Puberty In Offspring Research Articles

Dysregulation of Mir-193B and Mir-376A as a Biomarker of Prediabetes in Offspring of Gestational Diabetic Mice

Gestational diabetes mellitus (GDM) is a type of diabetes initiated during pregnancy and is characterized by maternal hyperglycemia that induces complications in mothers and children. In the current study, we used a GDM mouse model (through i.p. injection of a single dose of streptozocin, STZ, 60 mg/kg/bw) to investigate the biochemical and immunological changes in the blood and brain of diabetic mothers and their offspring relative to their appropriate controls. In addition, we estimated the expression levels of a set of microRNAs (miRNAs) to link between the dysregulation in the levels of miRNAs and the exposure to oxidative stress during embryonic development, as well as metabolic changes that occur after birth and during puberty in offspring (5-weeks-old). At the biochemical level, newborn pups appeared mostly to suffer from the same oxidative stress conditions of their mothers as shown by the significant increase in nitric oxide (NO) and malondialdehyde (MDA) in blood and brain of diabetic mothers and their pups. However, the 5-week-old offspring showed a significant increase in proinflammatory cytokines, IL-1β, IL-6, and TNF-α, and based on their blood glucose levels, could be considered as prediabetic (with glucose mean value of 165 mg/dl). In the meantime, the tested miRNAs, especially miR-15b, miR-146a, and miR-138 showed mostly similar expression levels in diabetic mothers and newborn pups. In this regard, miR-15a and -15b, miR-146a, and miR-138 are downregulated in diabetic mothers and their newborn pups relative to their appropriate controls. However, in offspring of diabetic mothers at puberty age, these miRNAs displayed different expression levels relative to mothers and control offspring. Interestingly, miR-193 and miR-763 expression levels were significantly lower in diabetic mothers but upregulated in their 5-week-old offspring, suggesting that miR-193 and miR-763 could be used as biomarkers to differentiate between prediabetes and diabetes.

Maternal sympathetic stress impairs follicular development and puberty of the offspring.

Chronic cold stress applied to adult rats activates ovarian sympathetic innervation and develops polycystic ovary (PCO) phenotype. The PCO syndrome in humans originates during early development and is expressed before or during puberty, which suggests that the condition derived from in utero exposure to neural- or metabolic-derived insults. We studied the effects of maternal sympathetic stress on the ovarian follicular development and on the onset of puberty of female offspring. Timed pregnant rats were exposed to chronic cold stress (4 °C, 3 h/daily from 1000 to 1300 h) during the entire pregnancy. Neonatal rats exposed to sympathetic stress during gestation had a lower number of primary, primordial, and secondary follicles in the ovary and a lower recruitment of primary and secondary follicles derived from the primordial follicular pool. The expression of the FSH receptor and response of the neonatal ovary to FSH were reduced. A decrease in nerve growth factor (NGF) mRNA was found without change in the low-affinity NGF receptor. The FSH-induced development of secondary follicles was decreased. At puberty, estradiol plasma levels decreased without changes in LH plasma levels. Puberty onset (as shown by the vaginal opening) was delayed. Ovarian norepinephrine (NE) was reduced; there was no change in its metabolite, 3-methoxy-4-hydroxyphenylglycol, in stressed rats and no change in NE turnover. The changes in ovarian NE in prepubertal rats stressed during gestation could represent a lower development of sympathetic nerves as a compensatory response to the chronically increased NE levels during gestation and hence participate in delaying reproductive performance in the rat.

Mechanism of the delayed puberty onset in offspring of rats that consumed aqueous extract of hibiscus sabdariffa during pregnancy

Consumption of extracts of Hibiscus sabdariffa (family: malvaceae) during pregnancy has been shown to cause maternal malnutrition which has been linked to various adverse conditions like increased postnatal weight gain, delayed puberty onset and elevated body weight and body mass index at onset of puberty in the female offspring. The present study was designed to investigate the possible mechanism underlying this. Eighteen in-bred pregnant Sprague-Dawley rats were on day 1 of pregnancy, randomly divided into three groups of six animals each. Group A (control) was given tap water to drink. Group B was given 0.6g extract/100ml while Group C was given 1.8g extract/100ml as their drinking solution. All groups received normal rat chow and their drinking solution ad libitum. Fluid and food intake and dam weights were measured daily throughout pregnancy. On gestational day 18, blood sample was withdrawn from each rat for estimation of plasma Na ion and corticosterone levels. On the day of delivery, the solutions of the extracts of Hibiscus sabdariffa were withdrawn and replaced with tap water. After 21 days, the pups were weaned to tap water and food ad libitum. Pups weight and age and body mass index at onset of puberty were measured. The results of the present study showed that the increased postnatal weight gain, delayed puberty onset and elevated body mass index at onset of puberty in the offspring of rats that consumed HS during pregnancy was associated with elevated maternal plasma Na ion and corticosterone levels during pregnancy.

