Androgen threshold to activate copulation differs in male rats prenatally exposed to alcohol, stress, or both factors.

Few male rats prenatally exposed to a combination of alcohol and stress copulate spontaneously. This study determined adult sensitivity to testosterone (T) in males prenatally exposed to alcohol, to stress, or to both factors. Sexually naive males were tested with receptive females following castration and implantation of 20-, 30-, or 45-mm Silastic T-filled capsules. Serum T levels provided by these implants were measured. The behavior shown by males exposed only to prenatal alcohol did not differ from untreated control animals at any T dosage. Prenatal stress alone diminished the copulatory potential below control levels only when the intermediate T dosage was provided. Few males exposed to both alcohol and stress copulated under the lowest or the intermediate dose of adult T replacement, but most ejaculated normally when the largest capsule was implanted. The threshold to the sexual behavior-activating-properties of adult T exposure was moderately raised by prenatal stress but was severely affected when prenatal stress was combined with alcohol. We conclude that a diminished sensitivity to androgen in adulthood underlies some copulatory deficits resulting from treatments that alter fetal T levels. Such deficits may be concealed when behavior is evaluated in gonadally intact animals.

Fetal alcohol exposure blocks full masculinization of the dorsolateral nucleus in rat spinal cord.

Male rats prenatally exposed to a combination of stress and ethanol show severely impaired ejaculatory patterns. This study examined two sexually dimorphic nuclei in the lumbar spinal cord implicated in the control of male copulatory reflexes in rats whose mothers were exposed to alcohol, to stress, or to both treatments during pregnancy. Alcohol exposure led to a marked decrease (22%) in the number of motor neurons in the dorsolateral nucleus (DLN) of the adult male offspring, but no significant change in cell count was detectable in the sexually dimorphic nucleus of the bulbocavernosus (SNB). The combination of alcohol and stress did not enhance the effect on the DLN above that produced by alcohol alone. Somal sizes in the DLN and SNB were not altered by any of the treatment conditions. Alcohol exposure probably leads to incomplete masculinization of the DLN in male rats by decreasing testicular steroidogenesis during the fetal stage(s) when sexual differentiation is ongoing in that CNS structure.

Prenatal alcohol and stress interact to attenuate ejaculatory behavior, but not serum testosterone or LH in adult male rats.

Restraint stress reduced blood alcohol levels in pregnant rats given a liquid alcohol diet. The male offspring prenatally exposed to both stress and alcohol failed to ejaculate spontaneously, although they copulated normally following exogenous testosterone (T) administration. Males prenatally exposed only to alcohol or only to stress showed no behavioral deficits. Adult serum T and luteinizing hormone levels were normal in both of the fetal alcohol exposed male groups. It appears that the androgen threshold for ejaculatory behavior is elevated in males prenatally exposed to alcohol plus stress and cannot be realized with normal testosterone titers, but it can be attained with exogenous hormone administration. Presumably the alcohol and stress combination interfered with ontogenetic patterns of T needed to fully masculinize the fetal nervous system.

Critical periods of sensitivity of sexually dimorphic spinal nuclei to prenatal testosterone exposure in female rats.

Male rats normally have more neurons than do females in two nuclei of the lumbar spinal cord, the spinal nucleus of the bulbocavernosus (SNB) and the dorsolateral nucleus (DLN). Female rats exposed to testosterone propionate (TP) on the 2 days of gestation (Days 18 and 19) when males normally experience a surge in plasma testosterone showed a maximal increase in both SNB and DLN neuronal number. TP exposure just prior to, or following, Days 18 and 19 led to smaller increments. Administration of a small (5 microg) dose of TP after birth, while having no effect by itself, synergized with prenatal TP to enhance the number of SNB neurons. DLN neurons were less responsive to postnatal TP. The somal and nuclear size of SNB, but not DLN, neurons was increased by perinatal TP. Paradoxically, the number of DLN neurons with large somas (1358 microm2 or larger) was reduced by perinatal TP, a finding congruent with a previous report that females and feminized males have more of these large DLN neurons than control males. Our data suggest an exquisite sensitivity of the developing spinal nuclei to the timing of hormonal surges normally found in fetal males. Exposure to androgens during a brief prenatal period is needed to assure responsiveness to the low amounts of androgen circulating during neonatal ontogeny, when the process of sexual differentiation is completed.

Sexually dimorphic areas in the rat medial amygdala: resistance to the demasculinizing effect of prenatal stress.

Exposure to prenatal stress blocks full masculinization of several sexually dimorphic nuclei in the brain and spinal cord of male rats. We now compare the adult volume of the medical amygdala (MA) and two of its component cell groups, posterodorsal (MePD) and posteroventral (MePV), in prenatally stressed male rats and nonstressed males and females. Previous reports of sex differences (male > female) in the overall size of the MA and the MePD component were confirmed, and we identified a previously unreported sex difference (male > female) in MePV. Prenatal stress had no effect on the size of the total MA, or of the MePD or MePV in males. Maternal stress attenuates the surge in plasma testosterone (T) which normally occurs on days 18 and 19 of gestation in male rats. This brief suppression of T during prenatal development leads to incomplete masculinization of some sexually dimorphic features of the CNS (i.e. the SDN-MPOA of the hypothalamus, and SNB and DLN of the spinal cord) but not others (i.e. the MA, MePD, and MePV). The selective effects of prenatal stress on neural differentiation may be due to differences in the onset and duration of the periods when each of these structures in most sensitive to T and/or its metabolites.

