Testosterone, progesterone, and corticosterone titers were measured by RIA in plasma of stressed and control pregnant rats and their male and female fetuses on days 17, 18, 19, and 21 of gestation and on the day of birth. The regimen of stress used (three 45-min periods of restraint under intense illumination daily from days 14–21 of pregnancy) causes failure of masculinization and defeminization of behavioral potentials in male offspring. In fetuses of both sexes, corticosterone titers increased sharply between days 17 and 18 postconception (pc) to a peak that was maintained through day 19 and then declined. This pattern resembled that obtained for testosterone in control male fetuses in which the levels of testosterone also rose sharply between days 17 and 18 pc. Corticosterone titers were elevated in samples obtained during the middle of the stress session from both the mothers (serum) and their male and female fetuses (plasma). Increased corticosterone levels were no longer evident in samples obtained...

Differential Effects of Maternal Stress on Circulating Levels of Corticosterone, Progesterone, and Testosterone in Male and Female Rat Fetuses and Their Mothers*

As fetal overexposure to glucocorticoids has been postulated to induce intrauterine growth retardation (IUGR) in humans, we investigated the effects of maternal 50% food restriction (FR50) in rats during the last week of gestation on the hypothalamo-pituitary adrenal (HPA) axis activity in both mothers and their fetuses. In mothers, FR50 increased both the plasma corticosterone (B) level from embryonic days 19–21 and the relative adrenal weight at term. FR50 decreased at term both the maternal plasma corticosteroid-binding globulin level and placental 11β-hydroxysteroid dehydrogenase type 2 expression. In newborns, maternal FR50 reduced body and adrenal weights, glucocorticoid and mineralocorticoid receptor expressions in the hippocampus, corticoliberin expression in the hypothalamic paraventricular nucleus, and plasma ACTH. In FR50 newborns, the plasma B level was increased at birth and decreased 2 h later. When maternal circulating B was maintained at the basal level by adrenalectomy and B supply, FR50 ...

Maternal Undernutrition during Late Gestation Induces Fetal Overexposure to Glucocorticoids and Intrauterine Growth Retardation, and Disturbs the Hypothalamo-Pituitary Adrenal Axis in the Newborn Rat1

Maternal infections with bacterial or viral agents during pregnancy are associated with an increased incidence of schizophrenia in the offspring at adulthood although little is known about the mechanism by which maternal infection might affect fetal neurodevelopment. Exposure of pregnant rodents to the bacterial endotoxin, lipopolysaccharide (LPS), results in behavioral deficits in the adult offspring that are relevant to schizophrenia. It is however unknown whether these effects are due to the direct action of the inflammatory stimulus on the developing fetus, or due to secondary immune mediators (cytokines) activated at maternal/fetal sites. In this study we sought to elucidate the site of action of LPS, following a single intraperitoneal (i.p.) injection, in pregnant rats at gestation day 18. Animals received 5 muCi of iodinated LPS ((125)I-LPS) and its distribution was assessed in maternal/fetal tissues (1-8 h). In addition, induction of the inflammatory cytokines, TNF-alpha, IL-1beta and IL-6, was measured in maternal/fetal tissues following maternal LPS challenge (0.05 mg/kg, i.p.) (2-8 h). (125)I-LPS was detected in maternal tissues and placenta, but not the fetus. This distribution was accompanied by significant increases in TNF-alpha, IL-1beta and IL-6 in maternal plasma and placenta, but not in fetal liver or brain. A significant increase in IL-1beta was however detected in fetal plasma, possibly due to transfer from the maternal circulation or placenta. Collectively, these data suggest that effects of maternal LPS exposure on the developing fetal brain are not mediated by the direct action of LPS, but via indirect actions at the level of the maternal circulation or placenta.

The role of cytokines in mediating effects of prenatal infection on the fetus: implications for schizophrenia.

1. The responsiveness of the rat hypothalamo-pituitary-adrenal (HPA) axis and hypothalamo-neurohypophysial system (HNS) to emotional (elevated plus-maze) and physical (forced swimming) stressors and to administration of synthetic corticotrophin-releasing hormone (CRH) was investigated during pregnancy and lactation. In addition to pregnancy-related adaptations at the adenohypophysial level, behavioural responses accompanying the neuroendocrine changes were studied. 2. Whereas basal (a.m.) plasma corticosterone, but not corticotrophin (adrenocorticotrophic hormone; ACTH), levels were increased on the last day (i.e. on day 22) of pregnancy, the stress-induced rise in both plasma hormone concentrations was increasingly attenuated with the progression of pregnancy beginning on day 15 and reaching a minimum on day 21 compared with virgin control rats. A similar attenuation of responses to both emotional and physical stressors was found in lactating rats. 3. Although the basal plasma oxytocin concentration was elevated in late pregnancy, the stress-induced rise in oxytocin secretion was slightly lower in day 21 pregnant rats. In contrast to vasopressin, oxytocin secretion was increased by forced swimming in virgin and early pregnant rats indicating a differential stress response of these neurohypophysial hormones. 4. The blunted HPA response to stressful stimuli is partly due to alterations at the level of corticotrophs in the adenohypophysis, as ACTH secretion in response to CRH in vivo (40 ng kg-1, i.v.) was reduced with the progression of pregnancy and during lactation. In vitro measurement of cAMP levels in pituitary segments demonstrated reduced basal levels of cAMP and a lower increase after CRH stimulation (10 nM, 10 min) in day 21 pregnant compared with virgin rats, further indicating reduced corticotroph responsiveness to CRH in pregnancy. 5. The reduced pituitary response to CRH in late pregnancy is likely to be a consequence of a reduction in CRH receptor binding as revealed by receptor autoradiography. [125I] CRH binding in the anterior pituitary was significantly reduced in day 11, 17 and 22 pregnant rats compared with virgin controls. 6. Anxiety-related behaviour of the animals as revealed by the time on and entries into the open arms of the elevated plus-maze was different between virgin and pregnant rats with decreased number of entries indicating increased anxiety with the progression of pregnancy (except on pregnancy day 18). The emotional behaviour, however, was not correlated with the neuroendocrine responses. 7. The results indicate that the reduced response of the HPA axis to stressors described previously during lactation is already manifested around day 15 of pregnancy in the rat and involves physiological adaptations at the adenohypophysial level. However, alterations in stressor perception at higher brain levels with the progression of pregnancy may also be involved.

https://physoc.onlinelibrary.wiley.com/doi/pdf/10.1111/j.1469-7793.1998.289br.x

Attenuated neuroendocrine responses to emotional and physical stressors in pregnant rats involve adenohypophysial changes

Early life genetic, epigenetic and environmental factors shaping emotionality in rodents.

Adrenal and plasma corticosterone levels were determined in rat foetuses and in intact or adrenalectomized mothers during late pregnancy. Foetal adrenal and plasma corticosterone concentrations reached a peak on day 19 of pregnancy, while maternal plasma corticosterone increased on day 18 and remained high until parturition. From day 18, mothers adrenalectomized on day 14 had corticosterone levels similar to those of intact pregnant rats. At every stage of gestation (except day 21) plasma corticosterone levels were higher in the foetuses than in the mothers. The corticosterone concentration in the maternal plasma correlated with the number of live foetuses during the last 3 days of gestation. These results suggest that corticosterone can cross the placenta from foetus to mother as early as day 18 and that the foetus contributes to the maternal corticosterone pool after day 18.

J. P. Dupouy

Papers

Maternal and foetal corticosterone levels during late pregnancy in rats.