Adverse Fetal Environment Research Articles

Maternal Hyperglycemia Induces Autonomic Dysfunction and Heart Failure in Older Adult Offspring.

Offspring exposed to an adverse fetal environment, such as gestational diabetes, may manifest increased susceptibility to several chronic diseases later in life. In the present study, the cardiovascular function of three different ages of offspring from diabetic rats was evaluated. Diabetes mellitus was induced in pregnant rats by a single dose of streptozotocin (50 mg/kg). The offspring from diabetic (OD) and control rats (OC) were evaluated at three different ages: 6, 12 or 18 months. In the corresponding OC groups, fasting glycemia, baseline mean arterial pressure, and sympathetic tonus increased in the OD rats at 12 (OD12) and 18 (OD18) months of age, while cardiac hypertrophy was observed in all OD groups. Cardiac function evaluation in vivo showed low left ventricular systolic pressure and+dP/dt in the OD18 rats, suggesting a systolic dysfunction. OD12 and OD18 groups showed high left ventricle end-diastolic pressure, suggesting a diastolic dysfunction. OD groups showed an age-related impairment of both baroreflex-mediated tachycardia and baroreflex-mediated bradycardia in OD12 and OD18 rats. In isolated hearts from OD18 rats, both inotropic and tachycardiac responses to increasing isoproterenol were significantly reduced compared to the corresponding OC group. These results suggest that gestational diabetes triggers the onset of hyperglycemia hypertension with impaired baroreflex sensitivity and heart failure in older age of offspring, representing important risk factors for death. Therefore, ensuring optimal glycemic control in diabetic pregnancy is important and serves as a key to preventing cardiovascular disease in the offspring in their older age.

S-43-3: INTRAUTERINE GROWTH RESTRICTION CAUSES AN ALTERATION IN KIDNEY GENE EXPRESSION

High blood pressure (BP) and kidney disease are the leading cause of death in the world population. Experimental and epidemiological studies indicate that the fetal environment is critical in determining adult cardiovascular (CV)-renal outcome. It is known that intrauterine growth restriction (IUGR) or low birth weight (LBW) induces an increased risk of hypertension and kidney disease in later life. Placental insufficiency is the common cause of IUGR. Low birth weight is a significant public health problem globally and is associated with short- and long-term consequences. About 15–20% of all births worldwide are LBW, representing more than 20 million births a year. Clinical studies indicate that birth weight is positively associated with glomerular filtration rate (GFR) and negatively associated with BP. Also, animal models of IUGR exhibit a higher susceptibility to ANGII induced high BP and kidney damage in response to acute ischemic reperfusion injury. Thus, these data suggest that IUGR programs greater risk of hypertension and renal dysfunction. However, the exact mechanisms linking an adverse fetal environment with a later increased risk of these diseases are unclear. Objective: This study aims to evaluate the global genetic change in the kidney of the animal model of IUGR. Design: female C57Bl/6J were mated with male C57bl/6J. Upon confirming the pregnancy by sperm plug (day 0 of gestation), the pregnant animal will be undergone reduced uterine perfusion surgery (RUP) or shame surgery at day 13 of gestation. The offspring of RUP mom will be labeled as IUGR, and from the sham will be labeled as control. The offspring will be used for blood pressure measurement using radio-telemetry and kidney microarray analysis when they reach 24 weeks. Results: Th IUGR offspring significantly has an increase in blood pressure compared to the control. The kidneys of male IUGR have 6529 gene upregulation compared to male control. The make IUGR also has 5713 genes dow-regulation as compared to same-sex control. The female IUGR has 1635 genes upregulated and 1513 genes downregulated compared to the kidney from the female control group. Conclusion: the complication during pregnancy, such as reduced uterine perfusion, which is commonly found in preeclampsia programs, alters gene expression in the kidneys of their offspring. This finding suggests that IUGR causes the gene alteration in the kidneys, which is the primary organ in controlling the blood pressure of the offspring, and may lead to the development of hypertension and kidney disease.

