From fathers to offspring: epigenetic impacts of diet and lifestyle on fetal development

The significance of diet induced inflammation in gestational tissue (chorioamnionitis) on fetal growth and development is emerging as an important area of research. Role of infection and intrauterine inflammation in preterm deliveries has been extensively explored, but, implication of sterile inflammation (not associated with infection) on fetal development has received little attention. Inflammation is generally thought to be the result of a local or systemic infection or products of infection; conversely, inflammation may result from high calorie intake or from diets low in micronutrients. While systemic inflammation is widely proposed as the predisposing factor for the increasing incidence of non-communicable diseases such as diabetes mellitus and cardiovascular diseases in adults, accumulating evidences now suggest that low grade intrauterine inflammation might impair linear growth and adversely affect myogenesis and adipogenesis that might have lasting effects on offspring. Given that intrauterine inflammation is frequently present, its origin and impact on fetal development needs attention. The public health implications of nutrition-mediated inflammation is of particular importance in India, which is burdened with problem of over-nutrition coupled with undernutrition and micronutrient malnutrition. Studies to unearth the link between nutrition and inflammation and its impact on fetal growth and development are needed. This review explores the potential consequences of intrauterine inflammation on fetal growth and development.

Neuregulin 1 (NRG1) is a multifunctional neurotrophin that mediates neurodevelopment and schizophrenia risk. The NRG1 gene undergoes extensive alternative splicing, and association of brain NRG1 type IV isoform expression with the schizophrenia-risk polymorphism rs6994992 is a potential mechanism of risk. Novel splice variants of NRG1-IV (NRG1-IVNV), with predicted unique signaling capabilities, have been cloned in fetal brain tissue. The authors investigated the temporal dynamics of transcription of NRG1-IVNV, compared with the major NRG1 isoforms, across human prenatal and postnatal prefrontal cortical development, and they examined the association of rs6994992 with NRG1-IVNV expression. NRG1 type I-IV and NRG1-IVNV isoforms were evaluated with quantitative real-time polymerase chain reaction in human postmortem prefrontal cortex tissue samples at 14 to 39 weeks gestation and postnatal ages 0-83 years. The association of rs6994992 genotype with NRG1-IVNV expression and the subcellular distribution and proteolytic processing of NRG1-IVNV isoforms were also determined. Expression of NRG1 types I, II, and III was temporally regulated during prenatal and postnatal neocortical development. NRG1-IVNV was expressed from 16 weeks gestation until age 3. Homozygosity for the schizophrenia risk allele (T) of rs6994992 conferred lower cortical NRG1-IVNV levels. Assays showed that NRG1-IVNV is a novel nuclear-enriched, truncated NRG1 protein resistant to proteolytic processing. To the authors' knowledge, this study provides the first quantitative map of NRG1 isoform expression during human neocortical development and aging. It identifies a potential mechanism of early developmental risk for schizophrenia at the NRG1 locus, involving a novel class of NRG1 proteins.

After completing this article, readers should be able to: 1. Describe the roles of insulin-like growth factor on fetal growth and development. 2. Delineate components of “maternal constraint.” 3. Explain the role of the placenta in regulating fetal growth. 4. Describe the effects of fetal glucose, amino acid, and fat supply on fetal growth. The principal determinants of fetal growth are fetal genotype and in utero environment. Environmental factors include maternal and paternal genetics, maternal size, and the capacity of the placenta to provide nutrients to the fetus. These environmental factors interact with the intrinsic growth pattern of the fetus, yielding a particular rate and composition of fetal growth. Most of the variation in fetal growth in a population is due to variations in environmental factors, not the fetal genome, although a genetically abnormal fetus clearly might not grow as well as a normal fetus if affected genes include those that are important for growth. Many genes contribute to fetal growth and birthweight. Techniques in which specific genes can either be deleted (“knockouts”) or overexpressed have led to greater understanding of how some of these genes regulate fetal growth. Such studies have shown that both maternal and paternal influences are present during fetal development and are passed on to the developing fetus by spermatozoa or oogonia by a mechanism called imprinting. Although the maternal genetic composition exerts greater influence than fetal genotype in the overall regulation of fetal growth, both maternal and paternal genomes are important in fetal growth and development (1)(2). For example, gynogenetic zygotes (two maternal genome copies) lead to underdeveloped extraembryonic tissues but well-developed embryos. The more modest regulation offered by the paternal genotype is essential for trophoblast development. For example, zygote nuclear transfer experiments have shown that androgenetic zygotes (two paternal genome copies) develop extensive trophoblast tissues but …

