Prenatal Life Research Articles

In utero exposure to cannabidiol disrupts select early-life behaviors in a sex-specific manner

Cannabidiol (CBD), one of the main components of cannabis, is generally considered safe. CBD crosses the placenta and its use during pregnancy is steadily increasing, the impact of gestational CBD’s effects on prenatal life and neurodevelopment are poorly understood. Here, we combined behavioral approaches and deep learning analysis to assess the sex-dependent neonatal behavior of CBD exposed progeny. Gestating C57BL6/J dams were exposed daily with vehicle or CBD (3 mg/Kg, s.c.), from gestational day 5 to 18. Body weight, pup ultrasound vocalizations (USVs, PND 10) and homing behavior (PND 13) were quantified in the progeny. Thus, male (but not female) pups from CBD-treated dams gained more weight than sham. There were sex-dependent differences in the coarse characteristics of ultrasonic vocalizations. Prenatally-CBD exposed male pups emitted shorter calls, whereas CBD females made more high frequency calls when compared with their control counterparts. There were significant qualitative changes in the syllabic USV repertoire reflected in call typologies and communication patterns. Finally, the homing behavior test showed that CBD-exposed females presented a greater vulnerability to gestational CBD than males. Only CBD-exposed female pups showed reduced motor and discriminatory abilities. Together the results suggest a sexual divergence in the consequences of in utero CBD exposure on neonates at early developmental ages, which may be predictive of adult psychopathology. Given the extent of cannabis and CBD use worldwide, these findings challenge the idea that CBD is a universally safe compound and reveal the need for additional studies on the effect of perinatal CBD exposure.

Prenatal arsenic exposure stymies gut butyrate production and enhances gut permeability in post natal life even in absence of arsenic deftly through miR122-Occludin pathway

This discourse attempts to capture a few important dimensions of gut physiology like microbial homeostasis, short chain fatty acid (SCFA) production, occludin expression, and gut permeability in post-natal life of mice those received arsenic only during pre-natal life. Adult Balb/c mice were fed with 4 ppm arsenic trioxide in drinking water during breeding and gestation. After the birth of the pups, the arsenic water was withdrawn and replaced with clean drinking water. The pups were allowed to grow for 28 days (pAs-mice) and age matched Balb/c mice which were never exposed to arsenic served as control The pAs-mice showed a striking reduction in Firmicutes to Bacteroidetes (F/B) ratio coupled with a decrease in tight junction protein, occludin resulting in an increase in gut permeability, increased infiltration of inflammatory cells in the colon and decrease in common SCFAs in which butyrate reduction was quite prominent in fecal samples as compared to normal control. The above phenotypes of pAs-mice were mostly reversed by supplementing 5% sodium butyrate (w/w) with food from 21st to 28th day. The ability of butyrate in enhancing occludin expression, in particular, was dissected further. As miR122 causes degradation of Occludin mRNA, we transiently overexpressed miR122 by injecting appropriate plasmids and showed reversal of butyrate effects in pAs-mice. Thus, pre-natal arsenic exposure orchestrates variety of effects by decreasing butyrate in pAs-mice leading to increased permeability due to reduced occludin expression. Our research adds a new dimension to our understanding that pre-natal arsenic exposure imprints in post-natal life while there was no further arsenic exposure.

Developmental origins of disease highlight the immediate need for expanded access to comprehensive prenatal care.

The prenatal environment plays a critical role in shaping fetal development and ultimately the long-term health of the child. Here, we present data linking prenatal health, via maternal nutrition, comorbidities in pregnancy (e.g., diabetes, hypertension), and infectious and inflammatory exposures, to lifelong health through the developmental origins of disease framework. It is well-established that poor maternal health puts a child at risk for adverse outcomes in the first 1,000 days of life, yet the full health impact of the in utero environment is not confined to this narrow window. The developmental origins of disease framework identifies cognitive, neuropsychiatric, metabolic and cardiovascular disorders, and chronic diseases in childhood and adulthood that have their genesis in prenatal life. This perspective highlights the enormous public health implications for millions of pregnancies where maternal care, and therefore maternal health and fetal health, is lacking. Despite near universal agreement that access to antenatal care is a priority to protect the health of women and children in the first 1,000 days of life, insufficient progress has been achieved. Instead, in some regions there has been a political shift toward deprioritizing maternal health, which will further negatively impact the health and safety of pregnant people and their children across the lifespan. In this article we argue that the lifelong health impact attributed to the perinatal environment justifies policies aimed at improving access to comprehensive antenatal care globally.

