Endocrine disrupting chemicals (EDCs), such as bisphenol A (BPA) and 17α-ethinylestradiol (EE2), can have far reaching health effects, including transgenerational abnormalities in offspring that never directly contacted either chemical. We previously reported reduced fertilization rates and embryo survival at F2 and F3 generations caused by 7-day embryonic exposure (F0) to 100 μg/L BPA or 0.05 μg/L EE2 in medaka. Crossbreeding of fish in F2 generation indicated subfertility in males. To further understand the mechanisms underlying BPA or EE2-induced adult onset and transgenerational reproductive defects in males, the present study examined the expression of genes regulating the brain–pituitary–testis (BPT) axis in the same F0 and F2 generation male medaka. Embryonic exposure to BPA or EE2 led to hyperactivation of brain and pituitary genes, which are actively involved in reproduction in adulthood of the F0 generation male fish, and some of these F0 effects continued to the F2 generation (transgenerational effects). Particularly, the F2 generation inherited the hyperactivated state of expression for kisspeptin (kiss1 and kiss2) and their receptors (kiss1r and kiss2r), and gnrh and gnrh receptors. At F2 generation, expression of DNA methyltransferase 1 (dnmt1) decreased in brain of the BPA treatment lineage, while EE2 treatment lineage showed increased dnmt3bb expression. Global hypomethylation pattern was observed in the testis of both F0 and F2 generation fish. Taken together, these results demonstrated that BPA or EE2-induced transgenerational reproductive impairment in the F2 generation was associated with alterations of reproductive gene expression in brain and testis and global DNA methylation in testis.

中文翻译：

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双酚 A 和 17α-炔雌醇诱导的青鳉、Oryzias latipes 脑-垂体-睾丸轴的跨代基因表达差异。

双酚 A (BPA) 和 17α-炔雌醇 (EE2) 等内分泌干扰化学物质 (EDC) 可能对健康产生深远影响，包括从未直接接触过这两种化学物质的后代出现跨代异常。我们之前报道过，青鳉胚胎暴露于 100 μg/L BPA 或 0.05 μg/L EE2 7 天（F0）会导致 F2 和 F3 代的受精率和胚胎存活率降低。F2代鱼的杂交表明雄性的生育力低下。为了进一步了解 BPA 或 EE2 诱导的雄性成年发病和跨代生殖缺陷的机制，本研究检查了同一 F0 和 F2 代雄性青鳉中调节脑-垂体-睾丸 (BPT) 轴的基因的表达。胚胎接触 BPA 或 EE2 会导致大脑和垂体基因过度激活，这些基因积极参与 F0 代雄性鱼成年后的繁殖，其中一些 F0 效应持续到 F2 代（跨代效应）。特别是，F2 代继承了 Kisspeptin（ kiss1和Kiss2）及其受体（kiss1r和Kiss2r）以及gnrh和gnrh受体的过度激活表达状态。在 F2 代，BPA 处理谱系的大脑中DNA 甲基转移酶 1 ( dnmt1 ) 的表达下降，而 EE2 处理谱系的dnmt3bb表达增加。在 F0 和 F2 代鱼的睾丸中观察到整体低甲基化模式。总而言之，这些结果表明，BPA 或 EE2 诱导的 F2 代跨代生殖障碍与大脑和睾丸中生殖基因表达的改变以及睾丸中整体 DNA 甲基化有关。