Department of Internal Medicine, Qilu Hospital of Shandong University, 107 West Wenhua Road, Jinan, Shandong, 250012, China.
Jinan Zhangqiu District Hospital of TCM, Jinan, Shandong, 250200, China.
Toxicology. 2021 Jun 30;458:152830. doi: 10.1016/j.tox.2021.152830. Epub 2021 Jun 7.
Previous studies have suggested that bisphenol A (BPA) has a toxic effect on bone development; however, its pathological mechanism has not been fully elucidated. In the present study, pregnant Wistar rats were intragastrically administered BPA (10 μg/kg per day) during gestational days 14-21. Then, bone tissues were obtained from neonatal rats on postnatal day 1 for histological analysis, and the bone mass of adult rat offspring was analyzed by micro-CT at postnatal week 10. Furthermore, osteoprogenitors from neonatal rats were obtained and treated with various concentrations of BPA in vitro to clarify the associated mechanism. In vivo, we found that prenatal BPA exposure reduced body weight and body length in female neonatal rats but not in male neonatal rats. Meanwhile, BPA exposure during pregnancy delayed bone development and reduced bone mass only in female rat offspring. Moreover, BPA exposure during pregnancy inhibited osteogenic function and downregulated the transforming growth factor β (TGF β) signaling pathway in the bone tissue of female neonatal rats. Our in vitro findings further indicated that various concentrations of BPA suppressed the osteogenic function of osteoprogenitors by downregulating the TGFβ signaling pathway. Meanwhile, BPA downregulated H3K9ac and expression levels of TGFβ via the ERβ/HDAC5 signaling pathway. Collectively, this research revealed that prenatal BPA exposure impairs bone development and bone mass accumulation in female rat offspring, which was attributed to inhibitory osteogenic function via the ERβ/HDAC5/TGFβ signaling pathway.
先前的研究表明双酚 A（BPA）对骨骼发育有毒性作用，但它的病理机制尚未完全阐明。在本研究中，妊娠 Wistar 大鼠在妊娠第 14-21 天经胃内给予 BPA（每天 10μg/kg）。然后，在产后第 1 天从新生大鼠中获取骨组织进行组织学分析，并在产后第 10 周通过 micro-CT 分析成年大鼠后代的骨量。此外，从小鼠中获得成骨前体细胞并在体外用不同浓度的 BPA 处理，以阐明相关机制。在体内，我们发现产前 BPA 暴露降低了雌性新生大鼠的体重和体长，但对雄性新生大鼠没有影响。同时，妊娠期间 BPA 暴露仅延迟了雌性大鼠后代的骨骼发育并降低了骨量。此外，妊娠期间 BPA 暴露抑制了雌性新生大鼠骨组织中的成骨功能，并下调了转化生长因子 β（TGFβ）信号通路。我们的体外研究结果进一步表明，不同浓度的 BPA 通过下调 TGFβ 信号通路抑制成骨前体细胞的成骨功能。同时，BPA 通过 ERβ/HDAC5 信号通路下调 H3K9ac 和 TGFβ 的表达水平。总之，这项研究揭示了产前 BPA 暴露会损害雌性大鼠后代的骨骼发育和骨量积累，这归因于通过 ERβ/HDAC5/TGFβ 信号通路抑制成骨功能。
