In Huntington's disease (HD), reduced neuronal glucose transport plays an important role. We investigated the effects of GLUT3 knock-down (KD) on the trajectory of the HD phenotype in zQ175 model mice. GLUT3 (G3) expression was reduced in heterozygous (HT) and homozygous mice. zQ175 mice when crossed with Emx1-G3KD HT mice, created conditional GLUT3-KD in cortical pyramidal neurons (CPNs), allowing examination of Q175WT/G3WT, Q175WT/G3KD, Q175HT/G3WT, and Q175HT/G3KD genotypes. Immunohistochemically, higher GLUT3 expression and number of GLUT3 positive CPNs were observed in Q175WT/G3WT compared to Q175WT/G3KD, Q175HT/G3WT, and Q175HT/G3KD, with no difference among these three groups, supporting a protective floor effect. Behaviorally, Q175HT/G3KD mice faced difficulty learning tasks and thereby performed worse than the other three groups. Electrophysiologically, the basic membrane properties of cortical pyramidal neurons (CPNs) were not affected. In contrast, in striatal medium-sized spiny neurons (MSNs) significant increases in cell membrane input resistance occurred in Q175HT/G3WT and Q175HT/G3KD compared to Q175WT/G3WT and Q175WT/G3KD, with no difference between Q175HT/G3WT and Q175HT/G3KD. Upon examination of spontaneous glutamatergic and GABAergic synaptic currents, the cumulative interevent intervals (IEI) revealed increased glutamatergic activity in GLUT3 KD, suggesting increased cortical excitability, with a concomitant compensatory increase in GABA synaptic activity. In striatal MSNs, a subtle but significant decrease in sEPSCs frequency occurred between Q175HT/G3WT and Q175HT/G3KD. The key change was an increase in frequency of sIPSCs in Q175HT/G3WT and Q175HT/G3KD compared to Q175WT/G3WT. These results underscore complex modifications of the HD phenotype among groups related to the interplay between GLUT3 KD, compensatory mechanisms, and floor effects.

Hypoglycemia and impaired metabolic transition are frequently observed in neonates during the first 24–48 h after birth [1, 2]. Severe (< 36 mg/dL or 2 mmol/L) and recurrent (3 or more episodes) hypoglycemia can cause neurological injury and developmental delays. The ambiguity regarding a threshold blood glucose concentration remains due to differing values proposed by various professional organizations. This poses a challenge in diagnosing neonatal hypoglycemia in addition to using a single blood glucose value, which in itself is not entirely reflective of various key molecular processes uncovered by in vitro or pre-clinical studies. The symptoms of hypoglycemia can also be present in conditions other than hypoglycemia, e.g., sepsis and polycythemia, and in many cases, hypoglycemia is clinically unrecognized. Therefore, early screening of at-risk and otherwise healthy-appearing neonates is essential. Continuous glucose monitoring and early interventions such as glucose gel, breast and formula feeding, and intravenous glucose administration are utilized to prevent long-term neurological impairments. However, the safe limits of serum glucose that will prevent neuroglycopenia and neural injury are elusive. The impact of early screening and available therapies on neurodevelopmental outcomes remains uncertain due to the absence of a robust clinical design and combining all causes of neonatal hypoglycemia without making further distinctions from other conditions. This review highlights the controversies in definitions and the most recent information on long-term neurodevelopmental outcomes that may impact the early management of NH. Conclusion: Optimizing the definitions and treatment of neonatal dysglycemia is crucial for preventing hypoglycemia-related brain injury. Continuous glucose monitoring technology in neonates offers a promising approach for real-time screening and early intervention.