CORD BLOOD LIPID PROFILE IN PRETERM AND TERM NEWBORNS: A HOSPITAL BASED COMPARATIVE STUDY FROM NORTH KANARA REGION OF INDIA

Introduction: Background: Cardiovascular diseases are common cause of moertality in developed countries and also are rising trend in developing countries. It has its roots in adverse fetal environment; which lead to adult diseases like Coronary artery diseases in later life. Aim: The objective of this study was to compare & contrast the lipid profiles in term and preterm neonates. Materials and Methods: a case-control study was conducted in departments of Pediatrics & Obstetrics of Karwar Institute of Medical Sciences, Karwar, Karnataka of India over a period of 10 months. 500 deliveries were recruited randomly which met the inclusion criteria after informed written consent;babies were divided into Comparison group 1 (Preterm gestation of <37weeks gestational age)& comparison group 2 (term gestation of >37 weeks gestational age).Cord blood lipd-profiles of these babies were compared & studied. Results: Out of 500 babies studied,there were 197 preterm (<37weeks gestational age) & 409 term babies (>37 weeks gestational age) babies.The Mean gestational age was 39.55±1.11 weeks for term babies & 34.50 ± 2.77 weeks for preterm babies.The mean TC level (73.76±27.98 mg/dL) was higher in comparison group 1(preterms) compared to comparison group 2(term)babies(62.60 ± 34.20mg/dL) and this difference was statistically very significant(P=0.003). The mean low density lipoprotein(LDL) level (35.54 ± 20.96mg/dL) was more higher in comparison group 1(preterms) compared to comparison group 2(term)babies (27.89 ± 15.62 mg/dL) and this difference was statistically very significant(P=0.001). The mean very low density lipoprotein(VLDL) level (11.12 ± 5.13mg/dL) was more higher in comparison group 1(preterms) compared to comparison group 2(term)babies (8.68 ± 7.55 mg/dL) and this difference was statistically very significant(P=0.003).The mean Triglycerides(TGs) levels of comparison group 1(preterms) & comparison group 2(term)babies were comparable with no statistical significance(42.63 ± 25.80mg/dL of preterm babies ; 42.43 ± 28.10mg/dL of term babies;P=0.948).The mean High density lipoprotein(HDL) levels of comparison group 1(preterms comparison) & comparison group 2(term)babies were comparable with low statistical significance(26.37 ± 13.65mg/dLof reterm babies ; 24.78 ± 10.76mg/dL of term babies;P=0.218). Conclusion: Levels of most lipid components were observed to be higher in preterm babies compared to term babies.

Adverse Maternal Fetal Environment Partially Mediates Disparate Outcomes in Non-White Neonates with Major Congenital Heart Disease

To determine whether differential exposure to an adverse maternal fetal environment partially explains disparate outcomes in infants with major congenital heart disease (CHD). Retrospective cohort study utilizing a population-based administrative California database (2011-2017). Primary exposure: Race/ethnicity. Primary mediator: Adverse maternal fetal environment (evidence of maternal metabolic syndrome and/or maternal placental syndrome). Composite of 1-year mortality or severe morbidity and days alive out of hospital in the first year of life (DAOOH). Mediation analyses determined the percent contributions of mediators on pathways between race/ethnicity and outcomes after adjusting for CHD severity. Included were 2747 non-Hispanic White infants (reference group), 5244 Hispanic, and 625 non-Hispanic Black infants. Hispanic and non-Hispanic Black infants had a higher risk for composite outcome (crude OR: 1.18; crude OR: 1.25, respectively) and fewer DAOOH (-6 & -12days, respectively). Compared with the reference group, Hispanic infants had higher maternal metabolic syndrome exposure (43% vs 28%, OR: 1.89), and non-Hispanic Black infants had higher maternal metabolic syndrome (44% vs 28%; OR: 1.97) and maternal placental syndrome exposure (18% vs 12%; OR, 1.66). Both maternal metabolic syndrome exposure (OR: 1.21) and maternal placental syndrome exposure (OR: 1.56) were related to composite outcome and fewer DAOOH (-25 & -16days, respectively). Adverse maternal fetal environment explained 25% of the disparate relationship between non-Hispanic Black race and composite outcome and 18% of the disparate relationship between Hispanic ethnicity and composite outcome. Adverse maternal fetal environment explained 16% (non-Hispanic Black race) and 21% (Hispanic ethnicity) of the association with DAOOH. Increased exposure to adverse maternal fetal environment contributes to racial and ethnic disparities in major CHD outcomes.

