Maternal diabetes-mediated RORA suppression in mice contributes to autism-like offspring through inhibition of aromatase

Retinoic acid-related orphan receptor alpha (RORA) suppression is associated with autism spectrum disorder (ASD) development, although the mechanism remains unclear. In this study, we aim to investigate the potential effect and mechanisms of RORA suppression on autism-like behavior (ALB) through maternal diabetes-mediated mouse model. Our in vitro study in human neural progenitor cells shows that transient hyperglycemia induces persistent RORA suppression through oxidative stress-mediated epigenetic modifications and subsequent dissociation of octamer-binding transcription factor 3/4 from the RORA promoter, subsequently suppressing the expression of aromatase and superoxide dismutase 2. The in vivo mouse study shows that prenatal RORA deficiency in neuron-specific RORA null mice mimics maternal diabetes-mediated ALB; postnatal RORA expression in the amygdala ameliorates, while postnatal RORA knockdown mimics, maternal diabetes-mediated ALB in offspring. In addition, RORA mRNA levels in peripheral blood mononuclear cells decrease to 34.2% in ASD patients (n = 121) compared to the typically developing group (n = 118), and the related Receiver Operating Characteristic curve shows good sensitivity and specificity with a calculated 84.1% of Area Under the Curve for ASD diagnosis. We conclude that maternal diabetes contributes to ALB in offspring through suppression of RORA and aromatase, RORA expression in PBMC could be a potential marker for ASD screening.

Effects of Maternal Diabetes and Diet on Gene Expression in the Murine Placenta

Adverse exposures during pregnancy have been shown to contribute to susceptibility for chronic diseases in offspring. Maternal diabetes during pregnancy is associated with higher risk of pregnancy complications, structural birth defects, and cardiometabolic health impairments later in life. We showed previously in a mouse model that the placenta is smaller in diabetic pregnancies, with reduced size of the junctional zone and labyrinth. In addition, cell migration is impaired, resulting in ectopic accumulation of spongiotrophoblasts within the labyrinth. The present study had the goal to identify the mechanisms underlying the growth defects and trophoblast migration abnormalities. Based upon gene expression assays of 47 candidate genes, we were able to attribute the reduced growth of diabetic placenta to alterations in the Insulin growth factor and Serotonin signaling pathways, and provide evidence for Prostaglandin signaling deficiencies as the possible cause for abnormal trophoblast migration. Furthermore, our results reinforce the notion that the exposure to maternal diabetes has particularly pronounced effects on gene expression at midgestation time points. An implication of these findings is that mechanisms underlying developmental programming act early in pregnancy, during placenta morphogenesis, and before the conceptus switches from histiotrophic to hemotrophic nutrition.

Role of heme oxygenase in the regulation of the renal hemodynamics in a model of sex dependent programmed hypertension by maternal diabetes

Intrauterine programming of cardiovascular and renal function occurs in diabetes because of the adverse maternal environment. Heme oxygenase 1 (HO-1) and -2 (HO-2) exert vasodilatory, and antioxidant actions, particularly in conditions of elevated HO-1 expression, or deficient nitric oxide levels. We evaluated whether the activity of the heme-HO system is differentially regulated by oxidative stress in the female offspring of diabetic mothers, contributing to the improved cardiovascular function compared to male. Diabetes was induced in pregnant rats by a single dose of Streptozotocin (STZ, 50mg/kg i.p) in late gestation. Three months old male offspring from diabetic mothers (MOD) exhibited higher blood pressure values (BP), higher renal vascular resistance (RVR), worse endothelium -dependent response to Acetylcholine and an increased constrictor response to Phenylephrine, compared to those in aged matched female (FOD), which were abolished by chronic Tempol (1mM) treatment. In anesthetized animals, Stannous mesoporphyrin (SnMP; 40 µmol/kg i.v.) administration, to inhibit HO activity, increased RVR in FOD and reduced glomerular filtration rate in MOD, without altering these parameters in control animals. Compared to MOD, FOD showed lower nitrotirosyne levels, and higher HO-1 protein expression in renal homogenates. Indeed, chronic treatment with Tempol to MOD, prevented elevations in nitrotyrosine levels, and the acute renal hemodynamics response to SnMP. Then, maternal diabetes results in sex specific hypertension, and renal alterations associated to oxidative stress, mainly in adult male offspring, which are reduced in the female offspring, by elevation in HO-1 expression and lower oxidative stress levels.

