Intrauterine Growth Restriction Alters Hippocampal Expression and Chromatin Structure of Cyp19a1 Variants

We evaluated the impact of uteroplacental insufficiency (UPI), and subsequent intrauterine growth restriction (IUGR), on serum testosterone and hippocampal expression of Cyp19a1 variants and aromatase in rats. Additionally, we determined UPI induced histone modification of the promoter regions of Cyp19a1 variants using chromatin immunoprecipitation. Cyp19a1 is the gene encoding the protein aromatase, that catalyzes the biosynthesis of estrogens from androgens and is necessary for masculinization of the brain. IUGR was induced via bilateral uterine artery. UPI increased serum testosterone in day of life 0 (D(0)) and day of life 21 (D(21)) IUGR males to 224% and 299% of control values, respectively. While there was no significant impact of UPI on testosterone in D(0) females, testosterone in D(21) IUGR females was 187% of controls. Cyp19a1 variant 1.f and variant II are expressed in the rat hippocampus at D(0) and D(21). UPI significantly reduced expression of Cyp19a1 variant 1.f in D(0) males, with no impact in females. Similarly at D(0), UPI reduced expression of aromatase, the protein encoded by Cyp19a1, in males. Dimethylation of H3K4 was increased in the promoter region of variant 1.f (P1.f) and trimethylation of H3K4 was decreased in the promoter region of variant II (PII). At D(21), dimethylation of H3K4 is significantly reduced in PII of IUGR males. We conclude that UPI increases serum testosterone and reduces Cyp19a1 variant 1.f expression in the hippocampus of D(0) IUGR males. Additionally, UPI alters the chromatin structure of CYP19a1 at both D(0) and D(21).