Physiological role and diagnostic value of anti-Mullerian hormone in pediatrics

Background. Anti-Mullerian hormone (AMH) has now gained popularity as a marker of ovarian reserve. It is important to determine the place and role of AMH in children. The purpose of this work was to analyze the data of the scientific literature on the role of AMH in pediatric practice. Materials and methods. A review of the literature in PubMed was conducted, limiting itself to articles in English and updating the search in February 2022. The search term was “anti-Mullerian hormone”. A total of 437 manuscripts were found, including 37 review articles. The search was gradually narrowed with filters of clinical trials and systematic reviews to 75 articles. The references of the original and review articles were then checked to ensure a complete review. AMH is responsible for the differentiation of the gonads, provokes the regression of Mullerian ducts in the male fetus, correlates with karyotype, sexual development, levels of luteinizing hormone, follicle-stimulating hormone, and its serum levels reflect the ovarian reserve in women, even in childhood. Serum AMH is high from prenatal life to puberty. In postnatal period, the secretion of AMH by the testes is stimulated by follicle-stimulating hormone and strongly inhibited by androgens. AMH is of clinical value as a marker of testicular tissue in men with differences in sexual development and cryptorchidism, as well as in the assessment of persistent Mullerian duct syndrome. Determination of AMH is useful for assessing the function of the gonads without the need for stimulation tests and guides the etiological diagnosis of childhood male hypogonadism. In women, AMH is used as a prognostic marker of ovarian reserve and fertility. The use of criteria developed for adult women is problematic for adolescent girls, as clinical signs associated with polycystic ovary syndrome are normal phenomena of puberty. AMH can be used as an additional criterion in the diagnosis of polycystic ovary syndrome in adolescents. However, the lack of an international standard for AMH limits comparisons between AMH analyzes. Conclusions. AMH has broad clinical diagnostic utility in pediatrics, but interpretation is often complex and should be made in the context of not only the age and sex, but also the stage of development and puberty of the child. Recognition of the role of AMH beyond the development and maturation of the gonads may lead to new diagnostic and therapeutic applications that will further expand its use in pediatric practice.

Biliary atresia & choledochal malformation–—Embryological and anatomical considerations

The two main biliary pathologies in paediatric practice, biliary atresia and choledochal malformations (CM), have their origins within prenatal life. Nevertheless, the actual mechanisms remain elusive with many unanswered questions. The extrahepatic bile duct develops as a funnel-like structure emerging from the foregut from about 3-4 weeks of gestation into the mesenchyme of the septum transversum. The cranial elements of this contain hepatoblasts - the precursors to the two key cell lines that will become hepatocytes and biliary epithelial cells. The intrahepatic bile ducts develop separately and emerge from a complex process involving the ductal plate surrounding the in-growing portal venous system from about the 7-8th week of gestation.A developmental defect at some point(s) in this process may be the cause of at least some variants of BA - the Biliary Atresia Splenic Malformation syndrome particularly - though evidence in the more common isolated BA is much more circumstantial. Similarly, some types of choledochal malformation, specifically the cystic type of CM, are invariably present during prenatal life although again an actual aetiological mechanism remains elusive.

Epigenome-wide analysis of maternal exposure to green space during gestation and cord blood DNA methylation in the ENVIRONAGE cohort