Examination of human fetal pancreatic endocrine cell development can provide further insight in, defining the developmental patterns of endocrine cells and identifying β-cell progenitors. In this study we performed a comprehensive immunohistochemical analysis of human fetal pancreatic sections aged from 7.7 to 38 weeks post conception (wpc), as well as 10 weeks post natal (wpn), and adult sections. We examined expression and co-expression of insulin, glucagon, cytokeratin19 (CK19), vimentin as well as the transcription factors PDX1, SOX17 and NGN3. Insulin and glucagon expression significantly increased in the first (1-12 wpc) and second (13-24 wpc) trimesters and formed islet-like clusters which resembled adult human islets in the third (24-38 wpc) trimester. Insulin and glucagon coexpressing cells were observed from 8.4 to 23 wpc and peaked during the first trimester. PDX1 expression was observed predominantly in duct-like structures prior to 15 wpc, then, was localized to islet structures in the second trimester at 17 wpc. Co-localization of PDX1 and insulin was observed throughout fetal development and in most insulin cells. SOX17 expressing cells were in spatial proximity to the glucagon expressing cells late in the first and second trimesters and did not co-express either insulin or glucagon. NGN3 was detected from 7.7 to 14.4 wpc within the pancreatic mesenchyme. Expression peaked between 10.6-12.1 wpc and was not detected past 15 wpc. NGN3 cells co-expressed vimentin but did not co-express insulin or CK19. We present a unique qualitative assessment of insulin, glucagon, PDX1, SOX17 and NGN3 expression and co-expression patterns, during human fetal pancreatic development. In combination with in vitro human embryonic stem cell isolation studies, in vivo characterization of β-cell progenitors during fetal development, will improve progenitor cell isolation and differentiation of viable β-cell progenitors destined for transplantation.

Tissue-resident macrophages (TRMs) play critical roles in tissue homeostasis and disease. Many populations of TRMs derive from fetal progenitors and independently self-maintain across the lifespan through in situ proliferation. Here, we have identified the interleukin-7 receptor (IL7R) as a novel regulator of TRM development. Using an IL7R-Cre lineage tracing model, we observed that adult TRMs in the brain, epidermis, liver, and lung were highly labeled by IL7R-cre, in the absence of IL7Ra mRNA or protein expression. To gain insight into developmental expression of IL7Ra, we profiled surface expression, mRNA expression, and IL7R-cre driven labeling across fetal development. Erythromyeloid progenitors, putative TRM precursors, were barely labeled by IL7Ra-cre, and IL7R deletion did not affect YS hematopoiesis. In contrast, we observed IL7Ra mRNA expression in fetal monocytes, and robust IL7Ra surface expression on developing TRMs during late gestation. Sorted Ly6chi fetal liver monocytes cultured ex vivo with M-CSF differentiated into macrophages expressing IL7R, suggesting a precursor-product relationship. Blockade of the IL7R with a monoclonal antibody during gestation impaired liver, lung, and epidermal TRM cellularity at birth, with a concomitant increase in cellularity of liver monocytes, suggesting that IL7Ra regulates TRM differentiation from fetal monocytes during fetal development. These data reveal dynamic regulation of IL7Ra expression in TRMs and TRM precursors during late gestation, and provide evidence that IL7R signaling regulates fetal TRM development. Ongoing work addresses downstream signaling and the specific developmental processes regulated by IL7R signaling during fetal TRM development.

