Mechanisms Of Fetal Programming Research Articles

Epigenetic mechanisms of fetal programming in excessive intake of synthetic folates at the preconception stage

To date, there is no doubt that taking folic acid at the perigravid stage in an adequate dosage has a positive effect on fetal development and the course and outcome of pregnancy. There is extensive evidence that during pregnancy, folate deficiency is associated with spontaneous miscarriages, premature birth, and premature detachment of the normally positioned placenta, and it can cause intrauterine malformations of the nervous and cardiovascular systems of the fetus.
 Understanding the need to reduce such severe complications, which have both medical and social significance, has contributed in a number of countries to the introduction of programs for food fortification and routine prescribing of folic acid preparations to pregnant women. The measures taken significantly reduced the incidence of fetal congenital malformations, but at the same time, this strategy had a negative effect, resulting in a chronic overdose of synthetic folic acid. Recent studies have shown that the accumulation of non-metabolized folic acid in a pregnant woman may be associated with obstetric pathology and impaired development of fetuses and newborns. There is growing evidence that prolonged folic acid overdose during pregnancy, especially in the presence of altered levels of other vitamins, may lead to such diseases in children as autism and multiple amyotrophic sclerosis. Thus, this issue requires in-depth study in order to move from the routine prescription of folic acid preparations to personalized nutritional support for women at the preconception stage and during pregnancy.

Molecular mechanisms involved in fetal programming and disease origin in adulthood.

Fetal programming occurs during the gestational age when exposure to environmental stimuli can cause long-term changes in the fetus, predisposing it to develop chronic non-communicable diseases (CNCD) in adulthood. Herein, we summarized the role of low-calorie or high-fat diets during pregnancy as fetal programming agents that induce intrauterine growth restriction (IUGR), amplified de novo lipogenesis, and increased amino acid transport to the placenta, which favor the CNCD onset in the offspring. We also outlined how maternal obesity and gestational diabetes act as fetal programming stimuli by reducing iron absorption and oxygen transport to the fetus, stimulating inflammatory pathways that boost neurological disorders and CNCD in the progeny. Moreover, we reviewed the mechanisms through which fetal hypoxia elevates the offspring's risk of developing hypertension and chronic kidney disease in adult life by unbalancing the renin-angiotensin system and promoting kidney cell apoptosis. Finally, we examined how inadequate vitamin B12 and folic acid consumption during pregnancy programs the fetus to greater adiposity, insulin resistance, and glucose intolerance in adulthood. A better understanding of the fetal programming mechanisms may help us reduce the onset of insulin resistance, glucose intolerance, dyslipidemia, obesity, hypertension, diabetes mellitus, and other CNCD in the offspring during adulthood.

211 Overcoming the Growth Deficits Programmed by Maternofetal Stress

Abstract Prolonged maternofetal stress stunts placental development and causes fetal programming that reduces fetal growth and birthweight. Low birthweight due to intrauterine growth restriction (IUGR) of the fetus increases perinatal mortality. More commonly, however, it results in lifelong impairment of muscle growth capacity and metabolic function. In humans, low birthweight increases risk for obesity, diabetes, and other metabolic disorders by an estimated 18-fold. Similarly, low birthweight livestock exhibit greater early death loss, poor growth efficiency, and lower-quality carcasses at harvest. These animals manifest poor feed-to-gain ratios, less lean mass, and greater fat deposition. Together, these outcomes increase production costs, decrease value, and reduce the amount of meat produced per animal. The fetal programming mechanisms linking stress induced IUGR to impaired postnatal growth and metabolic efficiency are largely unknown. However, recent findings in IUGR fetal and neonatal lambs produced experimentally by maternal heat stress and maternofetal inflammation (and pair-fed controls) indicated skeletal muscle-centric programming of adrenergic and inflammatory pathways. Specifically, studies found reduced β2 adrenergic tone and enriched inflammatory signaling pathways. These changes coincided with intrinsic myoblast dysfunction, reduced muscle fiber hypertrophy, and impaired skeletal muscle glucose metabolism. Additionally, IUGR fetal and neonatal lambs exhibited impaired β cell function that may also be associated with adrenergic and inflammatory programming. Subsequent studies have investigated these mechanisms as potential therapeutic targets for interventions and treatments, which is a fundamental step in developing strategies to improve outcomes in low birthweight humans and livestock.