BackgroundDNA methylation programming is sensitive to prenatal life environmental influences, but the impact of maternal exposure to green space on newborns DNA methylation has not been studied yet. MethodsWe conducted a meta-epigenome-wide association study (EWAS) of maternal exposure to green space during gestation with cord blood DNA methylation in two subsets of the ENVIRONAGE cohort (N = 538). Cord blood DNA methylation was measured by Illumina HumanMethylation 450K in one subset (N = 189) and EPICarray in another (N = 349). High (vegetation height>3 m (m)), low (vegetation height<3 m) and total (including both) high-resolution green space exposures during pregnancy were estimated within 100 m and 1000 m distance around maternal residence. In each subset, we sought cytosine-phosphate-guanine (CpG) sites via linear mixed models adjusted on newborns' sex, ethnicity, gestational age, season at delivery, sampling day, maternal parity, age, smoking, education, and estimated blood cell proportions. EWASs results were meta-analysed via fixed-effects meta-analyses. Differentially methylated regions (DMRs) were identified via ENmix-combp and DMRcate algorithms. Sensitivity analyses were additionally adjusted on PM2.5, distance to major roads, urbanicity and neighborhood income. In the 450K subset, cord blood expression of differentially methylated genes was measured by Agilent microarrays and associated with green space. Results147 DMRs were identified, 85 of which were still significant upon adjustment for PM2.5, distance to major roads, urbanicity and neighborhood income, including HLA-DRB5, RPTOR, KCNQ1DN, A1BG-AS1, HTR2A, ZNF274, COL11A1 and PRSS36 DMRs. One CpG reached genome-wide significance, while 54 CpGs were suggestive significant (p-values<1e-05). Among them, a CpG, hypermethylated with 100 m buffer total green space, was annotated to PAQR9, whose expression decreased with 1000 m buffer low green space (p-value = 1.45e-05). ConclusionsOur results demonstrate that maternal exposure to green space during pregnancy is associated with cord blood DNA methylation, mainly at loci organized in regions, in genes playing important roles in neurological development (e.g., HTR2A).

Equine Stomach Development in the Foetal Period of Prenatal Life-A Histological and Histometric Study.

Histological and morphometrical analysis of the stomach wall was performed during the foetal period divided into three age groups (4th-11th month of gestation). The material was taken from non-glandular (the blind ventricular sac) and glandular parts (the plicated edge margin/cardiac part, the body of stomach and the pyloric part) of the stomach. It was preserved and prepared according to the standard protocol. The histological slides were stained (H-E, Masson-Goldner and PAS). The analyses were performed using the light microscope. All measurements were statistically elaborated. The crown-rump length growth rate was estimated as isometric. The blind ventricular sac growth rate was lower than CRL (negative allometric) and the partition of stomach mucosa into non-glandular and glandular part occurred in the 1st age group. The plicated edge margin/cardiac part and the pyloric part shoved similar tendencies. Only the body of stomach demonstrated a higher growth rate than CRL (positive allometric), which can be explained due to the strongest development of fundic glands. Moreover, comparing the adult reference group to the three parts of the foetal period, all metric values were lower than those achieved prenatally. The blind ventricular sac was covered with the multiple plane epithelium. The glandular parts of stomach that formed the superficial concave areas were covered with the simple columnar epithelium in the 1st age group, which developed to the cardiac, fundic, and pyloric glands in the 2rd and 3rd age groups. The propria mucosae was built with the mesenchyme, which differentiated later to the loose connective tissue. The muscular layer of mucosa was not clearly distinguishable in the 1st age group. The muscular layer of the stomach wall was formed with myoblasts in the 1st age group and later in the 2nd and the 3rd age groups built with fusiform myocytes divided into internal and external layers. The non-differentiated cells of glandular epithelium transformed into the parietal and chief cells. The first were visible in the gastric glands of the 2nd age group. Both of them were present in the 3rd age group gastric mucosa. The PAS staining proved a moderate PAS-positive reaction in the 2rd age group, while it was estimated as intense Pas-positive in the gastric glands in the 3rd age group and was comparable to postnatal observation (the adult reference group).

Preterm neonates distinguish rhythm violation through a hierarchy of cortical processing

Rhythm is a fundamental component of the auditory world, present even during the prenatal life. While there is evidence that some auditory capacities are already present before birth, whether and how the premature neural networks process auditory rhythm is yet not known. We investigated the neural response of premature neonates at 30–34 weeks gestational age to violations from rhythmic regularities in an auditory sequence using high-resolution electroencephalography and event-related potentials. Unpredicted rhythm violations elicited a fronto-central mismatch response, indicating that the premature neonates detected the rhythmic regularities. Next, we examined the cortical effective connectivity underlying the elicited mismatch response using dynamic causal modeling. We examined the connectivity between cortical sources using a set of 16 generative models that embedded alternate hypotheses about the role of the frontal cortex as well as backward fronto-temporal connection. Our results demonstrated that the processing of rhythm violations was not limited to the primary auditory areas, and as in the case of adults, encompassed a hierarchy of temporo-frontal cortical structures. The result also emphasized the importance of top-down (backward) projections from the frontal cortex in explaining the mismatch response. Our findings demonstrate a sophisticated cortical structure underlying predictive rhythm processing at the onset of the thalamocortical and cortico-cortical circuits, two months before term.