Abstract 9331: Adverse Maternal Fetal Environment Partially Mediates Disparate Outcomes in Hispanic and Non Hispanic Black Infants With Critical Congenital Heart Disease

Introduction: Etiologies of racial and ethnic disparities in critical congenital heart disease (CCHD) outcomes are not fully understood. We sought to determine whether differential exposure to an adverse maternal fetal environment (AMFE) partially explains disparate outcomes. Methods: We included infants with CCHD in a population-based administrative California database (2011-2017). Primary exposure was race/ethnicity. Primary mediator was AMFE, defined as maternal metabolic syndrome (MMS: any diabetes, abnormal BMI, or hyperlipidemia) or maternal placental syndrome (MPS: pre-eclampsia/ eclampsia, gestational hypertension, or placental abruption). Outcomes: days alive out of hospital in first year of life (DAOOH); composite of 1-year mortality or severe morbidity (e.g., ECMO, cardiac arrest, BPD, etc.). Mediation analyses (CCHD severity-adjusted) determined % contribution to outcome for each mediator on pathways between race/ethnicity and outcomes. Results: Included were 2,747 Non-Hispanic (NH) White [REF group], 5,244 Hispanic, and 625 NH Black infants. Hispanic and NH Black infants had higher risk for composite outcome (crude OR, 1.18; crude OR, 1.25 respectively) and fewer DAOOH (-6 & -12 days, respectively). Relative to NH White infants (MMS 28%; MPS 12%), Hispanic infants had higher MMS exposure (43%, OR, 1.89), while NH Black infants had higher MMS (44%, OR, 1.97) & MPS exposure (18%, OR, 1.66). Both MMS exposure (OR, 1.21) and MPS exposure (OR 1.56) were related to composite outcome and fewer DAOOH (-25 & -16 days, respectively). AMFE explained 25% of relationship between NH Black race and composite outcome, and 18% of relationship between Hispanic ethnicity and composite outcome. AMFE explained 16% (NH Black race) and 21% (Hispanic ethnicity) of the association with DAOOH (Table). Conclusions: Increased exposure to AMFE contributes to disparate outcomes in NH Black and Hispanic infants with CCHD. This novel finding merits clinical attention.

Reducing embryonic mtDNA copy number alters epigenetic profile of key hepatic lipolytic genes and causes abnormal lipid accumulation in adult mice.

Adverse fetal environment, in particular a shortage or excess of nutrients, is associated with increased risks of metabolic diseases later in life. However, the molecular mechanisms underlying this developmental origin of adult diseases remain unclear. Here, we directly tested the role of mitochondrial stress in mediating fetal programming in mice by enzymatically depleting mtDNA in zygotes. mtDNA-targeted plasmid microinjection is used to reduce embryonic mtDNA copy number directly, followed by embryo transfer. Mice with reduced zygote mtDNA copy number were born morphologically normal and showed no accelerated body weight gain. However, at 5 months of age these mice showed markedly increased hepatic lipidosis and became glucose-intolerant. Hepatic mRNA and protein expressions of peroxisome proliferator-activated receptor α (Pparα), a key transcriptional regulator of lipid metabolism, were significantly decreased as a result of increased DNA methylation in its proximal regulatory region. These results indicate that perturbation of mitochondrial function around the periconceptional period causes hypermethylation and thus suppressed expression of PPARα in fetal liver, leading to impaired hepatic lipid metabolism. Our findings provide the first direct evidence that mitochondrial stress mediates epigenetic changes associated with fetal programming of adult diseases in a mammalian system.

Developmental Exposure to Endocrine Disrupting Chemicals and Its Impact on Cardio-Metabolic-Renal Health.

Developmental origin of health and disease postulates that the footprints of early life exposure are followed as an endowment of risk for adult diseases. Epidemiological and experimental evidence suggest that an adverse fetal environment can affect the health of offspring throughout their lifetime. Exposure to endocrine disrupting chemicals (EDCs) during fetal development can affect the hormone system homeostasis, resulting in a broad spectrum of adverse health outcomes. In the present review, we have described the effect of prenatal EDCs exposure on cardio-metabolic-renal health, using the available epidemiological and experimental evidence. We also discuss the potential mechanisms of their action, which include epigenetic changes, hormonal imprinting, loss of energy homeostasis, and metabolic perturbations. The effect of prenatal EDCs exposure on cardio-metabolic-renal health, which is a complex condition of an altered biological landscape, can be further examined in the case of other environmental stressors with a similar mode of action.

Third Trimester Fetal Cardiac Blood Flow and Cardiac Outcomes in School-Age Children Assessed By Magnetic Resonance Imaging.