Environmental health influences in pregnancy and risk of gestational diabetes mellitus: a systematic review

BackgroundGestational diabetes mellitus (GDM) is one of the most common pregnancy complications globally. Environmental risk factors may lead to increased glucose levels and GDM, which in turn may affect not only the health of the mother but assuming hypotheses of "fetal programming", also the health of the offspring. In addition to traditional GDM risk factors, the evidence is growing that environmental influences might affect the development of GDM. We conducted a systematic review analyzing the association between several environmental health risk factors in pregnancy, including climate factors, chemicals and metals, and GDM.MethodsWe performed a systematic literature search in Medline (PubMed), EMBASE, CINAHL, Cochrane Library and Web of Science Core Collection databases for research articles published until March 2021. Epidemiological human and animal model studies that examined GDM as an outcome and / or glycemic outcomes and at least one environmental risk factor for GDM were included.ResultsOf n = 91 studies, we classified n = 28 air pollution, n = 18 persistent organic pollutants (POP), n = 11 arsenic, n = 9 phthalate n = 8 bisphenol A (BPA), n = 8 seasonality, n = 6 cadmium and n = 5 ambient temperature studies. In total, we identified two animal model studies. Whilst we found clear evidence for an association between GDM and air pollution, ambient temperature, season, cadmium, arsenic, POPs and phthalates, the findings regarding phenols were rather inconsistent. There were clear associations between adverse glycemic outcomes and air pollution, ambient temperature, season, POPs, phenols, and phthalates. Findings regarding cadmium and arsenic were heterogeneous (n = 2 publications in each case).ConclusionsEnvironmental risk factors are important to consider in the management and prevention of GDM. In view of mechanisms of fetal programming, the environmental risk factors investigated may impair the health of mother and offspring in the short and long term. Further research is needed.

Placental Vascular Abnormalities in Association With Prenatal and Long-Term Health Characteristics Among HIV-Exposed Uninfected Adolescents and Young Adults.

HIV-exposed uninfected (HEU) individuals are predisposed to adverse health outcomes, which in part may stem from the influence of an altered intrauterine milieu on fetal programming. The placenta serves as a readout for the effects of the maternal environment on the developing fetus and may itself contribute to the pathogenesis of disease. US academic health system. We leveraged a previously established registry-based cohort of HEU adolescents and young adults to identify 26 subjects for whom placental histopathology was available. We further obtained placental tissue from 29 HIV-unexposed pregnancies for comparison. We examined differences in placental histopathology between the groups and related villous vascularity in the HEU group to prenatal maternal characteristics and long-term health outcomes. Placentas from HEU pregnancies demonstrated a higher blood vessel count per villus as compared with controls (5.9 ± 1.0 vs. 5.4 ± 0.8; P = 0.05), which was independent of maternal prenatal age, race, body mass index, smoking status, hemoglobin, and gestational age. Furthermore, within the HEU group, lower CD4+ T-cell count during pregnancy was associated with greater placental vascularity (r = -0.44; P = 0.03). No significant relationships were observed between placental blood vessel count per villus and body mass index z-score or reactive airway disease among HEU individuals later in life. Placentas from HEU pregnancies demonstrated increased villous vascularity compared with HIV-unexposed controls in proportion to the severity of maternal immune dysfunction. Further studies are needed to examine intrauterine exposure to hypoxia as a potential mechanism of fetal programming in HIV.