Susceptibility and resilience to maternal immune activation are associated with differential expression of endogenous retroviral elements

Endogenous retroviruses (ERVs) are ancestorial retroviral elements that were integrated into the mammalian genome through germline infections and insertions during evolution. While increased ERV expression has been repeatedly implicated in psychiatric and neurodevelopmental disorders, recent evidence suggests that aberrant endogenous retroviral activity may contribute to biologically defined subgroups of psychotic disorders with persisting immunological dysfunctions. Here, we explored whether ERV expression is altered in a mouse model of maternal immune activation (MIA), a transdiagnostic environmental risk factor of psychiatric and neurodevelopmental disorders. MIA was induced by maternal administration of poly(I:C) on gestation day 12 in C57BL/6N mice. Murine ERV transcripts were quantified in the placentae and fetal brains shortly after poly(I:C)-induced MIA, as well as in adult offspring that were stratified according to their behavioral profiles. We found that MIA increased and reduced levels of class II ERVs and syncytins, respectively, in placentae and fetal brain tissue. We also revealed abnormal ERV expression in MIA-exposed offspring depending on whether they displayed overt behavioral anomalies or not. Taken together, our findings provide a proof of concept that an inflammatory stimulus, even when initiated in prenatal life, has the potential of altering ERV expression across fetal to adult stages of development. Moreover, our data highlight that susceptibility and resilience to MIA are associated with differential ERV expression, suggesting that early-life exposure to inflammatory factors may play a role in determining disease susceptibility by inducing persistent alterations in the expression of endogenous retroviral elements.

Temporal decline of sperm concentration: role of endocrine disruptors.

Male infertility is a widespread disease with an etiology that is not always clear. A number of studies have reported a decrease in sperm production in the last forty years. Although the reasons are still undefined, the change in environmental conditions and the higher exposure to endocrine-disrupting chemicals (EDCs), namely bisphenol A, phthalates, polychlorinated biphenyls, polybrominated diphenyl esters, dichlorodiphenyl-dichloroethylene, pesticides, and herbicides, organophosphates, and heavy metals, starting from prenatal life may represent a possible factor justifying the temporal decline in sperm count. The aim of this study is to provide a comprehensive description of the effects of the exposure to EDCs on testicular development, spermatogenesis, the prevalence of malformations of the male genital tract (cryptorchidism, testicular dysgenesis, and hypospadias), testicular tumor, and the mechanisms of testicular EDC-mediated damage. Animal studies confirm the deleterious impact of EDCs on the male reproductive apparatus. EDCs can compromise male fertility by binding to hormone receptors, dysregulating the expression of receptors, disrupting steroidogenesis and hormonal metabolism, and altering the epigenetic mechanisms. In humans, exposure to EDCs has been associated with poor semen quality, increased sperm DNA fragmentation, increased gonadotropin levels, a slightly increased risk of structural abnormalities of the genital apparatus, such as cryptorchidism and hypospadias, and development of testicular tumor. Finally, maternal exposure to EDCs seems to predispose to the risk of developing testicular tumors. EDCs negatively impact the testicular function, as suggested by evidence in both experimental animals and humans. A prenatal and postnatal increase to EDC exposure compared to the past may likely represent one of the factors leading to the temporal decline in sperm counts.

A perspective on diet, epigenetics and complex diseases: where is the field headed next?

Dietary factors can regulate epigenetic processes during life, modulating the intracellular pools of metabolites necessary for epigenetic reactions and regulating the activity of epigenetic enzymes. Their effects are strong during the prenatal life, when epigenetic patterns are written, allowing organogenesis. However, interactions between diet and the epigenome continue throughout life and likely contribute to the onset and progression of various complex diseases. Here, we review the contribution of dietary factors to the epigenetic changes observed in complex diseases and suggest future steps to better address this issue, focusing on neurobehavioral, neuropsychiatric and neurodegenerative disorders, cardiovascular diseases, obesity and Type 2 diabetes, cancer and inflammatory skin diseases.

