Maternal melatonin treatment rescues endocrine, inflammatory, and transcriptional deregulation in the adult rat female offspring from gestational chronodisruption

Abstract

IntroductionGestational chronodisruption impact maternal circadian rhythms, inhibiting the nocturnal increase of melatonin, a critical hormone that contributes to maternal changes adaptation, entrains circadian rhythms, and prepares the fetus for birth and successful health in adulthood. In rats, we know that gestational chronodisruption by maternal chronic photoperiod shifting (CPS) impaired maternal melatonin levels and resulted in long-term metabolic and cardiovascular effects in adult male offspring. Here, we investigated the consequences of CPS on mother and adult female offspring and explored the effects of melatonin maternal supplementation. Also, we tested whether maternal melatonin administration during gestational chronodisruption rescues maternal circadian rhythms, pregnancy outcomes, and transcriptional functions in adult female offspring.MethodsFemale rats raised and maintained in photoperiod 12:12 light: dark were mated and separated into three groups: (a) Control photoperiod 12:12 (LD); (b) CPS photoperiod; and (c) CPS+Mel mothers supplemented with melatonin in the drinking water throughout gestation. In the mother, we evaluated maternal circadian rhythms by telemetry and pregnancy outcomes, in the long-term, we study adult female offspring by evaluating endocrine and inflammatory markers and the mRNA expression of functional genes involved in adrenal, cardiac, and renal function.ResultsIn the mothers, CPS disrupted circadian rhythms of locomotor activity, body temperature, and heart rate and increased gestational length by almost 12-h and birth weight by 12%, all of which were rescued by maternal melatonin administration. In the female offspring, we found blunted day/night differences in circulating levels of melatonin and corticosterone, abnormal patterns of pro-inflammatory cytokines Interleukin-1a (IL1a), Interleukin-6 (IL6), and Interleukin-10 (IL10); and differential expression in 18 out of 24 adrenal, cardiac, and renal mRNAs evaluated.ConclusionMaternal melatonin contributed to maintaining the maternal circadian rhythms in mothers exposed to CPS, and the re-establishing the expression of 60% of the altered mRNAs to control levels in the female offspring. Although we did not analyze the effects on kidney, adrenal, and heart physiology, our results reinforce the idea that altered maternal circadian rhythms, resulting from exposure to light at night, should be a mechanism involved in the programming of Non-Communicable Diseases.

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

“…As well, gestational chronodisruption impact fetal hormonal rhythms like prolactin, corticosterone and melatonin 4,65,67 . Collectively these results support that fetal physiology was impacted by melatonin suppression since we and others have demonstrated that maternal melatonin treatment reversed this effect in the fetus restoring normal fetal physiology 18,42,67,77,83 . Moreover, the work of our group and others has widely demonstrated that melatonin signals impact the molecular clockwork of several brain and peripheral regions in fetuses from a number of species in which melatonin receptors are expressed (reviewed in 1,18,53,67,80,87 ), similar to those reported in adults (Table 1).…”

“…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).…”

“…Additionally, melatonin's role in alleviating symptoms of diverse pathologies such as cancer, psychiatric disorders, and metabolic disorders including diabetes, obesity, and hypertension, is potentially associated with epigenetic mechanisms 99,106 . While the exact participation of melatonin in processes involved in imprinting and fetal programming remains unclear, the positive effects observed thus far warrant consideration that postnatal melatonin might prevent the progression of certain pathologies related to fetal programming, likely via a reprogramming mechanism potentially mediated by melatonin 21,77 …”

Melatonin and Kidney Health: From Fetal Stage to Later Life

“…So far, there have been several animal studies reporting that melatonin exogenous supplementation during gestation could be beneficial for both mother and fetus [62], while only a small proportion of them have focused on offspring outcomes [55]. Here, we list in Table 1 a summary of reports relevant to reprogramming effects of melatonin on kidneyrelated diseases in offspring [63][64][65][66][67][68][69][70][71][72][73][74][75][76][77][78]. The therapeutic duration is restricted solely to fetal to early childhood stages prior to disease onset.…”

“…Table 1 illustrates various maternal insults that can induce the developmental programming of kidney-related disease in adult offspring, which can be averted by the early use of melatonin. These early life insults include gestational chronodisruption [63], maternal continuous light exposure [65], maternal caloric restriction [66], maternal N G -nitro-L-argininemethyl ester (L-NAME) exposure [67], maternal high methyl-donor diet [68], maternal high-fructose diet [69], maternal high-fructose diet plus post-weaning high-salt diet [70], antenatal glucocorticoid exposure [71], and antenatal glucocorticoid administration plus post-weaning high-fat diet [72].…”