Prenatal steroid administration leads to adult pericardial and hepatic steatosis in male baboons

Abstract

Developmental programming studies indicate that glucocorticoids modify fetal development. We hypothesized that administration of the synthetic glucocorticoid (sGC) betamethasone to pregnant baboons at doses and stages of fetal life equivalent to human obstetric practice to decrease premature offspring morbidity and mortality, programs lipid metabolism. In 10-year-old male baboons (human equivalent 40) exposed in fetal life to betamethasone or saline, we quantified pericardial fat and hepatic lipid content with magnetic resonance imaging and spectroscopy. sGC offspring delivered at term as do most sGC exposed human neonates. Pericardial fat thickness (7.7 ± 3.6 mm vs. 3.1 ± 1.1 mm, M ± SD; p = 0.022; n=5) and hepatic fatty acids (13.3 ± 11.0 % vs. 2.5 ± 2.2 %; p = 0.046; n=5) increased following sGC without birth weight or current body morphometric differences. Our results indicate that antenatal sGC therapy caused abnormal fat deposition and adult body composition in mid-life primate offspring. The concern raised is that this degree of pericardial and hepatic lipid accumulation can lead to harmful local lipotoxicity. In summary, developmental programing by sGC produces a mid-life metabolically obese but normal weight phenotype. Prior studies show sexually dimorphic responses to some programming challenges thus female studies are necessary.

Light and Circadian Signaling Pathway in Pregnancy: Programming of Adult Health and Disease

“…Given that only a few human studies are available on this issue and that these observational studies cannot directly establish a causal relationship between maternal chronodisruption and lifelong health in the offspring, animal models are of great importance to identify which mechanisms underlying maternal circadian disruption may influence the programming of offspring phenotypes and lead to the development of specific preventive interventions. Table 1 summarizes various animal models utilized to investigate the relationship between maternal circadian rhythm disruption and offspring health [56][57][58][59][60][61][62][63][64][65][66][67][68][69][70][71][72][73][74]. Of note is that not only constant light, but also diurnal light deficiency and/or continuous darkness, are disruptive for the circadian system.…”

“…Prenatal DEX exposure was reported to induce arrhythmic glucocorticoid secretion and an absence of circadian oscillations in hippocampal clock gene expression in adult offspring [66]. Moreover, antenatal GC exposure is related to hypertension [67,73], liver steatosis [69,72], hippocampal lesions [70], kidney disease [71,73], obesity [72], and an impaired HPA axis [74]. Although SCN ablation [78], timed food access [79], and genetic manipulation (e.g., CLOCK mutant mice) [80] have been employed to disrupt circadian rhythms in pregnant animals, their long-term effects on offspring have not been studied yet.…”

“…Altered seasonal variations of reproductive hormones in 60-day-old rat offspring [63] Increased depressive-like responses in adult swine offspring [64] Induced glucose intolerance in 18-week-old rat offspring [65] Glucocorticoid exposure Prenatal dexamethasone treatment Induced depression-like behavior, arrhythmic glucocorticoid secretion, and absent circadian oscillations in hippocampal clock gene expression in 12-month-old mice offspring [66] Altered clock genes in adipose tissue and enhanced obesity, insulin dysregulation, and hypertension in 6-month-old rat offspring [67] Induced hypertension in 16-week-old rat offspring [68] Induced liver steatosis in 7-day-old offspring [69] Altered hippocampal morphology in 16-week-old rat offspring [70] Altered transcriptome in 16-week-old offspring kidney [71] Prenatal betamethasone treatment Induced obesity and liver steatosis in 10-year-old baboons [72] Induced hypertension and renal dysfunction in 1.5-year-old sheep [73] Altered hippocampal expression of HPA-related genes in 3.5-year-old sheep [74] Studies tabulated according to animal models and techniques. HPA: hypothalamic-pituitary-adrenal.…”

“…A developing fetus is prone to exposure to excessive glucocorticoids through exogenous administration (e.g., preterm birth) or through excess maternal corticosteroids (e.g., stressed pregnancies). The HPA axis is particularly susceptible to developmental programming by GCs, impairing a variety of organ systems, such as the kidneys [68,71,72], liver [69,72], central nervous system [70], and endocrine system [72,74]. As rhythmic GCs coordinate central and peripheral clocks, prenatal GC exposure-induced obesity and hypertension are relevant to altered clock genes in peripheral tissues [67].…”

Efficacy and safety of antenatal steroids

“…Very-long-term effects of fetal ANS exposure evaluated hepatic and pericardial lipid deposition in 10-yr-old baboons (human equivalent 40 yr) exposed to the three weekly ANS courses during fetal life (61). The ANS-exposed primates delivered spontaneously at term, as do many ANS-exposed human neonates.…”