THE RATIO BETWEEN THE LENGTH OF THE SECOND AND FOURTH DIGIT (2D:4D RATIO) AS A BIOMARKER OF OVARIAN RESERVE IN INFERTILE PATIENTS

Ovarian reserve is established during intrauterine life, with a peak at 20 weeks of gestation. The 2D:4D ratio, which is also established during prenatal life, has been proposed as a non-invasive biomarker of the prenatal hormonal environment. It has been suggested that an intrauterine environment rich in androgens induces a development of the 2D:4D ratio < 1 while estrogen exposure during prenatal life leads to a higher 2D:4D ratio. However, whether 2D:4D ratio can be used to could predict ovarian reserve needs further investigation.

Prenatal exposure to residential green space and cord blood DNA methylation: epigenome wide association studies in the ENVIRONAGE cohort

Background and aim DNA methylation may be an underlying mechanism between green space and health. Although newborn DNA methylation is sensitive to environmental influences during prenatal life, the impact of green space has not been studied yet. This study evaluated whether prenatal exposure to residential green space is associated with cord blood DNA methylation. Methods We conducted epigenome-wide association studies using data from two subpopulations (N=198 and 349) of the ENVIRONAGE cohort. Cord blood DNA methylation was measured by Illumina HumanMethylation 450K and EPIC BeadChip arrays, respectively in the two subpopulations. High (vegetation &amp;#x3e;3m), low (vegetation &amp;#x3c;3m) and total (including both) green space exposure was estimated within 100 and 1000 m distance around the maternal residence using high-resolution data. We used linear mixed models to identify differentially methylated sites, and two different approaches (ENmix-combp and DMRcate) to identify differentially methylated regions. Functional analysis was performed by associating green space with cord expression of the genes mapped to the identified signals. Results Prenatal exposure to total, low and high residential green space within 100 and 1000 m was associated with six differentially methylated regions (annotated to COL9A3, GPR27, LINC00612, LINC01973, PARD6G-AS1, ZNF274 genes), in common to the two subsets. Methylation at 7 CpGs was associated with prenatal exposure to total and high green space at 100 and 1000 m distance, with no overlap between the two subsets. Expression level of the FSTL3 gene decreased with prenatal exposure to total green space at 1000 m buffer. Conclusions Our results demonstrate that prenatal residential exposure to green space is associated with cord blood DNA methylation, mainly at loci organized in regions, and that these signals may have functional relevance. Keywords: Residential green space, Epigenomics, Gene expression

Ultrafine particulate matter exposure during second year of life associated with increased risk of autism spectrum disorder in mixtures model

Background and Aim: Prenatal and early life exposure to air pollution has been shown to be associated with autism spectrum disorder (ASD) risk, but the results have been mixed and to our knowledge, no study has reported on effects of combined exposures to multiple air pollutants using a mixtures approach. We applied a multidomain, multipollutant approach to assess the association between ASD and air pollution. Methods: The study consisted of 484 TD children and 707 children with ASD from the CHARGE case-control study. Air pollution exposures for NO2, and Ozone, fine (PM2.5) and ultrafine (PM0.1) particles were predicted using a chemical transport model with statistical bias adjustment based on ground-based monitors. Averages were calculated for each pregnancy period (pre-pregnancy, each trimester of pregnancy, and first and second year of life) for all births between the year 2000 and 2016. The air pollution (AP) variables were natural log transformed and then standardized. We estimated individual and joint effects of AP exposure with ASD and evaluated potential interactions among AP variables for each pregnancy period, using component-wise and hierarchal Bayesian Kernel Machine Regression (BKMR) models. Results: In component-wise BKMR models that included PM0.1, NO2, and Ozone, we found a strong increasing risk of ASD in year 2 of life with increasing PM0.1 (Posterior inclusion probability, PIP, = 0.99). This held true in hierarchal models when grouped by time or by pollutant. In component-wise BKMR models that included PM2.5, NO2, and Ozone, we found that NO2 and Ozone in years 1 and 2 were associated with ASD in an inverted U shape. No robust associations were observed in the prenatal or pregnancy periods. Conclusions: PM0.1 appears to be associated with an increased risk of ASD in year 2 of life. Future research should examine ultrafine particulate matter in relation to ASD.

