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Prenatal glucocorticoid modifies hypothalamo-pituitary-adrenal regulation in prepubertal guinea pigs
F Dean1, C Yu, R I Lingas
1Departments of Physiology and Obstetrics and Gynecology, Faculty of Medicine, University of Toronto, Ont. M5S 1A8, Canada.
Insights
Prenatal exposure to synthetic glucocorticoids like dexamethasone alters fetal growth and sex-specific hypothalamo-pituitary-adrenal (HPA) axis function in guinea pigs, impacting stress responses and brain corticosteroid receptor regulation postnatally.
Area of Science:
- Neuroendocrinology
- Developmental biology
- Reproductive science
Background:
- Synthetic glucocorticoids can cross the placenta, potentially affecting fetal development.
- The developing brain is particularly vulnerable to hormonal influences during critical growth periods.
- Sex-specific differences in stress response and neurodevelopment are well-documented.
Purpose of the Study:
- To investigate the sex-specific effects of prenatal dexamethasone exposure on hypothalamo-pituitary-adrenal (HPA) axis function in juvenile guinea pigs.
- To determine if prenatal glucocorticoid exposure alters central corticosteroid receptor regulation in a sex-specific manner.
- To examine the impact on growth and stress reactivity following in utero dexamethasone administration.
Main Methods:
- Pregnant guinea pigs received dexamethasone or vehicle during late gestation.
- Offspring were assessed at rest and after isolation stress on postnatal day 18.
- Plasma cortisol levels and brain mRNA expression of glucocorticoid receptor (GR) and pro-opiomelanocortin (POMC) were analyzed.
Main Results:
- Dexamethasone exposure increased gestation length and altered fetal growth.
- Elevated basal cortisol was observed in male offspring, while females showed attenuated stress responses.
- Prenatal dexamethasone altered hippocampal GR mRNA expression in a sex-specific manner (decreased in females, increased in males).
Conclusions:
- Prenatal glucocorticoid exposure significantly impacts offspring growth and HPA axis function.
- These effects are highly sex-specific, influencing stress responses and central corticosteroid receptor expression.
- Findings highlight the long-term consequences of maternal hormonal environment on neurodevelopment and HPA axis regulation.
Abstract:
We hypothesized that exposure to synthetic glucocorticoid during rapid brain growth (d50-52, birth = 68 days) in fetal guinea pigs modifies hypothalamo-pituitary-adrenal (HPA) function after birth, and that this involves changes in central corticosteroid receptor regulation. On the basis of our previous studies, we proposed that this effect is sex-specific. Pregnant guinea pigs were treated with dexamethasone (1 mg/kg) or vehicle on d50-51 of gestation, and juvenile offspring were euthanized at rest or following isolation stress on postnatal day 18. Dexamethasone increased the length of gestation (1.5 days) and altered body and organ (brain, heart, adrenal) growth. Resting plasma cortisol concentrations were significantly elevated in young male, but not female guinea pigs exposed to dexamethasone as fetuses. In female offspring born to dexamethasone-treated mothers, cortisol responses to isolation stress were attenuated. In males, elevated basal cortisol levels were not increased further by isolation. In the brain, hippocampal glucocorticoid receptor (GR) mRNA levels were significantly lower (10-25%) in females exposed to dexamethasone in utero. In contrast, GR mRNA levels were elevated (10-20%) in males from this prenatal treatment group. Mineralocorticoid receptor mRNA in the limbic system and GR mRNA levels in the pars distalis were unaffected. Pro-opiomelanocortin mRNA was significantly lower (30%) in the male pars intermedia following dexamethasone exposure. In conclusion, prenatal glucocorticoid exposure affects growth and HPA function as well as limbic and hypothalamic GR expression in juvenile offspring, and these effects are highly sex-specific.