Fetal programming of polycystic ovary syndrome: Effects of androgen exposure on prenatal ovarian development

Polycystic ovary syndrome (PCOS) is a common form of anovulatory infertility with a strong hereditary component but no candidate genes have been found. The inheritance pattern may be due to in utero androgen programming on gene expression and mitochondria. Mitochondria are maternally inherited and alterations to mitochondria after fetal androgen exposure may explain one of the mechanisms of fetal programming in PCOS. Our aim was to investigate the role of excessive prenatal androgens in ovarian development by identifying how hyperandrogenemia affects gene expression and mitochondria in neonatal ovary. Pregnant dams were injected with dihydrotestosterone on days 16–18 of pregnancy. Day 0 ovaries were collected for gene expression and mitochondrial studies. RNAseq showed differential gene expressions which were related to mitochondrial dysfunction, fetal gonadal development, oocyte maturation, metabolism, angiogenesis, and PCOS. Top 20 up and downregulated genes were validated with qPCR and Western Blot. Transcriptional pathways involved in folliculogenesis and genes involved in ovarian and mitochondrial function were dysregulated. Further, DHT exposure altered mitochondrial ultrastructure and function by increasing mitochondrial oxygen consumption and decreasing mitochondrial efficiency with increased proton leak within the first day of life. Our data indicates that one path that leads to PCOS begins at birth and is programmed in utero by androgens.

How mother's obesity may affect the pregnancy and offspring.

One of the main reasons for the epidemic of obesity, which has already influenced the economic condition of health system worldwide, is our modern lifestyle having an unbalanced calorie intake and insufficient physical activity. Maternal-fetal nourishment and metabolism are the mechanisms of fetal programming of obesity-adiposity and non-communicable diseases that have been most extensively investigated. A mother's obesity is related to adverse outcomes for both mother and baby. Maternal overnutrition is also associated with a higher risk of gestational diabetes, preterm birth, large-for-gestational-age babies, fetal defects, congenital anomalies, and perinatal death. Women with obesity should be encouraged to reduce their body mass index (BMI) prior to pregnancy, and to limit weight gain during pregnancy. Obstetric ultrasound imaging in pregnant women is negatively affected by abdominal adipose tissue, having an adverse influence on congenital anomaly detection rates and the estimation of fetal weight.

Intrauterine Exposure to Diabetic Milieu Does Not Induce Diabetes and Obesity in Male Adulthood in a Novel Rat Model.

Several studies show an association of maternal diabetes during pregnancy with adverse offspring metabolic health. Other studies, however, suggest that this effect might be biased by obesity, which is independently associated with offspring metabolic disease and often coexistent to maternal diabetes. We performed a prospective study in a rat model to test the hypothesis that the burden of a diabetic pregnancy without obesity deteriorates metabolic health in male offspring. We generated maternal type 2 diabetes before conception that persisted during pregnancy by knockdown of the insulin receptor in small hairpin RNA-expressing transgenic rats. Male WT (wild type) offspring were followed up until adulthood and metabolically challenged by high-fat diet. Blood glucose was measured continuously via a telemetry device. Glucose and insulin tolerance tests were performed, and body composition was analyzed. Weight gain and glucose levels during adolescence and adulthood were similar in male offspring of diabetic and control pregnancies. Body weight and fat mass after high-fat diet, as well as glucose and insulin tolerance tests, were unaltered between male adult offspring of both groups. Glycemic control consisting of up to 49 000 individual glucose measures was comparable between both groups. Intrauterine exposure to maternal hyperglycemia and hyperinsulinemia without obesity had no impact on male offspring metabolic health in our model. We conclude that the intrauterine exposure itself does not represent a mechanism for fetal programming of diabetes and obesity in our model. Other maternal metabolic parameters during pregnancy, such as obesity, might impact long-term offspring metabolic health.

The impact of placental pathology discordance in multiple gestation pregnancies on bronchopulmonary dysplasia-associated pulmonary hypertension.

