School of Pharmaceutical Sciences, Ohu University, Japan.
J Toxicol Sci. 2013;38(3):485-94. doi: 10.2131/jts.38.485.
Recent studies have reported that bisphenol A (BPA) influences brain development in fetal exposure to mice. The X-chromosome codes many neurodevelopment-related genes leading to abnormal development, such as mental retardation and intellectual deficiency. For females, most of expressions of X-linked genes are regulated by X-chromosome inactivation (XCI), which occurs during fetal period, and this mechanism is regulated by Xist and its antisense, Tsix. To clarify the possibility of X-mediated effect as a mechanism of neurodevelopmental disorders by BPA, pregnant ICR mice were orally administered 0.02 or 50 mg/kg of BPA on gestational days 6 and 15. Postnatally at days 2, 4 and weeks 3 and 7, mRNA expression of XCI-regulating factors (Xist and Tsix), X-linked neurodevelopment-related genes (Fmr1, Gdi1, Nlgn3, Pak3 and Ophn1), and sexual differentiation-related genes (ERα, ERβ and AR) were examined in cerebrums of female pups. Anogenital distance (AGD) and serum estradiol were also examined. In the 50 mg/kg exposed-group, reduced Xist, Fmr1, Gdi1, Nlgn3, and Pak3 and increased Tsix were observed simultaneously. Moderately reduced Xist, Gdi1, Nlgn3 and Pak3 were observed at 0.02 mg/kg BPA. ERα, ERβ and AR expression changes, shortened AGDs and reduced estradiol levels were observed in each exposure group. Fetal exposure to BPA changed expression of XCI-regulating factors and may alter the expression levels of X-linked neurodevelopment-related genes disrupting the XCI mechanism and function. This X-mediated effect is considered one of the mechanisms of various BPA-induced neurodevelopmental disorders.
最近的研究报告称，双酚 A（BPA）会影响胎儿暴露于小鼠的大脑发育。X 染色体编码许多与神经发育相关的基因，导致异常发育，如智力迟钝和智力缺陷。对于女性来说，大多数 X 连锁基因的表达都受到 X 染色体失活（XCI）的调节，这种失活发生在胎儿期，这个机制受到 Xist 和其反义 RNA Tsix 的调节。为了阐明 BPA 作为神经发育障碍机制的 X 介导效应的可能性，将 ICR 孕鼠在妊娠第 6 天和第 15 天经口给予 0.02 或 50mg/kg 的 BPA。在产后第 2、4 天以及第 3 和第 7 周，检测雌性幼鼠大脑中 XCI 调节因子（Xist 和 Tsix）、X 连锁神经发育相关基因（Fmr1、Gdi1、Nlgn3、Pak3 和 Ophn1）和性别分化相关基因（ERα、ERβ 和 AR）的 mRNA 表达情况。还检测了肛门生殖器距离（AGD）和血清雌二醇水平。在 50mg/kg 暴露组中，观察到 Xist、Fmr1、Gdi1、Nlgn3 和 Pak3 表达减少，同时 Tsix 表达增加。在 0.02mg/kg BPA 暴露组中，观察到 Xist、Gdi1、Nlgn3 和 Pak3 表达中度减少。在每个暴露组中，还观察到 ERα、ERβ 和 AR 表达变化、AGD 缩短和雌二醇水平降低。BPA 对胎儿的暴露改变了 XCI 调节因子的表达，并可能改变 X 连锁神经发育相关基因的表达水平，从而破坏 XCI 机制和功能。这种 X 介导的效应被认为是 BPA 引起的各种神经发育障碍的机制之一。
