Effects of Prenatal Dexamethasone Treatment on Postnatal Physical, Endocrine, and Social Development in the Common Marmoset Monkey

Abstract

The prophylactic treatment of diagnosed preterm delivery with synthetic glucocorticoids, such as dexamethasone (DEX), is commonplace. Long-term effects of such treatment are not well understood. In the present study, we exposed pregnant common marmosets (Callithrix jacchus), small-bodied monkeys that are therefore advantageous for long-term primate studies, to daily repeated DEX (5 mg/kg orally) either during early (d 42-48) or late (d 90-96) pregnancy (gestation period of 144 d). Relative to control, we investigated DEX effects in terms of maternal endocrinology (plasma cortisol and estrogen titers) and offspring physical growth, plasma and urinary ACTH and cortisol titers, and social and maintenance behaviors from birth to weaning. Both DEX treatments resulted in markedly reduced maternal plasma cortisol titers during treatment and reduced estimated gestation period. Both treatments were without effects on neonate morphometric measurements and basal hypothalamic-pituitary-adrenal axis activity. Early DEX treatment resulted in increased infant body weight at postnatal d 56 and 84, co-occurring at the behavioral level with increased time spent in eating solid food, a mobile state, solitary play, and exhibiting tail hair piloerection. The constellation of physical and behavioral effects of early DEX suggests interesting parallels with the human metabolic syndrome, providing primate support that the latter is causally associated with the fetal environment, including prenatal programming. This novel primate in vivo evidence for postnatal effects of prenatal synthetic glucocorticoid exposure indicates the importance of improved understanding of this acute clinical treatment in terms of its long-term effects on offspring well-being.

Responses of the Hypothalamopituitary Adrenal Axis and the Sympathoadrenal System to Isolation/Restraint Stress in Sheep of Different Adiposity

“…Thus, in the lean ewes the adrenal gland responded to a small ACTH stimulus and this is similar to what we have found in lactating ewes [5]. Dissociation between the secretion of ACTH and cortisol has also been reported in rats [60,61,62]. Despite the differences between lean and fat ewes in ACTH and cortisol secretion suggesting different mechanisms of adrenal responsiveness to ACTH, we did not directly test cortisol responses to ACTH in lean and fat ewes in the current experiment.…”

Early-Life Glucocorticoid Exposure: The Hypothalamic-Pituitary-Adrenal Axis, Placental Function, and Long-term Disease Risk

“…We have shown, using sheep as an animal model, that glucocorticoid administration in late gestation results in intrauterine growth restriction (IUGR) and significant alterations in metabolic and HPA axis function and regulation in both the fetus and postnatal animals (39 -41). Similar results have been shown across many species (42)(43)(44)(45), thus suggesting that early-life exposure to high levels of glucocorticoids leads to long-term metabolic programming. Historical data from epidemiological studies have established that a suboptimal intrauterine environment is associated with an increased risk of developing cardiovascular disease, hypertension, type 2 diabetes, and the metabolic syndrome (46 -52); any or all of these associations are underpinned by changes in the endocrine set point of the HPA axis (12,(53)(54)(55)(56)(57).…”

“…Hauser et al (42) demonstrated that early dexamethasone treatment in marmosets significantly reduced maternal plasma cortisol levels during treatment. Showing characteristics of the metabolic syndrome, infant body weight was increased postnatally and was associated with changes in food intake behavior (42).…”

Adrenals

“…Two potentially important studies published this year have used somewhat different approaches to try to address these issues. By using a non-human primate model, de Vries et al have shown that prenatal exposure to repeated high doses of dexamethasone was associated with altered ␤ cell function and blood pressure in offspring between 8 and 12 months of age (see also Hauser et al [7] for a study in marmoset monkeys). In addition, Karemaker et al have shown in a retrospective cohort study that postnatal dexamethasone treatment (0.5 mg/kg/day) for lung disease in preterm humans was associated with altered neuroendocrine stress response and immunological parameters in late childhood.…”