Bronchopulmonary dysplasia-associated pulmonary hypertension (BPD-PH) may either be concordant or discordant between multiple gestation births. Abnormal placental development, particularly maternal vascular malperfusion, may account for discordance in BPD-PH through fetal programming mechanisms. Maternal vascular malperfusion is a placental histologic lesion associated with intrauterine growth restriction and BPD-PH. We conducted a retrospective longitudinal cohort study of infants born <29 weeks gestation with available placental histology at Prentice Women's Hospital in Chicago from 2005–2012. The primary outcome was discordant BPD-PH associated with placental maternal vascular malperfusion. We secondarily assessed whether the risk of BPD-PH and placental lesions was different among infants of multiple (compared to singleton) gestations. The cohort consisted of 135 multiple gestation infants and 355 singletons. In a separate cohort of 39 singletons and 35 multiples, associations between 12 cytokines and angiogenic growth factors in cord blood plasma for biomarker discordance, maternal vascular malperfusion, and bronchopulmonary dysplasia were explored. Among multiples, discordant maternal vascular malperfusion was not associated with BPD-PH (OR = 1.9 (0.52, 6.9); p = 0.33) in infants exposed to placental maternal vascular malperfusion. However, singleton infants were more likely to develop BPD-PH (compared to multiples) after adjusting for mode of delivery, chorioamnionitis, chronic hypertension, placental abruption, small-for-gestational age birth weight, and gestational age (aOR = 2.7 (1.2, 5.8); p = 0.038). Singletons were more likely to be small-for-gestational age (11% vs 4%, p = 0.025) and have placental lesions compared to their multiple-gestation counterparts (96% vs 81%, p < 0.001), principally severe maternal vascular malperfusion (17% vs 4%, p < 0.001) and chronic inflammation (32% vs 11%, p < 0.001). Increased risk of BPD-PH in singleton pregnancies <29 weeks gestation compared to multiples may be related to increased frequency of these histologic lesions. Placental pathology in singleton and multiple gestation pregnancies may serve as an early biomarker to predict BPD-PH.

1024: hu-IGF-1 nanoparticle placental injection for fetal growth restriction treatment is safe

We previously demonstrated nanoparticle mediated trophoblast-specific Hu-IGF-1 expression increased placental nutrient transport to maintain fetal growth in a surgically induced mouse model of fetal growth restriction (FGR, Jones, 2015). Modelling FGR in a guinea pig permits a longer gestation for developing treatment of pre-existing FGR (Roberts, 2018). Our aim was to investigate mechanisms of fetal programming in FGR in Guinea pigs and assess the impact of nanoparticle mediated transgene delivery. Control dams (n=5) received chow ad Libitum while the maternal nutrient restricted (MNR) group (n=3) received 70% preconception diet through mid-gestation which increased to 90% ad Libitum from 30 d.p.c. through necropsy. Pregnancy was confirmed by transabdominal ultrasound on 21 d.p.c. Tran-placental injection of nanoparticles (HPMA-DMAEMA:PLAC1Hu-IGF1 or HPMA-DMAEMA:CYP19Hu-IGF1) was performed at 30-36 d.p.c under ultrasound guidance. Dams were sacrificed 5 days post-injection, and maternal, placental and fetal demographics collected. Fetal organs were harvested and processed for expression analysis. Whole RNA isolation was performed and TGF-β, TNF-α, CTGF, and MMP-2 RNA expression was analyzed by qPCR in fetal liver, heart, and brain. To assess proliferation and vessel density immunohistochemistry was performed with anti-Ki67 and anti-CD31 antibodies on fetal liver and heart. Fetal weight, organ size and glucose was significantly reduced in restricted compared to control offspring with brain sparing in the restricted group (Table 1). TGFβ in fetal restricted heart increased 1 fold over controls (P< 0.5) and 4.5 fold in brain (P< 0.01). CTGF increased 1.5 fold (P< 0.05) in fetal brain with no alteration in TNFα or MMP-2 (Figure 1). Despite reduced organ weights, proliferation (Ki-67) rates and vascular (CD31) were similar between controls and MNR in the fetal heart and liver. Our model recapitulates FGR with brain sparing and initial experiments with NP-IGF-1 demonstrate no detrimental impact to fetal growth and development in normal pregnancy.View Large Image Figure ViewerDownload Hi-res image Download (PPT)