WITHDRAWN: Human placental barrier-brain organoid-on-a-chip for modeling maternal PM2.5 exposure

1 During the twentieth century, major scientific studies focused on a discovery the etiology and treatment of adult pathologies and, to a lesser extent, neonatal pathologies, in order to provide better health for our society. Newborns represent our future, so it is important to ameliorate fetal and newborn health. In fact, many studies in recent decades showed that the genetics, diet, and environment of newborns and infants are correlated with their adult health. Thus, it is important to develop the best tools of research possible to understand the maternal-fetal relationship. Studies on the maternal-fetal relationship first focused on the influence of maternal intake on fetal output, usually by the administration of a substance to the mother, which was later searched for in the metabolites of the fetus. Fortunately, the rapid evolution of scientific and methodological knowledge allowed researchers to pass from global physiologic studies to cellular and genomic studies. In addition, the ethics of research are more defined, ensuring improved treatment of subjects without invasive approaches. In this context of maternal-fetal exchange, it is essential to reconsider our vision of the interaction between mother and fetus, by including the placenta (mother placenta fetus). Placenta represents a complex unit of study. It is considered a great multiple organ because it ensures essential functions of respiration, nutrition, and waste elimination, and it possesses many metabolic activities, such as hormone production, enzyme activities, and lipid synthesis. Finally, we must keep in mind that the maternal-placental-fetal relationship represents a particular research domain, since it applies to two distinct, closely related persons. During pregnancy, multiple physiologic, genetic, and environment factors influence normal fetal growth and development. The mother is the essential vector of nutriments, toxic substances and pathogens by which any intervention can modulate fetal growth and development. Therefore, it is crucial to increase our knowledge about the role and implication of genetic, dietary, and environmental factors in order to provide the fetus with an appropriate environment. Many expert researchers are therefore reunited in this special issue to discuss the maternal-fetal exchange, reviewing all recent discoveries in their respective domain, and increasing our knowledge of this important field of research. It is well accepted that fetal development is influenced by at least three closely related factors: placental functions and the fetus’s ability to use nutrients, internal factors (e.g., diseases, genetics), and external factors (e.g., diet, medication, environment). Thus, maternal, placental, and fetal physiology and biochemistry can be influenced by these factors. For example, gestational diabetes could induce fetal macrosomia and preeclampsia, both pathologies that could induce maternal and neonatal morbidity. This special issue approaches the maternal-placental-fetal relationship under various topics. It discusses trophoblastic differentiation, leading to functional placenta, and the influence of maternal nutrition on fetal development, including placental exchange and transport mechanisms of glucose, amino acids, lipids, and calcium. These subjects are followed by the influence of the placental and fetal hormones on placental and fetal growth and development. Pathologies such as preeclampsia, gestational diabetes and intrauterine growth retardation are also reviewed. Finally, a potential biological marker for early detection of preeclampsia is presented. I hope that this special issue will improve our knowledge of the maternal-placental-fetal relationship.

Although the outcome of pregnancy for women with diabetes mellitus has improved in recent years, the infant of the diabetic mother has an increased risk of major clinical problems, particularly in the early neonatal period. These include birth injury due to macrosomia, neonatal hypoglycemia, respiratory distress syndrome, and serious congenital anomalies. Because of the great difficulties encountered during attempts to investigate these problems in clinical research protocols, there is a continuing need to establish appropriate animal models of the diabetic pregnancy. Studies carried out over the past decade, primarily with chemically-induced diabetes have suggested techniques which might be useful. In general, the choice of the animal to be studied will depend on the hypotheses being addressed. For instance, small animals such as rabbits and rats made diabetic with streptozotocin have been successfully used for investigation of fetal lung development. Furthermore, the rat model has been helpful for evaluation of fetal anomalies associated with maldevelopment of the spine and central nervous system. Larger animals, such as the nonhuman primate, are more appropriate for studying placental function and amniotic fluid composition in diabetic pregnancies. The task group on pregnancy and fetal development recommends that animal models of diabetes mellitus be used for a more extensive hormonal and metabolic characterization of diabetic mothers during pregnancy, for investigation of placental physiology with respect to the transfer of substrates from mother to fetus, for systematic and comprehensive study of mechanisms controlling fetal lung development, and for delineation of the pathophysiology of neonatal hypoglycemia. It is further recommended that animal models of spontaneous diabetes such as the BB/W rat be used in future studies dealing with pregnancy and fetal development. Because females with spontaneous diabetes show reduced conception rates, there is a pressing need to enhance the fertility of these animals in order to intensify studies on fetal development.