2B-6 Maternal high fat nutrition either pre-conceptionally and/or throughout pregnancy and lactation leads to early-onset puberty in offspring and is further exacerbated by a post-weaning high fat diet

2B-6 Maternal high fat nutrition either pre-conceptionally and/or throughout pregnancy and lactation leads to early-onset puberty in offspring and is further exacerbated by a post-weaning high fat diet

4A-6 Early-onset puberty in offspring after maternal undernutrition is exaggerated by a post-weaning high fat diet: sex specific evidence of nutritional mismatch

4A-6 Early-onset puberty in offspring after maternal undernutrition is exaggerated by a post-weaning high fat diet: sex specific evidence of nutritional mismatch

Prevention of Programmed Hyperleptinemia and Hypertension by Postnatal Dietary ω-3 Fatty Acids

Fetal programming is now recognized as a key determinant of the adult phenotype, with major implications for adult-onset diseases including hypertension. Two mediators of fetal programming are maternal nutrition and fetal glucocorticoid exposure. Recent studies show that postnatal dietary manipulations can exacerbate programming effects, but whether programming effects can be attenuated by postnatal dietary manipulations, and thus provide a possible therapeutic strategy, is unknown. In this study, we tested the hypothesis that a postnatal diet enriched with long-chain omega-3 fatty acids attenuates programmed hyperleptinemia and hypertension. Pregnant rats were treated with dexamethasone (Dex) from d 13 to term, and offspring were cross-fostered to mothers on either a standard diet or a diet high in omega-3 fatty acids and remained on these diets postweaning. Maternal Dex reduced birthweight and delayed the onset of puberty in offspring. Hyperleptinemia (associated with elevated leptin mRNA expression in adipose tissue) and hypertension were evident in offspring by 6 months of age in Dex-exposed animals consuming a standard diet, but these effects were completely blocked by a high omega-3 diet. These results demonstrate for the first time that manipulation of postnatal diet can limit adverse outcomes of fetal programming, with programmed hyperleptinemia and hypertension prevented by a postnatal diet enriched with omega-3 fatty acids. This raises the possibility that dietary supplementation with omega-3 fatty acids may provide a viable therapeutic option for preventing and/or reducing adverse programming outcomes in humans.

Experience with new testing guidelines with endocrine-sensitive end-points

Concerns about the effects of endocrine disruptors on humans and wildlife have resulted in revised governmental testing guidelines (e.g., U.S. Environmental Protection Agency, Organization for Economic Cooperation and Development, U.S. Food and Drug Administration), adding endpoints to enhance their capability to detect endocrine active compounds. Based on experience with these testing guidelines, I present my opinions and data on study design, performance, results, endpoints, interpretation, and recommendations for improvement. New regulatory endpoints must be reproducible, robust, sensitive, relevant, and consistent. These new endpoints are appropriate: anogenital distance, examination of culled pups on postnatal day 4, examination for retained nipples/areolae in preweanling males, weanling necropsy, acquisition of puberty in offspring, prebreed estrous cyclicity, reproductive organ weights and histopathology, and andrology. Endpoints considered not appropriate are ovarian primordial follicle counts, stage of estrous for parental females at demise, and single blood sample at necropsy to measure circulating levels of relevant hormones. In conclusion: (1) regulatory guidelines represent only the minimum requirements and should/will change as science improves and scientific and societal concerns arise; (2) scientists must interact to identify and refine new methods, endpoints, and mechanisms; (3) the objective of these studies is to provide good science and useful information for risk assessment. Regulatory agencies should convene workshops with stakeholders to discuss issues such as new fundamental/applied information, mechanisms, and current and new endpoints. Interactions will lead to enhanced science, periodic revisions of testing guidelines, and improved risk assessment.