Takeda Tomoki, Matsuo Yuki, Nishida Kyoko, Fujiki Akihisa, Hattori Yukiko, Koga Takayuki, Ishii Yuji, Yamada Hideyuki
Graduate School of Pharmaceutical Sciences, Kyushu University.
J Toxicol Sci. 2017;42(1):13-23. doi: 10.2131/jts.42.13.
Our previous studies demonstrated that treating pregnant rats with dioxins, including 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), targets the pituitary expression of luteinizing hormone (LH) to attenuate testicular steroidogenesis in fetuses, resulting in the imprinting of sexual immaturity of the offspring after reaching maturity. Furthermore, we found that although TCDD disturbs the tricarboxylic acid (TCA) cycle in the fetal hypothalamus, maternal co-treatment with α-lipoic acid (α-LA), a cofactor of the TCA cycle, restores a TCDD-produced reduction in the LH-evoked steroidogenesis as well as the TCA cycle activity in fetuses. However, the mechanism underlying the beneficial effect of α-LA remains to be fully elucidated. To address this issue, we compared the effect of α-LA with that of thiamine, another cofactor of the TCA cycle. As with α-LA, supplying thiamine to dams exposed to TCDD alleviates the reduced level of not only hypothalamic ATP but also pituitary LH and testicular steroidogenic protein in fetuses. However, thiamine had a much weaker effect than α-LA. In agreement with ATP attenuation, TCDD activated AMP-activated protein kinase (AMPK), a negative regulator of LH production, whereas the supplementation of α-LA allowed recovery from this defect. Furthermore, α-LA restored the TCDD-produced reduction in the pituitary expression of the receptor for gonadotropin-releasing hormone (GnRH), an upstream regulator of LH synthesis. These results suggest that α-LA rescues TCDD-produced attenuation during fetal steroidogenesis due not only to facilitation of energy production through the TCA cycle but also through suppression of AMPK activation, and the pituitary GnRH receptor may serve as a mediator of these effects.
我们之前的研究表明，用二噁英（包括2,3,7,8-四氯二苯并对二噁英（TCDD））处理怀孕大鼠，会靶向黄体生成素（LH）的垂体表达，从而减弱胎儿的睾丸类固醇生成，导致后代成熟后出现性不成熟的印记。此外，我们发现，尽管TCDD会扰乱胎儿下丘脑的三羧酸（TCA）循环，但母体同时给予α-硫辛酸（α-LA，TCA循环的一种辅助因子），可恢复TCDD导致的LH刺激的类固醇生成减少以及胎儿的TCA循环活性。然而，α-LA有益作用的潜在机制仍有待充分阐明。为解决这个问题，我们比较了α-LA与TCA循环的另一种辅助因子硫胺素的作用。与α-LA一样，给暴露于TCDD的母鼠供应硫胺素，不仅可减轻胎儿下丘脑ATP水平的降低，还可减轻垂体LH和睾丸类固醇生成蛋白水平的降低。然而，硫胺素的作用比α-LA弱得多。与ATP减少一致，TCDD激活了AMP激活的蛋白激酶（AMPK），这是LH产生的负调节因子，而补充α-LA可使这种缺陷恢复。此外，α-LA恢复了TCDD导致的促性腺激素释放激素（GnRH，LH合成的上游调节因子）垂体受体表达的降低。这些结果表明，α-LA挽救了TCDD导致的胎儿类固醇生成减弱，这不仅是因为通过TCA循环促进了能量产生，还因为抑制了AMPK激活，并且垂体GnRH受体可能是这些作用的介导者。