Evidence of epigenetic age acceleration among adults with prenatal and early life arsenic exposure in Northern Chile

Evidence of epigenetic age acceleration among adults with prenatal and early life arsenic exposure in Northern Chile

Histomorphological changes in the goat, &lt;em&gt;Capra hircus &lt;/em&gt;L. rumen during different stages of gestation

Understanding the fetal development is essential to treat different anomalies of livestock after birth. Biological and anatomical data on the developing rumen of goat is scanty. Here, we investigated histomorphological changes in the ruminal part of the fore stomach of the goat, Capra hircus L. to elucidate the transformation of rumen prior to its functional state. For this study, 36 developing rumen were collected from healthy and normal embryos/foeti of either sex of goat from the first stage of prenatal life until birth. Tissues were processed by paraffin embedding technique and sections were stained. Definite four layers of the tubular structure were elucidated first at 51 days of gestation. We observed the ruminal wall lined by undifferentiated stratified epithelium up to 100 days which gradually became stratified squamous keratinized epithelium at 145 days of foetal life. Throughout the gestation lamina muscularis was absent. Reticular fibers evident first followed by collagen and elastic fibers. The prenatal development of the goat ruminal mucosa evidenced a considerable resemblance with the post natal rumen; however, certain morphological changes are still incomplete in order to meet the functional demands in postnatal life

Continued exposure to D-galactose in postnatal period may inhibit excessive primordial follicle reduction in rats exposed prenatally to D-galactose.

We aimed to compare the ovarian reserve of rats exposed to oral D-galactose during prenatal and early life with rats exposed to D-galactose only during the prenatal period. Fifteen female pregnant Wistar rats were randomly divided into three groups. The first and second groups were fed a D-galactose enriched diet (35%) from the third day of pregnancy to parturition (PP)and the third day to the end of lactation (PL), respectively. The control group (C group) was fed a standard diet. The study population was the female offspring of three groups (PP', PL', and C'), in which some reproductive factors were examined between 45 and 50 days of age. When compared with the PP' group, the number of primordial follicles was significantly higher in the PL' group at PND 45-50 (40 vs. 30; p= .01); however, the antimullerian hormone level was significantly reduced in the PL' group versus control group (-2.2, 95% confidence interval [CI]: -2.83, -1.53 ng/ml p=.000), and follicle-stimulating hormone level significantly increased in PP' group versus control (4.5 mIU/ml, 95% CI: 1.40-7.62, p=.005). There was no significant difference in leukocyte infiltration or antiovarian antibody among the groups. Continued exposure to D-galactose during the lactation period inhibits the primordial follicle loss in rats in terms of producing fewer atretic follicles.

Effect of perfluoroalkyl exposure in pregnancy and infancy on intrauterine and childhood growth and anthropometry. Sub study from COPSAC2010 birth cohort.

Perfluoroalkyl substances PFOS and PFOA are persistent and bioaccumulative exogenous chemicals in the human body with a range of suspected negative health effects. It is hypothesised that exposure during prenatal and early postnatal life might have particularly detrimental effects on intrauterine and childhood growth. In a Danish longitudinal mother-child cohort we investigate effect of PFOS and PFOA in pregnancy and infancy on intrauterine and childhood growth and anthropometry. COPSAC2010 is an ongoing population based mother-child cohort of 738 pregnant women and their children followed from 24 week gestation with longitudinal deep clinical phenotyping until age 10 years. In this observational cohort sub study plasma PFOS and PFOA concentrations were semi-quantified by untargeted metabolomics in the mothers at week 24 and 1 week postpartum and in the children at ages 6 and 18 months and calibrated using a targeted pipeline. We examined associations to intrauterine and childhood growth and anthropometry, including interactions with child sex. Untargeted and targeted blood metabolomics profiles were integrated to investigate underlying mechanisms. Pregnancy plasma PFOA concentrations were associated with lower birth size -0.19 [-0.33; -0.05] BMI z-score per 1-ng/mL and increased childhood height (z-scored) at age 6: 0.18 [0.05; 0.31], but there was no association between childs' own infancy plasma PFOA concentration and height. Pregnancy plasma PFOS concentrations were also associated with lower birth BMI (-0.04 [-0.08; -0.01]), but in childhood pregnancy plasma PFOS concentration interacted with child sex on BMI and fat percentage at 6 years with negative associations in girls and positive in boys. The effect of maternal plasma PFOS concentration on lower girl BMI was borderline mediated through increasing child plasma lactosyl-ceramide levels (p-mediation=0.08). Similarly the effect of maternal plasma PFOS concentration on higher boy fat percentage was borderline mediated through increasing child plasma lactosyl-ceramide levels (p-mediation=0.07). Infancy concentrations of plasma PFOS associated with lower height in childhood, -0.06 z-score at age 6 [-0.19; -0.03]. Higher PFOS and PFOA plasma concentrations during pregnancy had detrimental effects on fetal growth. The effects on childhood growth were not similar as PFOA increased child height, opposite of PFOS in multipollutant models suggesting a differing fetal programming effect. Sex specific growth effects were borderline mediated through an altered lactosyl-ceramide metabolism, proposing a possible mechanism of PFOS that has long-lasting health consequences in this observational study. All funding received by COPSAC are listed on www.copsac.com. The Lundbeck Foundation (Grant no R16-A1694); The Novo Nordic Foundation (Grant nos NNF20OC0061029, NNF170C0025014, NNF180C0031764) The Ministry of Health (Grant no 903516); Danish Council for Strategic Research (Grant no 0603-00280B) and The Capital Region Research Foundation have provided core support to the COPSAC research center. Effort from JALS is supported by R01HL123915, R01HL141826, and R01HL155742 from NIH/NHLBI. CEW was supported by the Swedish Heart Lung Foundation (HLF 20180290, HLF 20200693). BC has received funding for this project from the European Research Council (ERC) under the European Union's Horizon 2020 research and innovation programme (grant agreement No. 946228). The funding agencies did not have any role in design and conduct of the study; collection, management, and interpretation of the data; or preparation, review, or approval of the manuscript.