Nutrition and Fetal Origins of Diseases in Adults

Accumulating evidence suggests that the early-life environment has lasting effects on health and disease into adulthood. The current concept of developmental origins of adulthood disease has expanded beyond the original observation by Barker and colleagues correlating low birth weight with adulthood cardiovascular and metabolic disorders. Notably, the fetal-neonatal nutritional environment has a significant role in influencing an individual’s wellness in adulthood. During critical periods of fetal and neonatal development, tissues and organ systems are most vulnerable to nutrient deficiencies. Through fetal programming mechanisms such as epigenetic modification, a biochemical process that regulates gene expression without altering the genetic code, developing tissues adapt to nutrient-poor environments to preserve normal development of critical organ systems, including the brain. However, these programmed adaptations can have negative long-term health consequences if the postnatal environment does not match the fetal-neonatal environment in which the programming occurred. These long-term adverse health outcomes constitute the true cost to society, in both increased medical costs and the indirect cost of lost productivity. Here we review the effects of nutrient deficiencies on fetal programming and subsequent health outcomes, as well as the potential mechanisms that underlie fetal programming. This review contains 3 Figures, 2 Tables and 115 references Key words: critical period, epigenetics, fetal programming, iron, long-chain polyunsaturated fatty acids, neurodevelopment, nutrient deficiency, protein-energy, vitamins, zinc

Obesity in mares promotes uterine inflammation and alters embryo lipid fingerprints and homeostasis.

Maternal body composition can be an important determinant for development of obesity and metabolic syndrome in adult offspring. Obesity-related outcomes in offspring may include epigenetic alterations; however, mechanisms of fetal programming remain to be fully elucidated. This study was conducted to determine the impact of maternal obesity in the absence of a high fat diet on equine endometrium and preimplantation embryos. Embryos were collected from normal and obese mares at 8 and 16 days and a uterine biopsy at 16 days (0 day=ovulation). With the exception of 8 day embryos, each sample was divided into two pieces. One piece was analyzed for gene expression markers related to carbohydrate metabolism, lipid homeostasis, inflammation, endoplasmic reticulum stress, oxidative stress, mitochondrial stress, and components of the insulin-like growth factor (IGF) system. The second piece was analyzed for lipid content using matrix-assisted laser desorption/ionization mass spectrometry. Obese mares had elevated concentrations of insulin, leptin, and total cholesterol, and they tended to have increased triglycerides and decreased insulin sensitivity. Embryos from obese mares had altered transcript abundance in genes for inflammation and lipid homeostasis, as well as endoplasmic reticulum, oxidative and mitochondrial stress and altered lipid fingerprints. Endometrium from obese mares had increased expression of inflammatory cytokines, lipid homeostasis regulation, mitochondrial stress, and the IGF2 system. This study demonstrates that increased adiposity in mares alters the uterine environment, transcript abundance of genes for cellular functions, and lipid profiles of embryos. These alterations could affect prenatal programming, with potential long-term effects in offspring.

Maternal obesity increases the risk of metabolic disease and impacts renal health in offspring.

Obesity, together with insulin resistance, promotes multiple metabolic abnormalities and is strongly associated with an increased risk of chronic disease including type 2 diabetes (T2D), hypertension, cardiovascular disease, non-alcoholic fatty liver disease (NAFLD) and chronic kidney disease (CKD). The incidence of obesity continues to rise in astronomical proportions throughout the world and affects all the different stages of the lifespan. Importantly, the proportion of women of reproductive age who are overweight or obese is increasing at an alarming rate and has potential ramifications for offspring health and disease risk. Evidence suggests a strong link between the intrauterine environment and disease programming. The current review will describe the importance of the intrauterine environment in the development of metabolic disease, including kidney disease. It will detail the known mechanisms of fetal programming, including the role of epigenetic modulation. The evidence for the role of maternal obesity in the developmental programming of CKD is derived mostly from our rodent models which will be described. The clinical implication of such findings will also be discussed.

Associations between biological markers of prenatal stress and infant negative emotionality are specific to sex