Background: Hyperemesis gravidarum (HG) is a condition characterized by severe nausea and vomiting experienced during pregnancy, with an incidence rate estimated to affect between 0.3% and 2% of pregnant individuals. As HG results in prolonged periods of maternal starvation and multiple nutritional deficiencies, it can potentially disrupt the delicate balance of nutrients and metabolic processes required for optimal fetal growth and development. This systematic review aims to analyze the impact of HG on fetal development and birth outcomes. Methods: The following databases were searched from January 2000 to March 2024: PubMed, Web of Science, Science Direct, Medline (Ovid), and Embase (Ovid). The search focused on HG and its pathogenesis, treatment, fetal development, and pregnancy-related adverse outcomes. Results: 6 out of 907 studies were included which focused on HG with fetal development and birth outcomes. All 6 studies were cohort studies and the quality was high. Meta-analysis revealed that HG is associated with an increased risk of preterm birth (odds ratio (OR): 1.2; 95% confidence interval (95% CI): 1.17–1.23) and small for gestational age (SGA) (OR: 1.30; 95% CI: 1.22–1.40). Conclusions: A limited number of studies have investigated the effects of HG on fetal development and birth outcomes. The present systematic review indicated an increased risk of preterm birth and SGA associated with HG; however, high heterogeneity among the limited included studies should be noted.

Our findings provide an early biomarker for brain maturational failure in fetuses with congenital heart disease, which may guide the development of future prenatal interventions aimed at reducing neurological compromise of prenatal origin in this high-risk population.

Tissue-resident macrophages (TRMs) play critical roles in tissue homeostasis and disease. Many populations of TRMs derive from fetal progenitors and independently self-maintain across the lifespan through in situ proliferation. Previously, we have identified the interleukin-7 receptor (IL7R) as a novel regulator of TRM development. We have shown that antibody blockade of the IL7R during gestation impaired liver, lung, and epidermal TRM cellularity at birth. Here we show that in vivo fetal rIL-7 stimulation of the IL7R increased neonatal liver and lung TRM. In order to determine how IL7R signaling regulates fetal macrophage development, apoptosis was measured after late gestation IL7R blockade. Apoptosis in the macrophages and monocytes of the liver and lung was dramatically increased after IL7R blockade, suggesting that increases in neonatal cellularity after rIL-7 treatment may be due to increased survival signaling in these tissues. Our previous analysis also revealed dynamic regulation of IL7R mRNA surface protein expression as fetal monocytes differentiate into CD64+ macrophages during fetal development. We performed intracellular staining for IL7Ra protein to determine that monocytes contain intracellular IL7R protein that is not expressed on the surface until differentiation, suggesting that regulation of IL7R expression occurs at the level of surface expression. These data reveal dynamic regulation of IL7Ra expression in TRMs and TRM precursors during late gestation and provide evidence that IL-7/IL7R signaling regulates fetal TRM development by facilitating cell survival. Ongoing work addresses downstream signaling and other developmental processes regulated by IL7R signaling during fetal TRM development.