Abstract Background Early identification of pregnancies at risk for gestational hypertension (gHTN) and preeclampsia (PE) remains a major clinical challenge. We investigated whether early‑pregnancy serum metabolomic profiles differentiate gHTN and PE prior to clinical onset. Methods High-resolution metabolomics (HRM) analysis was performed on 126 early-pregnancy serum samples collected at ≤ 20 weeks’ gestation from 97 pregnant women enrolled in the Placental Assessment in Response to Environmental Pollution study (PARENTs) cohort at UCLA. Metabolic profiles were compared among pregnancies that later developed gestational hypertension (gHTN; n = 14 mothers, 20 samples), preeclampsia (PE; n = 9 mothers, 11 samples), and pregnancies without ischemic placental disease (non-IPD; n = 74 mothers, 95 samples). Untargeted metabolome-wide association studies (MWAS) and pathway enrichment analyses were conducted. Multivariable linear regression models adjusted for key maternal and pregnancy characteristics such as maternal age, race/ethnicity, early-pregnancy BMI, fetal sex, and parity were used to evaluate associations. Results Distinct metabolic profiles differentiated gHTN and PE from non-IPD pregnancies. Alterations in the tryptophan metabolism pathway were observed in both gHTN and PE, with a significant dose–response relationship across groups (non-IPD > gHTN > PE, p = 0.008). Key metabolites, including tryptophan and its derivatives, were progressively depleted in association with increasing disease severity. Additionally, urea cycle metabolism was altered in gHTN, with higher levels of arginine and citrulline linked to nitric oxide production and vascular tone regulation. Comparisons between PE and gHTN revealed additional differences, including lower concentration of phenylalanine and pantothenic acid in PE, suggesting distinct metabolic alteration. Conclusion Early‑pregnancy metabolomic signatures reveal both shared and condition‑specific metabolic pathways underlying gHTN and PE, with tryptophan metabolism showing a dose–response relationship indicative of disease severity. These early gestational alterations may serve as biomarkers for hypertensive disorders of pregnancy (HDP), enabling closer monitoring and stratification in high-risk pregnancies. Further studies in larger cohorts are needed to validate these findings and explore therapeutic implications.

Polycyclic aromatic hydrocarbons (PAHs) are ubiquitous environmental contaminants generated from incomplete combustion and are detectable in nearly all individuals in the U.S. population. Prenatal PAH exposure has been linked to adverse birth and child health outcomes, but few studies have examined associations between biomarkers of PAHs and inflammation during pregnancy across gestational windows. We investigated associations between urinary PAH metabolites and urinary inflammatory markers among 159 pregnant women enrolled in the placental assessment in response to environmental exposures cohort (2016-2019). Urine samples were collected up to three times during pregnancy (10-17, 18-29, and ⩾30 gestational weeks). Hydroxylated PAHs metabolites were quantified using liquid chromatography-tandem mass spectrometry, and inflammatory markers (IL-6, IL-1β, TNF-α, and IL-10) were measured using immunoassays. Biomarker concentrations were adjusted for urinary dilution using specific gravity and log-transformation. Effect estimates were generated using linear mixed-effect models with random intercept for each participant to account for repeated measures, and linear regression to assess sampling-period-specific associations while adjusting for maternal age, ethnicity/race, parity, education, and BMI. We found that most PAH metabolites, particularly phenanthrene and naphthalene metabolites, are positively associated with urinary inflammatory markers, except for fluorene metabolites. In mixed-effects models, each doubling of urinary PAHs concentrations was associated with approximately 10%-50% increases in IL-6, IL-1β, TNF-α, and IL-10 levels. Sampling period-specific analyses indicated that associations with pro-inflammatory cytokines were stronger in early and mid-pregnancy (10-29 weeks), whereas associations with IL-10 were most pronounced later in pregnancy (⩾30 weeks). Results were robust to the exclusion of participants with preeclampsia. These findings indicate that prenatal PAH exposure is associated with sustained inflammatory activity across pregnancy, with gestational timing-specific patterns that may help explain windows of increased vulnerability for adverse pregnancy outcomes. This longitudinal evidence strengthens biologic plausibility linking environmental PAH exposure to maternal inflammatory processes.

Noninvasive early detection of patients at the highest risk for the development of adverse pregnancy outcomes (APOs) such as gestational diabetes mellitus (GDM), pre-eclampsia (PE) and gestational hypertension (gHTN) remains a major challenge. Current screening approaches, including maternal blood tests and ultrasound, are limited by either cost, invasiveness, need for specialized skills, or insufficient predictive accuracy. We tested the hypothesis that a novel liquid biopsy approach using Electric Field-Induced Release and Measurement (EFIRM) platform will detect urinary transcripts/proteins in early gestation differentiating patients for the prediction of subsequently developing APOs. In a small prospective study, urine collected temporally from consented pregnant subjects who later developed GDM (n = 12), PE (n = 12), or gHTN (n = 11), were compared to subjects who never developed APOs (Controls [CON], n = 15). Isolated cell-free RNA, subjected to gold standard RNA-sequencing with differential abundances were assessed (both p-adjusted and p-values), and identified early transcriptomic signatures of these APOs. Using EFIRM-derived transcripts we validated these candidate genes and assessed corresponding protein signals. We next developed logistic regression models with leave-one-out cross-validation to preliminarily predict specific APOs. A panel of urinary transcripts (IL1A, MAPK7, TSNARE1) predicted GDM (AUC = 0.96; sensitivity = 0.95, specificity = 0.62, and NPV = 0.95), while a separate panel (NPIPB4, GSDMD, HLA-DPB1) predicted PE (area under the curve [AUC] = 0.92; sensitivity = 0.91, specificity = 0.62, and negative predictive value [NPV] = 0.90), both being distinct from gHTN. These results support the potential of EFIRM as a noninvasive, real-time, multiplexed urine liquid biopsy platform for early screening and monitoring of APOs, suggesting its future utility in prenatal care at an early gestational age.