PurposeFetal programming is the idea that environmental stimuli can alter the development of the fetus, which may have a long-term effect on the child. We have recently reported that maternal prenatal cortisol predicts infant negative emotionality in a sex-dependent manner: high prenatal cortisol was associated with increased negative emotionality in females, and decreased negative emotionality in males. This study aims to test for this sex-specific effect in a different cohort, and investigate whether sex differences in fetal programming may be specific to glucocorticoid mechanisms by also examining a maternal salivary alpha-amylase (sAA) by sex interaction. Methods88 pregnant women (mean gestational age=27.4 weeks, SD=7.4) collected saliva samples at home over two working days to be assayed for the hormone cortisol (range=0.13–88.22nmol/l) and the enzyme alpha-amylase (range=4.57–554.8units/ml). Samples were collected at waking, 30-min post-waking and 12h post-waking. Two months after birth participants reported infant negative emotionality using the distress to limits subscale of the Infant Behavior Questionnaire. ResultsThe interaction between maternal prenatal cortisol and infant sex to predict distress to limits approached significance (p=0.067). In line with our previous finding there was a positive association between prenatal cortisol and negative emotionality in females, and a negative association in males. The interaction between sAA and sex to predict distress was significant (p=0.025), and the direction of effect was the same as for the cortisol data; high sAA associated with increased negative emotionality in females and reduced negative emotionality in males. ConclusionsIn line with our previous findings, this research adds to an emerging body of literature, which suggests that fetal programming mechanisms may be sex-dependent. This is the first study to demonstrate that maternal prenatal sAA may be an important biomarker for infant behavior, and the findings have implications for understanding sex differences in developmental psychopathology.

Perinatal Maternal Mental Health, Fetal Programming and Child Development.

Maternal mental disorders over pregnancy show a clear influence on child development. This review is focused on the possible mechanisms by which maternal mental disorders influence fetal development via programming effects. This field is complex since mental health symptoms during pregnancy vary in type, timing and severity and maternal psychological distress is often accompanied by higher rates of smoking, alcohol use, poor diet and lifestyle. Studies are now beginning to examine fetal programming mechanisms, originally identified within the DOHaD framework, to examine how maternal mental disorders impact fetal development. Such mechanisms include hormonal priming effects such as elevated maternal glucocorticoids, alteration of placental function and perfusion, and epigenetic mechanisms. To date, mostly high prevalence mental disorders such as depression and anxiety have been investigated, but few studies employ diagnostic measures, and there is very little research examining the impact of maternal mental disorders such as schizophrenia, bipolar disorder, eating disorders and personality disorders on fetal development. The next wave of longitudinal studies need to focus on specific hypotheses driven by plausible biological mechanisms for fetal programming and follow children for a sufficient period in order to examine the early manifestations of developmental vulnerability. Intervention studies can then be targeted to altering these mechanisms of intergenerational transmission once identified.

Prenatal Stress Induces Skeletal Malformations in Mouse Embryos

Dexamethasone, a synthetic glucocorticoid (GC), is clinically administered to woman at risk for premature labor to induce fetal lung maturation. However, exposure to repeated or excess GCs leads to intrauterine growth restriction (IUGR) and subsequently increases risk of psychiatric and cardio-metabolic diseases in later life through fetal programming mechanisms. GCs are key mediators of stress responses, therefore, maternal nutrient restriction or psychological stress during pregnancy also causes negative impacts on birth and neurodevelopment outcome of fetuses, and other congenital defects, such as craniofacial and skeletal abnormalities. In this study, to examine the effect of prenatal stress on fetal skeletal development, dexamethasone (1 mg/kg [DEX1] or 10 mg/kg [DEX10] maternal body weight per day) was administered intraperitoneally at gestational day 7.5~9.5 and the skeletons were prepared from embryos at day 18.5. Seven out of eighteen (39%) embryos treated with DEX10 showed axial skeletal abnormalities in either the T13 or L1 vertebrae. In addition, examination of the sternum revealed that xiphoid process, the protrusive triangular part of the lower end of the sternum, was bent more outward or inward in DEX group embryos. In conclusion, our findings suggest a possible link to the understanding of the effect of uterine environment to the fetal skeletal features.

