Prenatal dexamethasone or stress but not ACTH or corticosterone alter sexual behavior in male rats

Prenatal maternal stress in rats and mice can demasculinize and feminize the sexual behavior of adult male offspring. Causal mechanisms are unknown, but one attractive hypothesis is that stress activation of maternal adrenal glucocorticoid secretion is the responsible agent. To test this hypothesis, pregnant rats were exposed to a variety of substances which enhance glucocorticoid actions. These included ACTH (20 IU of a gel preparation, SC once daily), corticosterone (CORT; 7 mg/kg SC in oil, three times daily), or dexamethasone (DEX; 0.1 mg/kg, SC once daily). Controls included noninjected dams and a positive stress control group (restraint under bright lights three times daily). All treatments reduced maternal weight gain, DEX most potently. No treatment altered litter size, stillbirths, or sex ratio, but DEX reduced weight at birth, an effect still seen at postnatal day 85. DEX, CORT, and stress reduced male adrenal weight at birth, while DEX and CORT altered sexual differentiation as measured by anogenital distance. Stress impaired adult male sexual performance but not the lordosis quotient following exposure of animals to stud males. DEX affected both measures. No other treatment had any significant effect on sexual behavior. No treatment altered plasma LH levels, either basal or in response to an estrogen challenge in adult gonadectomized males. In adulthood there was no treatment effect on stress reactivity, measured behaviorally or by plasma glucocorticoids. Correlational analysis revealed that weight gain during pregnancy was the single best predictor of subsequent sexual performance. It is concluded that prenatal dexamethasone exposure demasculinizes and feminizes male offspring. Whether the similar effect of stress is mediated solely by adrenal glucocorticoids is less certain; the ACTH and CORT treatments produced maternal plasma corticosterone levels higher than in stressed dams, yet did not affect adult sexual behavior. Because at high doses many drugs elicit a maternal stress response, including glucocorticoid secretion, these findings suggest that there may be a common effect of prenatal drug exposure upon sexual differentiation in the rat.