BackgroundAn adverse fetal environment leads to fetal hemodynamic adaptations with cardiac flow alterations that may subsequently affect cardiac development. We examined the associations of third trimester placental and fetal cardiac hemodynamics with cardiac outcomes in school‐age children.Methods and ResultsWe performed a population‐based prospective cohort study among 547 mothers and their children. At a gestational age of 30.4 (95% range 28.4–32.7) weeks, we measured umbilical and cerebral artery resistance, cardiac output, and tricuspid and mitral E/A waves with Doppler. At the median age of 10.0 years (95% range 9.4–11.7) we measured cardiac outcomes with cardiac magnetic resonance imaging. Cardiac outcomes included right ventricular end‐diastolic volume) and right ventricular ejection fraction, left ventricular end diastolic volume and left ventricular ejection fraction, left ventricular mass, and left ventricular mass‐to‐volume ratio as left ventricular mass/left ventricular end diastolic volume. Higher third‐trimester umbilical artery resistance was associated with higher childhood right ventricular ejection fraction (P value <0.05), but not with other cardiac outcomes. The third‐trimester umbilical artery‐cerebral artery pulsatility index ratio was not associated with childhood cardiac outcomes. Higher third‐trimester fetal left cardiac output was associated with lower childhood left ventricular ejection fraction and higher left ventricular mass‐to‐volume ratio (P value <0.05). Third‐trimester fetal right cardiac output was not associated with childhood cardiac outcomes. A higher third‐trimester fetal tricuspid valve E/A ratio was associated with higher childhood right ventricular ejection fraction (P value <0.05).ConclusionsOur findings suggest that fetal cardiac fetal blood flow redistribution may have long‐term effects on cardiac structure and function. These results should be considered as hypothesis generating and need further replication.

Developmental origin and sex-specific risk for infections and immune diseases later in life.

The intrauterine environment is an important determinant of immunity later in life of the offspring. An altered prenatal immune development can result in a high postnatal risk for infections, chronic immune diseases, and autoimmunity. Many of these immune diseases show a strong sex bias, such as a high incidence of autoimmune diseases and allergies in adult females or a high risk for infections in males. Here, we comprehensively review established pathways and propose novel concepts modulating the risk for such poor immunity during childhood and throughout life. Moreover, we highlight how an adverse fetal environment may affect or aggravate the risk for poor immunity in a sex-specific manner. An improved understanding of a sex-specific susceptibility to poor immunity along with insights on how such risk can be modulated before or around birth will allow the development of tailored prevention strategies.

Lower birthweight and left-/mixed-handedness are associated with intensified age-related sex steroid decline in men. Findings from the Men's Health 40+ Study.

SummaryIn males, age‐related decline in free testosterone (T) and dehydroepiandrosterone (DHEA) by 2–3% per year has been reported. Estradiol (E2) and progesterone (P) seem to decrease as well, but to a lesser extent. Lower sex steroid levels in men have been related to physical and mental symptoms. Low birthweight and left‐/mixed‐handedness (L/MH) are indicators of an adverse fetal environment during pregnancy, and both have been linked to morbidity in later life. The aim of this study is to examine the relationship between lower birthweight as well as L/MH and age‐related sex steroid decline. In a cross‐sectional study design, saliva samples were collected under standardized conditions from healthy men for subsequent steroid hormone analysis using standard luminescence immunoassays. T (M = 67.57 pg/mL), DHEA (M = 247.91 pg/mL), E2 (M = 1.29 pg/mL), and P (M = 28.20 pg/mL) have been quantified leading to a final sample of 256 men providing complete data on sex hormones (M Age=57.8; SDAge = 10.8). Information on participants’ birthweight was obtained from birth reports (N = 134), and participants were asked about their handedness (right‐handed, left‐handed, mixed‐handed) (N = 256). Multivariate‐adjusted linear regression models relating each sex hormone individually and the principal component of declining steroid hormones (DSH)—an integrated hormonal parameter—with handedness and birthweight did not identify significant associations except for handedness and E2. Moderation analysis using robust regression accounting for bias due to influential data points detected a significant association between age and DSH for handedness (β = −0.0314, p = 0.040) but only a trend for birthweight (β = 0.0309, p = 0.073). For lower birthweight, a trend toward intensified age‐related sex steroid decline in men was observed, while for L/MH, a significant association with intensified age‐related sex steroid decline was identified. These results indicate that L/MH and potentially also lower birthweight might be considered as early risk factors for endocrine health in later life.