Deficiência de vitamina D na gravidez e o seu impacto sobre o feto, o recém‐nascido e na infância

ObjectiveVitamin D deficiency (VDD) in pregnant women and their children is an important health problem with severe consequences for the health of both. Thus, the objectives of this review were to reassess the magnitude and consequences of VDD during pregnancy, lactation and infancy, associated risk factors, prevention methods, and to explore epigenetic mechanisms in early fetal life capable of explaining many of the non‐skeletal benefits of vitamin D (ViD). Data sourceOriginal and review articles, and consensus documents with elevated level of evidence for VDD‐related clinical decisions on the health of pregnant women and their children, as well as articles on the influence of ViD on epigenetic mechanisms of fetal programming of chronic diseases in adulthood were selected among articles published on PubMed over the last 20 years, using the search term VitD status, in combination with Pregnancy, Offspring health, Child outcomes, and Programming. Data synthesisThe following items were analyzed: ViD physiology and metabolism, risk factors for VDD and implications in pregnancy, lactation and infancy, concentration cutoff to define VDD, the variability of methods for VDD detection, recommendations on ViD replacement in pregnant women, the newborn and the child, and the epigenetic influence of ViD. ConclusionsVDD is a common condition among high‐risk pregnant women and their children. The routine monitoring of serum 25(OH)D3 levels in antenatal period is mandatory. Early preventive measures should be taken at the slightest suspicion of VDD in pregnant women, to reduce morbidity during pregnancy and lactation, as well as its subsequent impact on the fetus, the newborn and the child.

Elevated fetal steroidogenic activity in autism

Autism affects males more than females, giving rise to the idea that the influence of steroid hormones on early fetal brain development may be one important early biological risk factor. Utilizing the Danish Historic Birth Cohort and Danish Psychiatric Central Register, we identified all amniotic fluid samples of males born between 1993 and 1999 who later received ICD-10 (International Classification of Diseases, 10th Revision) diagnoses of autism, Asperger syndrome or PDD-NOS (pervasive developmental disorder not otherwise specified) (n=128) compared with matched typically developing controls. Concentration levels of Δ4 sex steroids (progesterone, 17α-hydroxy-progesterone, androstenedione and testosterone) and cortisol were measured with liquid chromatography tandem mass spectrometry. All hormones were positively associated with each other and principal component analysis confirmed that one generalized latent steroidogenic factor was driving much of the variation in the data. The autism group showed elevations across all hormones on this latent generalized steroidogenic factor (Cohen's d=0.37, P=0.0009) and this elevation was uniform across ICD-10 diagnostic label. These results provide the first direct evidence of elevated fetal steroidogenic activity in autism. Such elevations may be important as epigenetic fetal programming mechanisms and may interact with other important pathophysiological factors in autism.

Review: Fetal Programming of Polycystic Ovary Syndrome by Androgen Excess — Evidence from Experimental, Clinical and Genetic Association Studies

ABSTRACT Objective Polycystic ovary syndrome (PCOS) is a common endocrine disorder of premenopausal women, characterized by hyperandrogenism, polycystic ovaries, and chronic anovulation along with insulin resistance and abdominal obesity as frequent metabolic traits. Although, PCOS manifests clinically during adolescence, emerging data suggest that the natural history of PCOS may originate in intrauterine life. Evidence Acquisition Evidence from experimental, clinical, and genetic research supporting the hypothesis for the fetal origins of PCOS has been analyzed. Evidence Synthesis Female primates, exposed in utero to androgen excess, exhibit the phenotypic features of PCOS during adult life. Clinical observations also support a potential fetal origin of PCOS. Women with fetal androgen excess disorders, including congenital 21-hydroxylase deficiency and congenital adrenal virilizing tumors, develop features characteristic of PCOS during adulthood despite the normalization of androgen excess after birth. The potential mechanisms of fetal androgen excess leading to a PCOS phenotype in humans are not clearly understood. However, maternal and/or fetal hyperandrogenism can provide a plausible mechanism for fetal programming of PCOS, and this, in part, may be genetically determined. Thus, genetic association studies have indicated that common polymorphic variants of genes determining androgen activity or genes that influence the availability of androgens to target tissues are associated with PCOS and increased androgen levels. These genomic variants may provide the genetic link to prenatal androgenization in human PCOS. Conclusion Prenatal androgenization of the female fetus induced by genetic and environmental factors, or the interaction of both, may program differentiating target tissues toward the development of PCOS phenotype in adult life.

301: Mechanisms of fetal programming of adverse metabolic profile and its prevention by pravastatin in a preeclampsia-like murine model

301: Mechanisms of fetal programming of adverse metabolic profile and its prevention by pravastatin in a preeclampsia-like murine model