Ge Xiyu, Weis Karen, Flaws Jodi, Raetzman Lori
Department of Molecular and Integrative Physiology, University of Illinois at Urbana-Champaign, 524 Burrill Hall, 407 South Goodwin Avenue, Urbana, IL, 61801, United States.
Department of Comparative Biosciences, University of Illinois at Urbana-Champaign, 2001 S. Lincoln Avenue, Urbana, IL, 61802, United States; Institute for Genomic Biology, University of Illinois at Urbana-Champaign, 1206 W. Gregory Drive, Urbana, IL, 61801, United States.
Reprod Toxicol. 2022 Mar;108:18-27. doi: 10.1016/j.reprotox.2021.12.008. Epub 2021 Dec 22.
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.
邻苯二甲酸盐是用于包括塑料、个人护理产品和建筑材料等产品中的化学物质，导致广泛接触。先前关于小鼠和人类孕期暴露于邻苯二甲酸二（2-乙基己基）酯（DEHP）的研究表明，暴露后代的青春期时间和生殖性能可能会受到影响。然而，在垂体水平的影响，特别是关于参与的信号通路以及对促性腺激素LH和FSH的直接影响，尚不清楚。我们假设在胚胎发育的关键时期（e15.5至e18.5）孕期暴露于DEHP会由于干扰雄激素和芳烃受体（AhR）信号通路而导致后代垂体中与生殖相关的mRNA表达出现性别特异性紊乱。我们发现，体内孕期暴露于DEHP会导致Fshb显著增加，特别是在雄性中，而抗雄激素氟他胺会导致雄性中Lhb和Fshb均显著增加。AhR靶基因Cyp1b1在暴露于DEHP的后代两性中均增加。在胚胎垂体培养中，DEHP代谢产物MEHP增加了两性的Cyp1a1和Cyp1b1 mRNA，并且与AhR拮抗剂共同处理可降低Cyp1b1的诱导。GHFT1细胞中的AhR报告基因检测证实MEHP可激活AhR信号通路。MEHP使两性的Lhb、Fshb和Gnrhr mRNA均显著降低，但与AhR拮抗剂共同处理并未恢复垂体培养中的mRNA水平。总之，我们的数据表明邻苯二甲酸盐可通过激活AhR信号通路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在暴露的小鼠和人类中观察到的生殖功能障碍。