The Effects of Prenatal Diet on Calf Performance and Perspectives for Fetal Programming Studies: A Meta-Analytical Investigation.

Simple SummaryPrenatal nutrition can reshape an animal’s developmental trajectory, with persistent long-term consequences for the progeny. In prenatal life, the effects induced by the intrauterine conditions can be expressed as changes in offspring growth and meat quality. Thus, there are diverse sources of variations that contribute to the variations reported for fetal-programming responses in beef cattle, making it difficult to interpret and apply the results. In this sense, finding a common factor among the studies with which to group them may offer an opportunity to quantify the fetal-programming effects holistically and to obtain more applicable responses. With the increasing number of publications, it is important to summarize the quantitative measurements available in the scientific literature. In the present study, data from 35 publications were used. We verified that there is a gap related to the effects of maternal nutrition to females, at the beginning of gestation, and in zebu and crossbred animals, indicating new perspectives for future fetal-programming studies. In summary, our findings highlight an association between prenatal energy and protein supply and its effects on the offspring birth weight, weaning weight, and the daily weight gain of pregnant beef cows during pregnancy.This meta-analysis aimed to identify knowledge gaps in the scientific literature on future fetal-programming studies and to investigate the factors that determine the performance of beef cows and their offspring. A dataset composed of 35 publications was used. The prenatal diet, body weight (BW), average daily gain (ADG) during pregnancy, and calf sex were elicited as possible modulators of the beef cows and their offspring performance. Then, the correlations between these variables and the outcomes of interest were investigated. A mixed multiple linear regression procedure was used to evaluate the relationships between the responses and all the possible explanatory variables. A knowledge gap was observed in studies focused on zebu animals, with respect to the offspring sex and the consequences of prenatal nutrition in early pregnancy. The absence of studies considering the possible effects promoted by the interactions between the different stressors’ sources during pregnancy was also detected. A regression analysis showed that prenatal diets with higher levels of protein improved the ADG of pregnant beef cows and that heavier cows give birth to heavier calves. Variations in the BW at weaning were related to the BW at birth and calf sex. Therefore, this research reinforces the importance of monitoring the prenatal nutrition of beef cows.

Multigenerational metabolic disruption: Developmental origins and mechanisms of propagation across generations.

It has been long known that the environment plays a critical role in the etiology of disease. However, it is still unclear how the large variety of environmental factors humans are exposed to interact with each other to lead to disease. Metabolic disorders are just one example of human disorders that have been associated with environmental exposures. Obesity and type 2 diabetes have become a health and economic burden worldwide as the number of affected people has tripled in the last 40 years. Animal and human studies have shown a strong association between exposure to environmental chemicals during critical windows of susceptibility such as periconception, prenatal, and early life, whose effect can persist through development and across generations. However, little is known about the mechanisms driving this persistence. Here, we review historical and current knowledge on the effect of exposure to environmental factors during in utero development and discuss mechanisms for these disorders to be propagated across generations.