PND 56. The results showed that BPA at 5 mg/kg, 10 mg/kg, 20 mg/kg and 40 mg/kg significantly incre...
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