There is concern about adverse effects of thyroid hormone (TH) disrupting chemicals on TH-dependent brain development. Bisphenol A (BPA) and its analogues, such as bisphenol F (BPF), are known to have the potential to interfere with TH signaling, but whether they affect TH-dependent brain development is not yet well documented. Here, we conducted the T3-induced Xenopus laevis metamorphosis assay, a model for studying TH signaling disruption, to investigate the effects of BPA and BPF (10–1000 nM) on TH signaling in brains and subsequent brain development. While 48-hr treatment with 1 nM T3 dramatically upregulated TH-response gene expression in X. laevis brains at stage 52, 1000 and/or 100 nM BPA also caused significant transcriptional up-regulation of certain TH-response genes, whereas BPF had slighter effects, suggesting limited TH signaling disrupting activity of BPF in brains relative to BPA at the lack of TH. In the presence of 1 nM T3, 1000 and/or 100 nM of BPF as well as BPA antagonized T3-induced TH-response gene expression, whereas lower concentrations agonized T3 actions on certain TH-response genes, displaying an apparently biphasic effect on TH signaling. After 96 h exposure, T3 induced brain morphological remodeling coupled with cell proliferation and neuronal differentiation, whereas both BPA and BPF generally antagonized T3-induced changes in a concentration-dependent manner, with weak or no effects of bisphenol exposure alone. Overall, all results show that BPA and BPF interfered with TH signaling in Xenopus brains, especially in the presence of TH, and subsequently affected TH-dependent brain development. Given the evolutionary conservation of TH-dependent brain development among vertebrates, our findings from X. laevis warrant further studies to reveal potential influences of bisphenols on TH-dependent brain development in higher vertebrates.

人们担心甲状腺激素 (TH) 干扰化学物质对 TH 依赖性大脑发育的不利影响。双酚 A (BPA) 及其类似物，如双酚 F (BPF)，已知具有干扰 TH 信号传导的潜力，但它们是否影响 TH 依赖性大脑发育尚未得到充分证明。在这里，我们进行了 T3 诱导的非洲爪蟾变态试验，这是一种研究 TH 信号中断的模型，以研究 BPA 和 BPF（10-1000 nM）对大脑中 TH 信号传导和随后的大脑发育的影响。虽然用 1 nM T3 处理 48 小时显着上调X. laevis 中的TH 反应基因表达处于 52、1000 和/或 100 nM BPA 阶段的大脑也导致某些 TH 反应基因的显着转录上调，而 BPF 的影响较小，这表明相对于缺乏 TH 时的 BPA，TH 信号破坏大脑中 BPF 的活性有限. 在存在 1 nM T3 的情况下，1000 和/或 100 nM BPF 以及 BPA 拮抗 T3 诱导的 TH 反应基因表达，而较低浓度会激动 T3 对某些 TH 反应基因的作用，显示出对 TH 的明显双相效应信令。暴露 96 小时后，T3 诱导大脑形态重塑以及细胞增殖和神经元分化，而 BPA 和 BPF 通常以浓度依赖性方式拮抗 T3 诱导的变化，单独暴露双酚的影响较弱或没有影响。总的来说，非洲爪蟾的大脑，尤其是在存在 TH 的情况下，随后会影响 TH 依赖性大脑发育。鉴于脊椎动物中 TH 依赖性大脑发育的进化保守性，我们从X. laevis的发现值得进一步研究，以揭示双酚对高等脊椎动物 TH 依赖性大脑发育的潜在影响。