Adrenal-mediated rather than direct effects of nicotine as a basis of altered sex steroid synthesis in fetal and neonatal rat.

Prenatal nicotine interferes with rat sexual brain differentiation and may influence human puberty. We studied effects of nicotine and cotinine on perinatal steroid synthesis in offspring of time-pregnant rats. In vitro, cotinine inhibited testosterone synthesis in neonatal rat testis. Both compounds inhibited the brain aromatase of gestational day (GD) 19 male fetuses. Effective concentrations were higher than levels in maternal plasma and fetal tissue at GD 19 after nicotine treatment from GD 12, even though nicotine accumulated in fetal brain. In view of a dual effect of nicotine in male GD 18 fetuses, decreasing plasma testosterone and increasing corticosterone [Dev Brain Res 1991;62:23-31], we administered metyrapone on GD 17 to nicotine-treated dams. 11beta-Hydroxylase inhibition completely reversed the nicotine-induced reduction of plasma testosterone at GD 18. POMC mRNA in anterior pituitary of nicotine-exposed GD 18 fetuses was reduced, probably as a result of corticosterone feedback. These data reveal a novel type of interaction of nicotine with the fetal gonadal axis involving the adrenal.