Department of Integrative Physiology, Gunma University Graduate School of Medicine, Maebashi 371-8511, Japan.
Gunma University Heavy Ion Medical Center, Maebashi 371-8511, Japan.
Int J Mol Sci. 2023 Aug 14;24(16):12765. doi: 10.3390/ijms241612765.
Perfluorooctane sulfonate (PFOS) has been used in a wide variety of industrial and commercial products. The adverse effects of PFOS on the developing brain are becoming of a great concern. However, the molecular mechanisms of PFOS on brain development have not yet been clarified. We investigated the effect of early-life exposure to PFOS on brain development and the mechanism involved. We investigated the change in thyroid hormone (TH)-induced dendrite arborization of Purkinje cells in the primary culture of newborn rat cerebellum. We further examined the mechanism of PFOS on TH signaling by reporter gene assay, quantitative RT-PCR, and type 2 iodothyronine deiodinase (D2) assay. As low as 10 M PFOS suppressed thyroxine (T)-, but not triiodothyronine (T)-induced dendrite arborization of Purkinje cells. Reporter gene assay showed that PFOS did not affect TRα1- and TRβ1-mediated transcription in CV-1 cells. RT-PCR showed that PFOS suppressed D2 mRNA expression in the absence of T in primary cerebellar cells. D2 activity was also suppressed by PFOS in C6 glioma-derived cells. These results indicate that early-life exposure of PFOS disrupts TH-mediated cerebellar development possibly through the disruption of D2 activity and/or mRNA expression, which may cause cerebellar dysfunction.
全氟辛烷磺酸 (PFOS) 已广泛应用于各种工业和商业产品中。PFOS 对发育中大脑的不良影响引起了极大关注。然而，PFOS 对大脑发育的分子机制尚不清楚。我们研究了早期暴露于 PFOS 对大脑发育的影响及其涉及的机制。我们研究了新生大鼠小脑原代培养中甲状腺激素 (TH) 诱导的浦肯野细胞树突分支的变化。我们进一步通过报告基因检测、定量 RT-PCR 和 2 型甲状腺素脱碘酶 (D2) 检测研究了 PFOS 对 TH 信号的作用机制。低至 10μM 的 PFOS 可抑制甲状腺素 (T)，而不是三碘甲状腺原氨酸 (T) 诱导的浦肯野细胞树突分支。报告基因检测表明，PFOS 不会影响 CV-1 细胞中 TRα1 和 TRβ1 介导的转录。RT-PCR 显示 PFOS 在无 T 的情况下抑制原代小脑细胞中 D2 mRNA 的表达。PFOS 还抑制 C6 神经胶质瘤衍生细胞中的 D2 活性。这些结果表明，早期暴露于 PFOS 可能通过破坏 D2 活性和/或 mRNA 表达来破坏 TH 介导的小脑发育，从而导致小脑功能障碍。
