Prenatal exposure to the phthalate DEHP impacts reproduction-related gene expression in the pituitary.
Prenatal exposure to the phthalate DEHP impacts reproduction-related gene expression in the pituitary.
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DOI：
10.1016/j.reprotox.2021.12.008
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发表时间：
2022-03
期刊：
影响因子：
--
通讯作者：
Raetzman L
中科院分区：
文献类型：
--
作者：
Ge X;Weis K;Flaws J;Raetzman L
邻苯二甲酸盐是用于塑料、个人护理产品和建筑材料等产品的化学物质，导致广泛的接触。先前对小鼠和人类产前暴露于邻苯二甲酸二-（2-乙基己基）酯（DEHP）的研究表明，暴露于DEHP的后代的青春期时间和生殖性能可能受到影响。然而，对垂体的影响，特别是对促性腺激素LH和FSH的信号通路和直接影响尚不清楚。我们假设在胚胎发育的关键时期（e15.5至e18.5）产前暴露于DEHP会由于干扰雄激素和芳烃受体（AhR）信号而导致后代垂体中生殖相关mRNA表达的性别特异性中断。我们发现，体内产前DEHP暴露导致男性Fshb显著增加，而抗雄激素氟他胺导致男性Lhb和Fshb显著增加。dehp暴露后代的AhR靶基因Cyp1b1在两性中均升高。在胚胎垂体培养物中，DEHP代谢物MEHP增加了两性Cyp1a1和Cyp1b1 mRNA的表达，而与AhR拮抗剂共处理可降低Cyp1b1的诱导。GHFT1细胞AhR报告基因检测证实MEHP可以激活AhR信号。MEHP显著降低了两性垂体培养物中Lhb、Fshb和Gnrhr mRNA的表达，但与AhR拮抗剂联合治疗未恢复垂体培养物中Lhb、Fshb和Gnrhr mRNA的表达。总之，我们的数据表明邻苯二甲酸盐可以通过激活AhR信号和改变促性腺激素表达直接影响垂体功能。这表明DEHP对垂体的影响可能导致暴露小鼠和人的生殖功能障碍。
Phthalates are chemicals used in products including plastics, personal care products, and building materials, leading to widespread contact. Previous studies on prenatal exposure to Di-(2-ethylhexyl) phthalate (DEHP) in mice and humans demonstrated pubertal timing and reproductive performance could be affected in exposed offspring. However, the impacts at the pituitary, specifically regarding signaling pathways engaged and direct effects on the gonadotropins LH and FSH, are unknown. We hypothesized prenatal exposure to DEHP during a critical period of embryonic development (e15.5 to e18.5) will cause sex-specific disruptions in reproduction-related mRNA expression in offspring’s pituitary due to interference with androgen and aryl hydrocarbon receptor (AhR) signaling. We found that prenatal DEHP exposure in vivo caused a significant increase in Fshb specifically in males, while the anti-androgen flutamide caused significant increases in both Lhb and Fshb in males. AhR target gene Cyp1b1 was increased in both sexes in DEHP-exposed offspring. In embryonic pituitary cultures, the DEHP metabolite MEHP increased Cyp1a1 and Cyp1b1 mRNA in both sexes and Cyp1b1 induction was reduced by co-treatment with AhR antagonist. AhR reporter assay in GHFT1 cells confirmed MEHP can activate AhR signaling. Lhb, Fshb and Gnrhr mRNA were significantly decreased in both sexes by MEHP, but co-treatment with AhR antagonist did not restore mRNA levels in pituitary culture. In summary, our data suggest phthalates can directly affect the function of the pituitary by activating AhR signaling and altering gonadotropin expression. This indicates DEHP’s impacts on the pituitary could contribute to reproductive dysfunctions observed in exposed mice and humans.
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