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

中文翻译：

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雌性大鼠青春期和母体行为暴露于内分泌干扰物 (EDC) 混合物的多代和跨代结果

摘要

背景：

内分泌干​​扰物 (EDC) 对生育力和生殖发育的影响是现代社会日益关注的问题。尽管性成熟的神经内分泌控制是 EDCs 的主要目标，但人们对下丘脑在青春期和代际传递的排卵中断中的潜在作用知之甚少。

目标：

我们假设发育暴露于环境相关剂量的 EDC 混合物可以通过下丘脑的表观遗传重编程诱导雌性大鼠性成熟和母体护理的多代和/或跨代改变。我们调查了通过母体生殖系或通过涉及母体护理的非基因组机制传播破坏的生殖表型。

方法：

成年雌性 Wistar 大鼠在妊娠前、妊娠期和哺乳期结束前暴露于以下 13 种 EDC 的混合物：邻苯二甲酸二正丁酯 (DnBP)、邻苯二甲酸二(2-乙基己基)酯 (DEHP)、双酚 A ( BPA)、长春唑啉、丙氯嗪、腐霉利、利谷隆、环氧萘醌、二氯二苯基二氯乙烯、甲氧基亚胺酸辛酯、4-甲基亚苄基樟脑 (4-MBC)、对羟基苯甲酸丁酯和对乙酰氨基酚。围产期暴露的后代 (F1) 与未暴露的雄性交配以产生生殖细胞 (F2) 和跨代暴露的 (F3 和 F4) 雌性。几代人研究了性成熟、母体行为和下丘脑暴露目标。

结果：

生殖细胞 (F2) 和跨代 (F3) 暴露于 EDC 的女性，但不是 F1，显示青春期发病延迟和卵泡发生改变。我们报告了控制青春期和排卵的关键下丘脑基因（Kiss1、Esr1和Oxt）的跨代改变，并且我们确定了表观遗传抑制因子的下丘脑多梳组作为该机制的参与者。此外，我们发现下丘脑多巴胺能信号的丧失导致母体行为（F1-F3）的多代减少。使用交叉培养范式，我们发现母体表型的减少在未暴露的水坝饲养的暴露于 EDC 的幼崽中正常化，但没有实现青春期表型的逆转。

讨论：

发育暴露于 EDC 混合物的大鼠通过下丘脑表观遗传重编程表现出性成熟和母体护理的多代和跨代破坏。这些结果引起了人们对 EDC 混合物对后代影响的担忧。https://doi.org/10.1289/EHP8795