Fetal adrenal cortex function in pregnancy, complicated by maternal insulin-dependent diabetes mellitus

Fetal adrenal cortex glucocorticoid andfetal hypophysial adrenocorticotropic function in normal pregnancy and pregnancy, complicated with maternal insulin dependent diabetes mellitus were examined in the present study. Statistically significant feta l hypercortisolemia was observed in pregnancies, complicated by insulin-dependent diabetes mellitus. Correlations between vascular complications o f maternal insulin-dependent diabetes mellitus and fetal cortisol andACTG levels were revealed during the investigation. Severe vascular lesions o f maternal diabetes have been associated with delayed feta l lung maturity. Fetal pulmonary maturity was significantly associated with fe ta l cortisol levels.

Role of the fetal pancreas size in prediction of early neonatal hypoglycemia in maternal diabetes mellitus

Введение. Поджелудочная железа (ПЖ) плода играет роль в регуляции гликемии как у плода, так и у матери. Гипергликемия матери, независимо от типа сахарного диабета (CД) сопровождается гипергликемией у плода. Напряжение функции ПЖ плода обусловливает компенсаторное увеличение eё размеров, формирование фетальной гиперинсулинемии и развитие в первые часы жизни неонатальной гипогликемии. Клинические симптомы гипогликемии присутствуют в 25-33% случаев, частота лабораторной гипогликемии - в 21-60%. Цель - оценка прогностического значения увеличения размеров ПЖ плода накануне родов в качестве предиктора неонатальной гипогликемии при CД у матери. Методика. Проведена ультразвуковая морфометрия ПЖ у 241 беременной c CД (основная группа) и у 427 здоровых беременных (контрольная группа). В основной группе у 141 (58,5%) беременной родились дети c признаками диабетической фетопатии (ДФ). Оценивались размеры ПЖ плода. У новорождённых оценивалась гликемия в динамике в 1-e и 3-и сут жизни. Проведён ретроспективный корреляционный анализ размеров поджелудочной железы плода и характер гликемии новорожденных в 1-e и 3-и cут жизни. Результаты. Выявлена отрицательная корреляция толщины ПЖ и гипогликемии новорождённого в 1-e сут жизни c линейным коэффициентом корреляции (R) минус 0,66. В 1-e сут жизни у 87,5 % этих детей возникает гипогликемия, более выраженная у недоношенных, у 50% из них, сохраняющаяся к 3-м сут жизни. Заключение. Толщина ПЖ плода более информативный и воспроизводимый показатель, чем её длина, статистически значимый как в группе ДФ, так и без неё. Неудовлетворительный контроль за течением CД у матерей увеличивает риск гипогликемии новорождённого до 100%. Более выраженная гипогликемия выявляется у недоношенных детей, у половины которых гипогликемия сохраняется к 3-м сут жизни. Background. The fetal pancreas is involved in regulation of glucose levels in both fetal and maternal plasma. Maternal hyperglycemia, regardless of the type of diabetes mellitus (DM), is accompanied by fetal hyperglycemia. This stress of the fetal pancreatic function causes a compensatory increase in the pancreas size, the development of fetal hyperinsulinemia and of neonatal hypoglycemia in the first hours of life. The frequency of laboratory hypoglycemia varies 21-60%, while its clinical symptoms are present in 25-33% of cases. Aim. To assess the prognostic value of the increase in fetal pancreas size on the eve of delivery as a predictor of neonatal hypoglycemia in maternal DM. Methods. Ultrasound of the fetal pancreas was performed in 241 pregnant women with DM (main group) and in 427 healthy pregnant women (control group). In the main group, 141 (58.5%) pregnant women had children with signs of diabetic fetopathy (DF). The size of the fetal pancreas was estimated. In newborns, glycemia was measured on the 1st and 3rd days of life. A retrospective correlation analysis of the fetal pancreas size and the neonatal glycemia was performed on the 1st and the 3rd days of life. Results. A negative linear correlation was found between the pancreas thickness and neonatal hypoglycemia on the 1st day of life (linear correlation coefficient, R, -0.66). On the 1st day of life in 87.5-100% of these newborns, hypoglycemia is observed, which is more pronounced in premature infants and which remains through the 3rd day of life in 50% of them. Conclusion. The thickness of the fetal pancreas is a more informative and reproducible indicator than its length, which was statistically significant in groups both with and without DF. Poor glycemic control in mothers increases the risk of neonatal hypoglycemia up to 100%. More pronounced hypoglycemia is observed in premature infants and persists through the 3rd day of life in half of them.