Male and female sexual behavior potential of male rats prenatally exposed to the influence of alcohol, stress, or both factors.

Adult sexual behaviors were characterized in male rats prenatally exposed to ethanol, stress, or ethanol combined with stress; 60% to 75% of each group exhibited female-typical lordosis. A substantial proportion of males subjected to alcohol (44%) or to alcohol with stress (54%) failed to ejaculate. The adult genitalia and testicular size appeared normal in all groups. Either alcohol or stress can suppress fetal plasma testosterone. Thus, exposing pregnant dams to alcohol, particularly in association with stress, may alter the hormonal milieu of their male fetuses sufficiently to block full masculinization and defeminization of sexually dimorphic copulatory behavior potentials, but not anatomy. It appears that certain pharmacological and stressful factors can interact during fetal ontogeny to influence the process of sexual behavior differentiation.

Prenatal beta-endorphin can modulate some aspects of sexual differentiation in rats.

Sexually dimorphic traits were studied in offspring of rats injected with 33 micrograms rat beta-endorphin (beta-END) three times daily from Day 14 to Day 21 of pregnancy. beta-END males had shorter neonatal anogenital distances than did controls and were more likely to show the female lordosis pattern as adults, but they did not differ in male copulatory behavior. When given a choice between spending time with an estrous female or a male, beta-END males showed a lower preference for the female than did control males. The number and somal size of neurons in the bulbocavernosus and dorsolateral nucleus of the lumbar spinal cord were unaffected by drug exposure. Elevated beta-END during fetal ontogeny apparently alters the differentiation of some, but not all, sexually dimorphic traits. The data suggest that endogenous opioids may contribute to the etiology of the prenatal stress syndrome.

Prenatal flutamide alters sexually dimorphic nuclei in the spinal cord of male rats.

The effects of prenatal exposure to the antiandrogen flutamide on two sexually dimorphic nuclei of the lumbar spinal cord, the dorsolateral nucleus (DLN) and the spinal nucleus of the bulbocavernosus (SNB), were investigated. Rat dams were given daily injections of 5 mg flutamide or vehicle alone from day 11 through 21 of pregnancy. The spinal cords and perineal morphology of their male and female offspring were examined in adulthood. Flutamide reduced the number of SNB and DLN neurons, reduced the somal and nuclear area of SNB neurons, and reduced the weight of the perineal muscles in males. Flutamide produced no effect in females. No sexual dimorphism was found in the mean somal area of DLN neurons, but a sexual dimorphism was found in the distribution of somal areas in our samples; females had proportionately more large neurons than males. Flutamide-treated males also had proportionately more large neurons than control males but fewer than females. A sexual dimorphism was found in the nuclear areas of DLN neurons but flutamide did not influence this trait.

Naltrexone normalizes the suppression but not the surge of delta 5-3 beta-hydroxysteroid dehydrogenase activity in Leydig cells of stressed rat fetuses.

Rat fetuses from mothers stressed chronically by immobilization and high intensity illumination beginning on day 14 of gestation have higher than normal levels of delta 5-3 beta-hydroxysteroid dehydrogenase (3 beta HSD) activity in Leydig cells on day 17 of gestation and lower than normal levels on days 18 and 19. Plasma testosterone titers in normal and stressed male fetuses closely parallel the activity of 3 beta HSD in fetal Leydig cells. In the present study quantitative cytochemistry was used to determine whether the stress-induced alterations in 3 beta HSD activity could be prevented by treating the mother with naltrexone, an opioid receptor blocker, before each stress session. Naltrexone normalized 3 beta HSD activity on days 18 and 19 of gestation, suggesting that the stress-induced suppression involves the endogenous opioid system. In contrast, naltrexone did not prevent the elevation in enzyme activity seen on day 17 in stressed fetuses. The persistence of a stress-induced surge on day 17, in spite of naltrexone therapy, suggests that some nonopioid mechanism is operational at that time.

Naltrexone blocks the effects of prenatal stress on sexual behavior differentiation in male rats.

The male offspring of rats stressed three times daily during days 14-21 of pregnancy were more likely to show lordotic behavior when tested in adulthood than were control males. This feminization of sexual behavior was not observed if the mothers were injected with the opioid antagonist naltrexone before being stressed. These data suggest that endogenous opioids released under conditions of stress can alter the normal process of sexual behavior differentiation in the fetal male rat.

Environmental stress alters the developmental pattern of delta 5-3 beta-hydroxysteroid dehydrogenase activity in Leydig cells of fetal rats: a quantitative cytochemical study.

Quantitative cytochemistry was used to determine the effect of subjecting pregnant rats to environmental stress on the activity of delta 5-3 beta hydroxysteroid dehydrogenase (3 beta-HSD) in Leydig cells of their fetuses. Enzyme activity was measured by microspectrophotometry in individual Leydig cells in cryostat sections of fetal testes on Days 16-21 postconception. Fetuses of stressed mothers lacked the peak of enzyme activity on Days 18 and 19 of gestation that is characteristic of Leydig cells of normal fetuses at this time. In addition, both before and after these 2 days, 3 beta-HSD activity in Leydig cells of stressed fetuses was significantly higher than normal. The altered developmental pattern of 3 beta-HSD activity in the stressed fetuses largely corresponds to the changes in plasma testosterone found previously in male fetuses of mothers exposed to the same regimen of stress. Thus, in the fetal Leydig cell, the activity of 3 beta-HSD, a key steroidogenic enzyme, can be modified by environmental stress, and provides an index of steroidogenic activity of the fetal testes and of the titers of circulating testosterone.