Increased Bronchial Hyperresponsiveness and Higher Asymmetric Dimethylarginine Levels after Fetal Growth Restriction.

Bronchial hyperresponsiveness (BHR), a feature of asthma, is observed in preterm-born children and has been linked to intrauterine growth restriction. BHR is mediated via airway smooth muscle tone and is modulated by the autonomic nervous system, nitric oxide, and airway inflammation. Interactions among these factors are insufficiently understood. Methacholine-induced BHR (Met-BHR), fractional exhaled NO, and systemic soluble markers of nitric oxide metabolism and inflammation were determined in a population-based sample of 57 eleven-year-old children born extremely preterm (gestational age [GA] < 28 wk) or with extremely low birth weight (<1,000 g), and in a matched normal-birth weight term-born control group (n = 54). Bronchopulmonary dysplasia (BPD) was defined as the need for oxygen treatment at a GA of 36 weeks. In preterm-born children, birth weight below the 10th percentile for GA was associated with increased Met-BHR and higher plasma levels of asymmetric dimethylarginine (ADMA), with an increased odds ratio for being in the upper tertile of Met-BHR (11.8; 95% confidence interval, 3.3-42.4) and of ADMA (5.2; 95% confidence interval, 1.3-20.3). Met-BHR was correlated to ADMA level (r = 0.27, P = 0.007). There were no significant differences in Met-BHR, fractional exhaled NO, or z-FEV1 according to BPD status. No associations with systemic soluble markers of inflammation were observed for Met-BHR, birth, or BPD status. Intrauterine growth restriction in preterm-born children was associated with substantially increased Met-BHR and higher ADMA levels, suggesting altered nitric oxide regulation. These findings contribute to the understanding of the consequences from an adverse fetal environment; they should also be tested in term-born children.

Environmental enrichment mitigates the impact of ancestral stress on motor skill and corticospinal tract plasticity

BackgroundAn adverse fetal environment in utero has been associated with long-term alterations in brain structure and function, and a higher risk of neurological disorders in later life. A common consequence of early adverse experience is impaired motor system function. A causal relationship for stress-associated impairments and a suitable therapy, however, have not been determined yet. ObjectiveTo investigate the impact of ancestral stress on corticospinal tract (CST) morphology and fine motor performance in rats, and to determine if adverse programming by ancestral stress can be mitigated by environmental enrichment therapy in rats. MethodsThe study examined F3 offspring generated by three lineages; one with prenatal stress only in the F1 generation, one with compounding effects of multigenerational prenatal stress, and a non-stress control lineage. F3 offspring from each lineage were injected with biotinylated dextran amine (BDA) into the motor cortex for anterograde tracing of the CST. ResultsExamination of the CST revealed reduced axonal density in the ancestrally stressed lineages. These anatomical changes were associated with significant impairments in skilled walking, as indicated by reduced foot placement accuracy and disturbed inter-limb coordination. Therapeutic intervention by environmental enrichment reduced the neuromorphological consequences of ancestral stress and restored skilled walking ability. ConclusionsThe data suggest a causal relationship between stress-induced abnormal CST function and loss of fine motor performance. Thus, ancestral stress may be a determinant of motor system development and motor skill. Environmental enrichment may represent an effective intervention for the adverse programming by ancestral stress and trauma.

The Perinatal Origins of Cardiovascular Disease.

In recent decades, with advances in neonatal intensive care, extremely premature infants are now surviving into adulthood. Epidemiologic data on the health of these ex-premature infants have begun to reveal a concerning motif-that is, prematurity, in and of itself, seems to be a risk factor for cardiovascular and metabolic disease in later adulthood. The mechanisms underlying this increased risk are unclear, but it is believed that both adverse fetal environment and postnatal exposures for a premature infant likely contribute to the developmental programming of disease by altering the normal trajectory of maturation and aging of multiple organ systems. This article specifically focuses on perinatal factors that may affect risk for cardiovascular disease.