Objectives Before the Amsterdam Placental Workshop Group Consensus Statement, standardization in placental pathology assessment did not exist. This study evaluated the Amsterdam criteria’s utility in correlating ischemic placental disease (IPD) with placental pathologic lesions in a cohort of largely unsubmitted term placentas with favorable outcomes. Methods In this prospective case-controlled study at a single institution, all placentas were examined using Amsterdam protocols for gross sampling and microscopic review by 2 reviewers who were blinded to clinical history. Pathologic findings including hypoxic and chronic villitis of unknown etiology (VUE) scores were correlated with IPD status and whether the placenta was submitted to pathology using either a χ² test or Fisher exact test, as appropriate. Results A total of 172 placentas collected between 2017 and 2020 were included. Approximately 18.6% (n = 32) were in the IPD group, and 81.4% (n = 140) were in the non-IPD group. No statistically significant differences in microscopic findings were seen in ascending infection, maternal vascular malperfusion, fetal vascular malperfusion, or VUE between groups or by submission status. When tabulated as a hypoxic score, placentas from the IPD group were associated with greater hypoxic scores compared to non-IPD placentas (P = .011). A positive association was observed between greater VUE scores and hypoxic scores (P = .007). Conclusions In largely unsubmitted term placentas, the microscopic findings per Amsterdam criteria may be nonspecific. When tabulated as hypoxic or VUE scores, however, some clinicopathologic correlation may be seen in the setting of IPD. Further work is needed to refine the thresholds of meaningful reporting of placental pathology using the Amsterdam criteria.

Background COVID-19 infection in pregnancy is associated with preterm birth and an increased risk of severe disease, needing intensive care admission for management of maternal multi-organ failure. The placenta, a fetal organ, functions as a barrier at the maternal interface and expresses the SARS-CoV-2 viral receptors. However, placental infection and transplacental transfer of virus are rare, suggesting placental resistance to viral infection. Here, we seek to determine the impact of severe COVID-19 infection on maternal, newborn, and placental outcomes. Methods A prospectively recruited cohort of pregnant COVID-19 patients (n = 204) at a quaternary perinatal academic center were retrospectively analyzed. During pregnancy umbilical artery (UA) Doppler assessment was performed to assess placental function. At delivery, maternal and fetal outcomes were assessed, with paired maternal peripheral blood and placenta samples collected (n = 26) for bulk RNA sequencing (RNA-seq). Post-sequencing analysis with single cell deconvolution and pathway analysis was performed. Results Maternally-indicated preterm births were more frequent in severe, but not asymptomatic or mild/moderate COVID-19 infection. In severe COVID-19 infection, UA Doppler assessment was normal. Rates of fetal growth restriction and placenta:birth weight ratios were similar between groups. RNA-seq showed a distinct adaptive immune activation signature in peripheral blood while placental transcripts showed no significant changes in immune cell types. Conclusion Despite multi-organ failure, severe COVID-19 did not significantly impact placental function and transcriptomics with iatrogenic preterm birth indicated for maternal-indications.

Polycyclic aromatic hydrocarbon (PAH) exposure during pregnancy has been associated with increased oxidative stress. Few studies have evaluated the relationship between diet, urinary PAHs, and oxidative stress biomarkers among pregnant women. We enrolled a prospective cohort of pregnant women who gave birth at UCLA between 2016 and 2019. Dietary intake over the past month was evaluated by a food frequency questionnaire during mid-pregnancy, and three diet index scores were calculated: Healthy Eating Index (HEI) 2015, Alternate Mediterranean Diet (aMED), and Alternate Healthy Eating Index for Pregnancy (AHEI-P). Urine samples were collected up to three times during pregnancy and analyzed for PAH biomarkers, including 2-hydroxyfluorene + 3-hydroxyfluorene (FLUO2FLUO3), 1-hydroxyphenanthrene (PHEN1), 2-hydroxyphenanthrene (PHEN2), 3-hydroxyphenanthrene (PHEN3), 4-hydroxyphenanthrene (PHEN4), 2-hydroxynaphthalene (NAP2), and 1-hydroxypyrene (PYR1), and two oxidative stress biomarkers, malondialdehyde (MDA) and 8-hydroxyguanosine (8-OHdG). We employed multiple linear regression models to estimate effects of diet on measures of urinary PAHs and oxidative stress biomarkers. A better diet quality, as indicated by three diet indices, was associated with lower urinary PAH metabolites and lower concentrations of oxidative stress biomarkers. This pattern appeared to be consistent across all three sampling periods (9-17 weeks, 18-29 weeks, and 30 weeks-delivery). Healthier diets may lower PAH exposure and oxidative stress in pregnancy.

