Neonatal Exposure to Valproate Induces Long-Term Alterations in Steroid Hormone Levels in the Brain Cortex of Prepubertal Rats

• Published in: International journal of molecular sciences 2023-04, Vol.24 (7), p.6681
• Main Authors: Kim, Soon-Ae, Jang, Eun-Hye, Lee, Jangjae, Cho, Sung-Hee
• Format: Article
• Language: English
• Subjects: Animal models; Animals; Autism; autism spectrum disorder; Autism Spectrum Disorder - metabolism; Brain; Brain - metabolism; Cell cycle; Cerebral Cortex; Corticosteroids; Cortisol; Cytochrome P450; Cytochromes P450; Disease Models, Animal; Divalproex; Enzymes; Epigenetic inheritance; Epigenetics; Epilepsy; Estradiol - metabolism; Estrogen; Estrogens; Exposure; Female; Gene expression; Gene regulation; Genes; Glucocorticoids; Histone deacetylase; Hormones; Humans; Hydrocortisone - metabolism; Hydroxysteroids; Instrument industry; Long-term effects; Male; Metabolism; Metabolites; neonatal; Neonates; Nervous system; neurosteroid; Neurosteroids - metabolism; Neurotransmission; Pregnancy; Pregnanolone; Prenatal Exposure Delayed Effects - metabolism; Progesterone; Progestin; Rats; RNA; sex-specific difference; steroid hormone; Steroids; Teratogenicity; Transcription factors; Valproic acid; Valproic Acid - toxicity
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms24076681

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 ( ) expression was reduced in the prepubertal male cortex. Progesterone and allopregnanolone levels decreased, and 3β-hydroxysteroid dehydrogenase 1 gene ( ) 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 ( ) 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.