Developmental Programming of Capuchin Monkey Adrenal Dysfunction by Gestational Chronodisruption

Abstract

In the capuchin monkey (Cebus apella), a new-world nonhuman primate, maternal exposure to constant light during last third of gestation induces precocious maturation of the fetal adrenal and increased plasma cortisol in the newborn. Here, we further explored the effects of this challenge on the developmental programming of adrenal function in newborn and infant capuchin monkeys. We measured (i) plasma dehydroepiandrosterone sulphate (DHAS) and cortisol response to ACTH in infants with suppressed endogenous ACTH, (ii) plasma DHAS and cortisol response to ACTH in vitro, and (iii) adrenal weight and expression level of key factors in steroid synthesis (StAR and 3β-HSD). In one-month-old infants from mothers subjected to constant light, plasma levels of cortisol and cortisol response to ACTH were twofold higher, whereas plasma levels of DHAS and DHAS response to ACTH were markedly reduced, compared to control conditions. At 10 months of age, DHAS levels were still lower but closer to control animals, whereas cortisol response to ACTH was similar in both experimental groups. A compensatory response was detected at the adrenal level, consisting of a 30% increase in adrenal weight and about 50% reduction of both StAR and 3β-HSD mRNA and protein expression and the magnitude of DHAS and cortisol response to ACTH in vitro. Hence, at birth and at 10 months of age, there were differential effects in DHAS, cortisol production, and their response to ACTH. However, by 10 months of age, these subsided, leading to a normal cortisol response to ACTH. These compensatory mechanisms may help to overcome the adrenal alterations induced during pregnancy to restore normal cortisol concentrations in the growing infant.

From gestational chronodisruption to noncommunicable diseases: Pathophysiological mechanisms of programming of adult diseases, and the potential therapeutic role of melatonin

“…As adults, the offspring gestated under chronodisruption, display multiple physiological changes including increased heart rate, blood pressure, body weight, and glucose tolerance, among others (see Table 1). In this context it is important to keep in mind that the effects on the offspring of gestational chronodisruption have been studied experimentally in several species using models, such as maternal pinealectomy, 83,92–94 maternal exposure to constant light 67,78–80,84,85,95 and maternal exposure to chronic phase shifts during gestation, 20,21,23,76,77,96 that display in common the alteration or suppression of the maternal circadian rhythm of melatonin, shifting maternal circadian rhythms of glucose, and suppressing the maternal rhythms of activity, temperature, and heart rate. In these models has been demonstrated that the impairment in fetal organs at circadian and physiological levels are translated to the offspring inducing metabolic impairment, with higher response to intraperitoneal glucose challenge, increasing adrenal response to adrenocorticotropic hormone in vitro, free‐running of corticosterone and permanent effects in plasma melatonin, that remain for the whole life, in which the nocturnal increase of melatonin was absent (Table 1).…”

Challenging the Integrity of Rhythmic Maternal Signals Revealed Gene-Specific Responses in the Fetal Suprachiasmatic Nuclei

“…Answering this question is important for understanding the impact of maternal chronodisruption, which may occur in pregnant women exposed to modern lifestyles, on offspring. It has been found that chronodisruption in utero leads to pathological phenotypes later in adulthood ( Mendez et al, 2016 ; Richter et al, 2018 ; Salazar et al, 2018 ; Varcoe et al, 2018 ) that may not be rescued by quality of maternal care during postnatal period ( Smarr et al, 2017 ). Therefore, temporal organization during fetal development seems to be important for good health in adulthood.…”

Perinatal photoperiod associations with diabetes and chronotype prevalence in a cross-sectional study of the UK Biobank

“…Different perinatal light paradigms cause 'clock' genes in neurons from the suprachiasmatic nuclei (SCN, the "master" clock in the brain) of rodents to behave differentially in later life (Ciarleglio et al 2011;Tackenberg and McMahon 2018). Later life physiology, in particular metabolic processes, can also be differentially affected by different perinatal light paradigms (Ciarleglio et al 2011; Lewis and Erren 2017a;Mendez et al 2019;Mizutani et al 2017;Ohta et al 2006;Richter et al 2018;Salazar et al 2018). Daylight is the predominant environmental time-cue or 'zeitgeber' for the CTS in humans (Aschoff 1951(Aschoff , 1954Duffy et al 1996).…”