William J. Raum

Prenatal inhibition of hypothalamic sex steroid uptake by cocaine: effects on neurobehavioral sexual differentiation in male rats

Several adrenergically active drugs have been shown to prevent the masculinizing and/or defeminizing effects of testosterone on brain sexual differentiation. We examined the ability of the neuronal norepinephrine uptake blocker, cocaine, to produce similar effects. The ability of cocaine to inhibit sex steroid incorporation into the hypothalamus during a critical period for sexual differentiation of the brain was examined in females treated at birth with testosterone. Sixty minutes after administration, cocaine was observed to inhibit both testosterone and estradiol incorporation into the hypothalamus by approximately 50%. Long-term consequences of prenatal cocaine exposure were studied by injecting Sprague-Dawley dams twice daily with 3, 10 or 30 mg/kg of cocaine hydrochloride on days 15 through 20 of gestation and examining the offspring. In adulthood, cocaine-exposed males, but not females were found to exhibit significantly less marking behavior than controls. Cocaine-exposed males in the 10 mg/kg group tested for sex behavior exhibited demasculinization in some aspects of the behaviors tested. Measurement of plasma hormone levels in this group revealed elevated levels of plasma LH, but normal levels of FSH and testosterone. No differences were observed in cocaine-exposed males with respect to sex organ or adrenal weights, but thymus was approximately 25% smaller compared to control males at 80 days of age. In a separate experiment, dams were treated with 3 mg/kg of cocaine twice daily from days 15 through 21 of gestation and half of the male pups received additional injections twice a day for the first 5 days postnatally.(ABSTRACT TRUNCATED AT 250 WORDS)

Comparison of two weeks versus one week of prenatal ethanol exposure in the rat on gonadal organ weights, sperm count, and onset of puberty

Sprague-Dawley dams from Harlan Ind. (Indianapolis, IN) were administered a fortified ethanol liquid diet containing 35% ethanol derived calories for two weeks (E-2) beginning on day 7 or one week (E-1) beginning on day 13 of gestation and continuing through parturition. Control dams were pair-fed an isocaloric liquid diet containing no ethanol during these periods or remained on lab chow and water. E-2 dams consumed an average of 13.52 g ethanol/kg bwt during the first week of exposure (days 8-14) and 12.50 g ethanol/kg bwt the second week (days 14-20). E-1 dams consumed significantly less than E-2 dams during the second week (9.75 g/kg; p < 0.0001). Although the lower consumption in E-1 dams led to a significant decrease in maternal weight gained during the few days of pregnancy compared to E-2 dams, birthweights of E-1 offspring were significantly heavier than those of E-2 offspring (p < 0.05). No effect of ethanol was detected on anogenital distance at birth in either sex. Puberty was delayed in female offspring of both E-1 and E-2 dams (p < 0.01) as measured by age of vaginal opening. These data suggest that the primary teratogenic actions of ethanol in the rat on fetal growth, as well as delayed puberty in females, occur in the last week of gestation. In adult E-2 males, testis weight was significantly heavier than all other groups when indexed to body weight. No effect of prenatal ethanol exposure was observed on the indexed weights of prostate, epididymis, or seminal vesicles.(ABSTRACT TRUNCATED AT 250 WORDS)

Ethanol Exposure During the Last Week of Gestation in the Rat: Inhibition of the Prenatal Testosterone Surge in Males without Long-Term Alterations in Sex Behavior

In utero ethanol exposure decreases the prenatal testosterone (T) surge in male rats. To determine the functional significance of this suppression, we measured sex behavior in adult litter representatives of pregnant rats that were administered a fortified liquid diet containing 35% ethanol-derived calories from day 15 of gestation through parturition. Control dams were pair-fed an isocaloric liquid diet with the ethanol calories replaced by sucrose. Results from the behavioral studies showed that gonadally intact fetal alcohol-exposed (FAE) males exhibited little masculine sex behavior in the first of four weekly sessions. However, their behavior in the subsequent three tests was indistinguishable from pair-fed controls. Lordosis quotients in the same males following castration and estrogen and progesterone treatment were under 10%. In castrated FAE females, no effects of prenatal ethanol exposure were observed in masculine behaviors following androgen replacement or feminine sex behaviors following estrogen and progesterone replacement. Additional studies measured the duration of prenatal ethanol exposure necessary to inhibit the prenatal T surge in order to determine whether the inhibition was due to a direct effect of the drug. Results revealed an inhibition of the surge in males exposed to ethanol from days 14 through 20 of pregnancy, days 14 through 16 of pregnancy, or days 17 through 20 of pregnancy. A normal surge of T was observed on days 18-19 of gestation in control fetuses. These findings indicate that ethanol does not have to be present in blood at the time of the surge to have an inhibitory effect. They also reveal that the surge can be inhibited with as little as 24-36 h of ethanol exposure prior to its normal appearance on day 18 of gestation. In spite of this inhibition of the prenatal T surge, the behavioral results indicate that normal masculinization and defeminization of sex behavior occurs in FAE males exposed to ethanol after the beginning of the period of differentiation of the hypothalamus and testes.