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Neonatal Exposure to Valproate Induces Long-Term Alterations in Steroid Hormone Levels in the Brain Cortex of
Soon-Ae Kim1, Eun-Hye Jang1, Jangjae Lee2,3
1Department of Pharmacology, School of Medicine, Eulji University, Daejeon 34824, Republic of Korea.
Insights
Early valproic acid exposure in rats alters brain steroid levels and gene expression long-term, with sex-specific effects. This research highlights potential neurosteroid metabolic disruptions from developmental chemical exposure.
Area of Science:
- Neuroscience
- Endocrinology
- Developmental Toxicology
Background:
- Valproic acid (VPA) is used for epilepsy and mood disorders but is teratogenic.
- VPA's epigenetic effects and use in autism spectrum disorder (ASD) animal models are known.
- Long-term effects of early VPA exposure on brain glucocorticoid and neurosteroid synthesis are understudied.
Purpose of the Study:
- Investigate long-term changes in metabolic alterations and gene expression following early VPA exposure.
- Examine sex-specific differences in neurosteroid profiles and gene regulation.
- Assess effects on estradiol, progesterone, allopregnanolone, and cortisol pathways.
Main Methods:
- Utilized metabolic steroid profiling in rat cerebral cortex samples.
- Administered VPA (400 mg/kg) to neonatal rats.
- Analyzed gene expression of key steroidogenic enzymes and receptors (Cyp19a1, Hsd3b1, Nr3c1).
- Compared prepubertal and adult (8-week-old) rat outcomes.
Main Results:
- Neonatal VPA exposure reduced estradiol and Cyp19a1 expression in males.
- Progesterone, allopregnanolone, and Hsd3b1 expression decreased in females.
- Cortisol levels increased and Nr3c1 expression decreased in both sexes.
- Adult rats showed some normalized steroid levels but persistent changes in specific pathways.
Conclusions:
- Early VPA exposure induces lasting neurosteroid metabolic alterations in the brain.
- These effects exhibit significant sex-specific differences.
- Developmental exposure to environmental chemicals can have long-term neuroendocrine consequences.
Abstract:
Valproic acid (VPA) is a known drug for treating epilepsy and mood disorders; however, it is not recommended for pregnant women because of its possible teratogenicity. VPA affects neurotransmission and gene expression through epigenetic mechanisms by acting as a histone deacetylase inhibitor and has been used to establish animal models of autism spectrum disorder (ASD). However, studies on the long-term effects of early exposure to VPA on glucocorticoid and neurosteroid synthesis in the brain are lacking. Therefore, this study aimed to investigate the long-term changes in metabolic alterations and gene expression regulation according to sex, using metabolic steroid profiling data from cerebral cortex samples of rats four weeks after VPA exposure (400 mg/kg). In neonatal VPA-exposed models, estradiol levels decreased, and cytochrome P450 19A1 gene (Cyp19a1) expression was reduced in the prepubertal male cortex. Progesterone and allopregnanolone levels decreased, and 3β-hydroxysteroid dehydrogenase 1 gene (Hsd3b1) expression was also downregulated in the prepubertal female cortex. Furthermore, cortisol levels increased, and mRNA expression of the nuclear receptor subfamily 3 group C member 1 gene (Nr3c1) was downregulated in the cortices of both sexes. Unlike the neonatal VPA-exposed models, although a decrease in progestin and estradiol levels was observed in females and males, respectively, no differences were observed in cortisol levels in the cortex tissues of 8-week-old adult rats administered VPA for four weeks. These results indicate that early environmental chemical exposure induces long-term neurosteroid metabolic effects in the brain, with differences according to sex.