Fœtal impact of glucocorticoids in the programming of the disease

Epidemiological and experimental evidence suggests that an adverse fetal environment permanently “programmes” physiology leading to increased risks of cardiometabolic and neuropsychiatric disorders in later life. We originally hypothesised that fetal glucocorticoid overexposure might underpin this link. In genetically identical rodents, prenatal stress, glucocorticoid overexposure or inhibition/knockout of 11s-hydroxysteroid dehydrogenase type 2 (11β-HSD2), the feto-placental “barrier” to maternal glucocorticoids, reduces birth weight and causes permanent hypertension, hyperglycaemia, increased hypothalamic-pituitary-adrenal (HPA) axis activity and anxiety-related behaviours in adult offspring. The phenotype persists into a second generation and transmits via male and female lines. This implies epigenetic mediation, a mechanism emerging for HPA axis and metabolic programming. However, whilst first and second generation phenotypes are similar, the molecular mechanisms and epigenetic markers differ in each generation, implying strong selection on phenotype but weighing against neo-Lamarckian notions of ‘epigenetic inheritance’. Glucocorticoid programming appears of clinical relevance. In humans, placental 11β-HSD2 activity correlates directly with birth weight and inversely with infant blood pressure. Moreover, low birth weight babies have higher plasma cortisol levels throughout adult life, indicating HPA programming. Indeed, maternal glucocorticoid therapy or ingestion of liquorice (which inhibits 11β-HSD) alters offspring cognition, behaviour and HPA axis function. Stress has similar effects since the offspring of women pregnant during and directly exposed to the 9.11.2001 atrocity and who developed PTSD exhibit neuroendocrine changes but only if exposure was in the third trimester. Furthermore, exposure to the Nazi Holocaust exerted permanent effects upon glucocorticoid levels and steroid metabolism, effects dependent upon the age at exposure. The second (unexposed) generation also shows altered cortisol levels and metabolism, again with discordance in detail between generations. Overall, the data suggest that developmental exposure to excess glucocorticoids/stress programmes peripheral and CNS functions in adult life, predisposing to affective and other pathology, and these effects may impact on a subsequent generation. Any core mechanistic role for epigenetic processes in such early environment-induced effects is attractive but remains to be unequivocally established.

Prenatal origins of temperament: fetal growth, brain structure, and inhibitory control in adolescence.

ObjectiveIndividual differences in the temperamental dimension of effortful control are constitutionally based and have been associated with an adverse prenatal developmental environment, with structural brain alterations presenting a potential mechanism. We investigated this hypothesis for anatomically defined brain regions implicated in cognitive and inhibitory motor control.MethodsTwenty-seven 15–16 year old participants with low, medium, or high fetal growth were selected from a longitudinal birth cohort to maximize variation and represent the full normal spectrum of fetal growth. Outcome measures were parent ratings of attention and inhibitory control, thickness and surface area of the orbitofrontal cortex (lateral (LOFC) and medial (MOFC)) and right inferior frontal gyrus (rIFG), and volumetric measures of the striatum and amygdala.ResultsLower birth weight was associated with lower inhibitory control, smaller surface area of LOFC, MOFC and rIFG, lower caudate volume, and thicker MOFC. A mediation model found a significant indirect effect of birth weight on inhibitory control via caudate volume.ConclusionsOur findings support a neuroanatomical mechanism underlying potential long-term consequences of an adverse fetal developmental environment for behavioral inhibitory control in adolescence and have implications for understanding putative prenatal developmental origins of externalizing behavioral problems and self-control.

Prenatal Programming of Insulin Secretion in Intrauterine Growth Restriction

Intrauterine growth restriction (IUGR) impairs insulin secretion in humans and in animal models of IUGR. Several underlying mechanisms have been implicated, including decreased expression of molecular regulators of β-cell mass and function, in some cases shown to be due to epigenetic changes initiated by an adverse fetal environment. Alterations in cell cycle progression contribute to loss of β-cell mass, whereas decreased islet vascularity and mitochondrial dysfunction impair β-cell function in IUGR rodents. Animal models of IUGR sharing similar insulin secretion outcomes as the IUGR human are allowing underlying mechanisms to be identified. This review will focus on models of uteroplacental insufficiency.

