α-Lipoic acid potentially targets AMP-activated protein kinase and energy production in the fetal brain to ameliorate dioxin-produced attenuation in fetal steroidogenesis

• Published in: Journal of toxicological sciences Vol. 42; no. 1; pp. 13 - 23
• Main Authors: Takeda, Tomoki, Matsuo, Yuki, Nishida, Kyoko, Fujiki, Akihisa, Hattori, Yukiko, Koga, Takayuki, Ishii, Yuji, Yamada, Hideyuki
• Format: Journal Article
• Language: English
• Published: Japan The Japanese Society of Toxicology 2017; Japan Science and Technology Agency
• Subjects: Adenosine Triphosphate - metabolism; AMP; AMP-activated protein kinase; AMP-activated protein kinase (AMPK); AMP-Activated Protein Kinases - metabolism; Animals; Attenuation; Brain; Brain - drug effects; Brain - metabolism; Dioxin; Dioxins; Female; Fetus; Fetus - drug effects; Fetus - metabolism; Fetuses; Gonadotropin-releasing hormone; Gonadotropin-Releasing Hormone - genetics; Gonadotropins; Hypothalamus; Kidney - drug effects; Kidney - metabolism; Kinases; Lipoic acid; Liver - drug effects; Liver - metabolism; Luteinizing hormone; Luteinizing Hormone - blood; Luteinizing Hormone - genetics; Male; Myocardium - metabolism; Phosphoproteins - genetics; Phosphoproteins - metabolism; Pituitary; Pituitary (anterior); Polychlorinated Dibenzodioxins - toxicity; Pregnancy; Protein kinase; Proteins; Rats; Rats, Wistar; Receptors, LHRH - genetics; Reduction; RNA, Messenger - metabolism; Steroidogenesis; Supplements; TCDD; Testes; Testis - drug effects; Testis - metabolism; Thiamine; Thioctic Acid - pharmacology; Toxicology; Tricarboxylic acid (TCA) cycle; Tricarboxylic acid cycle; Vitamin B; α-Lipoic acid
• ISSN: 0388-1350; 1880-3989
• 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.