GIGA Neurosciences, Neuroendocrinology Unit, University of Liège, Liège, Belgium.
Division of Neuroscience, Oregon National Primate Research Center, Oregon Health & Science University (OHSU), Portland, Oregon, USA.
Environ Health Perspect. 2021 Aug;129(8):87003. doi: 10.1289/EHP8795. Epub 2021 Aug 12.
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.
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.
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.
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.
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.
内分泌干扰化学品 (EDC) 对生育能力和生殖发育的影响是现代社会日益关注的问题。尽管神经内分泌对性成熟的控制是 EDC 的主要靶标，但对于下丘脑在跨代传递的青春期和排卵障碍中的潜在作用知之甚少。
我们假设，通过下丘脑的表观遗传重编程，发育暴露于环境相关剂量的 EDC 混合物可能会导致雌性大鼠的性成熟和母性照顾的多代和/或跨代改变。我们研究了通过母体生殖系或涉及母性行为的非基因组机制传递受损的生殖表型。
成年雌性 Wistar 大鼠在妊娠和哺乳期前和期间以及哺乳期结束前暴露于以下 13 种 EDC 混合物中：邻苯二甲酸二丁酯 (DnBP)、邻苯二甲酸二(2-乙基己基)酯 (DEHP)、双酚 A (BPA)、伏氯唑、百菌清、丙环唑、环丙嘧啶、恶草酮、二氯二苯二氯乙烯、辛基甲氧基肉桂酸、4-甲基苄叉樟脑 (4-MBC)、丁基对羟基苯甲酸酯和对乙酰氨基酚。经产前暴露的后代 (F1) 与未暴露的雄性交配，以产生生殖细胞 (F2) 和跨代暴露 (F3 和 F4) 的雌性。在各代研究性成熟、母性行为和暴露的下丘脑靶点。
生殖细胞 (F2) 和跨代 (F3) EDC 暴露的雌性，但不是 F1，表现出发育延迟和卵泡发生改变。我们报道了控制青春期和排卵的关键下丘脑基因的跨代改变 (、、和 )，并且我们确定了下丘脑多梳组表观遗传抑制剂作为该机制的作用因子。此外，我们发现由于下丘脑多巴胺能信号的丧失，导致多代母性行为 (F1-F3) 减少。使用交叉寄养范式，我们发现，暴露于 EDC 的幼崽由未暴露的母体抚养时，其母性行为表型正常化，但青春期表型无法逆转。
发育暴露于 EDC 混合物的大鼠通过下丘脑的表观遗传重编程表现出性成熟和母性行为的多代和跨代破坏。这些结果引起了对 EDC 混合物对后代影响的关注。https://doi.org/10.1289/EHP8795.