Fetal PGC-1α Overexpression Programs Adult Pancreatic β-Cell Dysfunction

Adult β-cell dysfunction, a hallmark of type 2 diabetes, can be programmed by adverse fetal environment. We have shown that fetal glucocorticoids (GCs) participate in this programming through inhibition of β-cell development. Here we have investigated the molecular mechanisms underlying this regulation. We showed that GCs stimulate the expression of peroxisome proliferator–activated receptor-γ coactivator-1α (PGC-1α), a coregulator of the GCs receptor (GR), and that the overexpression of PGC-1α represses genes important for β-cell development and function. More precisely, PGC-1α inhibited the expression of the key β-cell transcription factor pancreatic duodenal homeobox 1 (Pdx1). This repression required the GR and was mediated through binding of a GR/PGC-1α complex to the Pdx1 promoter. To explore PGC-1α function, we generated mice with inducible β-cell PGC-1α overexpression. Mice overexpressing PGC-1α exhibited at adult age impaired glucose tolerance associated with reduced insulin secretion, decreased β-cell mass, and β-cell hypotrophy. Interestingly, PGC-1α expression in fetal life only was sufficient to impair adult β-cell function whereas β-cell PGC-1α overexpression from adult age had no consequence on β-cell function. Altogether, our results demonstrate that the GR and PGC-1α participate in the fetal programming of adult β-cell function through inhibition of Pdx1 expression.

Impact of Cadmium Exposure during Pregnancy on Hepatic Glucocorticoid Receptor Methylation and Expression in Rat Fetus

Adverse fetal environment due to maternal undernutrition or exposure to environmental chemicals alters glucocorticoid (GC) metabolism increasing the risk of metabolic disorders in adulthood. In this study, we investigated the effects of maternal exposure to cadmium (Cd, 50 ppm) during pregnancy in the methylation of fetal hepatic glucocorticoid receptor promoter (GR) and the correlation with its expression and that of the DNA methyltransferases (DNMT1a and 3a). We also studied the expression of liver phosphoenolpyruvate carboxykinase (PEPCK) and acyl-CoA oxidase (AOX), two enzymes involved in the metabolism of carbohydrates and lipids respectively. The methylation of the rat GR gene exon 110 (GR110) in nucleotides -2536 to -2361 was analyzed by pyrosequencing. Quantitative real time PCR was used to assess hepatic GR, PEPCK and AOX mRNA, and their protein levels using Western blotting analysis. Differential methylation was noted across groups at all CpG sites in the GR exon 110 in a sex-dependent manner. In males, CpG were more methylated than the controls (185±21%, p<0.001) but only CpG sites 1,6,7 and 9 showed a significantly different extent of methylation. In addition, a lower expression of GR (mRNA and protein) was found. On the contrary, in females, CpG were less methylated than the controls (62±11%, p<0.05) and overexpressed, affecting PEPCK and AOX expression, which did not change in males. The GR methylation profile correlates with DNMT3a expression which may explain epigenetic sex-dependent changes on GR110 promoter induced by Cd treatment. In conclusion, Cd exposure during pregnancy affects fetal liver DNMT3a resulting in sex-dependent changes in methylation and expression of GR110. Although these effects do not seem to be directly involved in the low birth weight and height, they may have relevant implications for long-term health.

Molecular mechanisms underlying the fetal programming of adult disease

Adverse events in utero can be critical in determining quality of life and overall health. It is estimated that up to 50% of metabolic syndrome diseases can be linked to an adverse fetal environment. However, the mechanisms linking impaired fetal development to these adult diseases remain elusive. This review uncovers some of the molecular mechanisms underlying how normal physiology may be impaired in fetal and postnatal life due to maternal insults in pregnancy. By understanding the mechanisms, which include epigenetic, transcriptional, endoplasmic reticulum (ER) stress, and reactive oxygen species (ROS), we also highlight how intervention in fetal and neonatal life may be able to prevent these diseases long-term.

Effects of in utero conditions on adult feeding preferences.

The fetal or early origins of adult disease hypothesis states that environmental factors, particularly nutrition, act in early life to program the risks for chronic diseases in adult life. As eating habits can be linked to the development of several diseases including obesity, diabetes and cardiovascular disease, it could be proposed that persistent food preferences across the life-span in people who were exposed to an adverse fetal environment may partially explain their increased risk to develop metabolic disease later in life. In this paper, we grouped the clinical and experimental evidence demonstrating that the fetal environment may impact the individual's food preferences. In addition, we review the feeding preferences development and regulation (homeostatic and hedonic pathways, the role of taste/olfaction and the reward/pleasure), as well as propose mechanisms linking early life conditions to food preferences later in life. We review the evidence suggesting that in utero conditions are associated with the development of specific food preferences, which may be involved in the risk for later disease. This may have implications in terms of public health and primary prevention during early ages.