BackgroundThe interaction of hormonal factors are crucial for good foetal development. During the second trimester of gestation, most of the main physiological processes of foetal development occur. Therefore, the aim of this study was to determine the variations in the physiological levels of cortisol, estriol, estrone sulphate, and progesterone during the second trimester (weeks 12–26) in order to establish normal ranges that can serve as indicators of foetal well-being and good functioning of the foetal-placental unit. MethodsSaliva samples from 106 pregnant women were collected weekly (from week 12 to week 26 of gestation), and hormonal measurements were assayed by an enzyme immunoassay. The technique used for hormone measurements was highly sensitive and served as a non-invasive method for sample collection. ResultsThe results revealed a statistically significant (p<0.05) difference between cortisol, progesterone, and oestrogens throughout the second trimester, with a more substantial relationship between oestrogens and progesterone [P4-E3 (r=0.427); P4-E1SO4 (r=0.419)]. By analysing these hormone concentrations, statistically significant (p<0.05) elevations in progesterone, cortisol, and estriol levels were found at the 16th [(P4 (0.78±0.088), C(1.99±0.116), E3(2.513±0.114)]; 18th [(P4 (1.116±0.144), C(3.409±0.137), E3(3.043±0.123)] and 23rd week of gestation [(P4(1.36±0.153), C(1.936±0.11), E3(2.657±0.07)]. Estrone sulphate levels appeared to increase progressively throughout the second trimester [from 1.103±0.03 to 2.244±0.09].ConclusionThe 18th week of gestation seems to constitute a very important week during foetal adrenal development, and the analysis of the main hormones involved in foetal development, provided more precise information regarding the proper functioning of the foetal unit and foetal development.

Initial research established the safety and efficacy of maternal exercise during pregnancy for mother and even the placenta. But what about baby? The next logical progression of research interest is what effect maternal exercise has on the fetus and its development. In order to investigate this further, research will need to control for factors that are known to influence activity state of the fetus, such as time of day, or recordings, as well as time since last maternal meal/snack. It is suggested that acute or chronic maternal exercise does not impact the fetal activity state. Though it appeared that acute maternal exercise may affect fetal breathing movements, many factors were not controlled. To further elucidate, follow-up studies focused on exposure to regular maternal exercise throughout gestation found no evidence of fetal distress or lack of oxygen throughout the pregnancy. The plethora of research clearly shows that the fetal heart is able to respond during acute bouts of maternal exercise. The effects of this response were further illuminated by a study of chronic exposure to maternal exercise. Fetal heart outcomes due to regular maternal exercise are similar to adult heart response to exercise training. Whether fetal motor activity is influenced by regular maternal exercise is an area that still needs further study. Lastly, the evidence of fetal nervous system development points to properly advancing gestation and possibly a more advanced trajectory. Overall, fetal development is not adversely affected from exposure to maternal exercise.KeywordsFetal developmentFetal activity stateFetal breathing activityHeart rate (HR)Fetal motor activityNervous system development

This review paper highlights mechanisms for nutritional regulation of maternal health and fetal development. Malnutrition (nutrient deficiencies or obesity) in pregnant women adversely affects their health by causing or exacerbating a plethora of problems, such as anaemia, maternal haemorrhage, insulin resistance, and hypertensive disorders (e.g. pre-eclampsia/eclampsia). Maternal malnutrition during gestation also impairs embryonic and fetal growth and development, resulting in deleterious outcomes, including intrauterine growth restriction (IUGR), low birthweight, preterm birth, and birth defects (e.g. neural tube defects and iodine deficiency disorders). IUGR and preterm birth contribute to high rates of neonatal morbidity and mortality. Major common mechanisms responsible for malnutrition-induced IUGR and preterm birth include: (i) abnormal growth and development of the placenta; (ii) impaired placental transfer of nutrients from mother to fetus; (iii) endocrine disorders; and (iv) disturbances in normal metabolic processes. Activation of a series of physiological responses leading to premature and sustained contraction of the uterine myometrium also results in preterm birth. Recent epidemiologic studies have suggested a link between IUGR and chronic metabolic disease in children and adults, and the effects of IUGR may be carried forward to subsequent generations through epigenetics. While advanced medical therapies, which are generally unavailable in low-income countries, are required to support preterm and IUGR infants, optimal nutrition during pregnancy may help ameliorate many of these problems. Future studies are necessary to develop effective nutritional interventions to enhance fetal growth and development and alleviate the burden of maternal morbidity and mortality in low- and middle-income countries.

Ligands and Activators of Nuclear Hormone Receptors Regulate Epidermal Differentiation During Fetal Rat Skin Development