ゼブラフィッシュ胚におけるビスフェノール類の化合物特異的なエストロゲン様作用および発生影響に関する作用機序の検討

抄録

The use of bisphenol A (BPA) has been replaced with bisphenol analogues (BPs) mostly due to its endocrine disruptive effect. However, toxicity of many of BPA alternatives remains poorly understood. This study aimed to evaluate estrogenic and developmental responses to BPA and its alternatives and to understand possible mechanisms of developmental toxicity using zebrafish embryos. Embryos exposed to BP alone or in combination with an estrogen receptor (ER) antagonist ICI were collected for quantifying the expression level of an ER target gene CYP19A1b or were observed for developmental toxicity. RNA-seq analysis was conducted for BPA, BP C2 and Bis-MP. The expression of CYP19A1b was induced by most of tested BPs (10 out of 14) in a concentration-dependent manner, with stronger potency for BP C2, Bis-MP and BPAF than BPA. Similarly, these 3 BPs caused cardiovascular toxicity with greater potency than BPA. ICI rescued cardiovascular toxicity caused by these 3 BPs, but not by BPA. In the same exposure condition, however, ICI suppressed the CYP19A1b induction by BPA and Bis-MP, but not by BP C2 or BPAF. RNA-seq analysis showed that alterations in lipid metabolism and oxidative stress response pathways may be involved in cardiovascular toxicity caused by BP C2 and Bis-MP, whereas the down regulation of G-protein coupled receptor pathway may be related to BPA-induced cardiovascular toxicity. In conclusion, some of BPA alternatives showed greater estrogenic potency and developmental toxicity than BPA. The mechanism of cardiovascular toxicity appears to differ among different BPs.