INTRODUCTION:This study investigated whether placental structure and function, measured using multiparametric MRI (mpMRI) in early second trimester, are associated with birth weight percentiles. We focused on pregnancies without ischemic placental disease (IPD), excluding cases with preeclampsia, fetal growth restriction (FGR), small for gestational age (SGA), or placental abruption. Clinical and pathological moderators were also examined. METHODS:In this prospective single-center cohort, 199 participants were recruited between 2017 and 2019. Placental MRI was performed at two gestational age (GA) windows: 14-16 weeks (w) and 19-24w. Placental volume, perfusion, and oxygenation were quantified and standardized to 16w for the first imaging timepoint and 20w for the second imaging timepoint. After excluding IPD cases, linear mixed-effects models were used to explore retrospective associations between MRI metrics and birth weight percentiles, adjusting for clinical and histopathological variables. RESULTS:Early second trimester mpMRI showed significant associations between placental volume (positive association) and perfusion (negative association) as early as 16w GA to birthweight percentiles (p < 0.05). The nonlinear three-way interaction between the change of mpMRI parameters between 16w and 20w GA (Δ w GA) was consistently positively associated to birth weight percentiles regardless of clinical and pathological factors (p < 0.05). DISCUSSION:Early second trimester mpMRI markers (volume and perfusion) at 16w and 20w GA are associated with birth weight outcomes, suggesting utility in early pregnancy monitoring. The three-way interaction between the mpMRI markers may serve as a composite marker for identifying variation in fetal growth trajectories.

We investigated the impact of chronic air pollutant (AP) exposure upon intestinal microbial diversity, composition, and metagenomic inferred functional pathways in murine pregestational and late gestational adult females, and male and female postnatal offspring (P21), compared to age- and sex- matched controls (CON). Intestinal microbiome analysis was undertaken with certain phenotypic characteristics in adult non-pregnant and pregnant females and the male and female offspring. In response to AP, pooled male and female offspring displayed no difference in E19 fetal and P1 postnatal body weights. At P21, females exposed in-utero to AP were heavier with increased fat and muscle mass at one month versus CON. Males were no different at P21 and 1 month revealing decreased fat mass and hyperglycemia. In pregestational/gestational females, AP did not change microbial α- or β-diversity from the respective CON. Gestational females showed AP induced changes in taxonomic composition such as reduced Bacteroides and increased Firmicutes, Verrucomicrobia, and Akkermansia, among others. In response to intra-uterine AP exposure, the offspring intestinal microbiome revealed more compelling differences in α- and β- diversity than adult females. While certain microbial changes were common in both sexes, sex-specific differences also emerged with reduced α-diversity, decreased Bacteroides and increased Akkermansia in males only. The metagenomic inferred pathways revealed perturbations in multiple pathways. We conclude that the offspring exposed in-utero to AP revealed sex-specific changes in microbial diversity, composition and function, displaying certain similarities with distinct differences from mothers. These early life changes were associated with the subsequent emergence of pre-diabetes and adiposity.

Prenatal exposures to ambient particulate matter (PM2.5) from traffic may generate oxidative stress and thus contribute to adverse birth outcomes. We investigated whether PM2.5 constituents from brake and tire wear affect levels of oxidative stress biomarkers (malondialdehyde [MDA], 8-hydroxy-2 '-deoxyguanosine [8-OHdG]) using urine samples collected up to 3 times during pregnancy in 156 women recruited from antenatal clinics at the University of California Los Angeles. Land use regression models with co-kriging were employed to estimate average residential outdoor concentrations of black carbon (BC), PM2.5 mass, PM2.5 metal components, and 3 PM2.5 oxidative potential metrics during the 4 weeks prior to urine sample collection. The 8-OHdG concentrations in mid-pregnancy increased by 24.8% (95% confidence interval [CI], 9.0-42.8) and 14.3% (95% CI, 0.4%-30.0%) per interquartile range (IQR) increase in PM2.5 mass and BC, respectively. The brake wear marker (barium) and the oxidative potential metrics were associated with increased MDA concentration in the first sample collected (10-17 gestational week), but 95% CIs included the null. Traffic-related air pollution contributed in early to mid-pregnancy to oxidative stress generation previously linked to adverse birth outcomes.This article is part of a Special Collection on Environmental Epidemiology.

To determine the basis for perinatal nutritional mismatch causing metabolic dysfunction-associated steatotic liver disease and diabetes mellitus, we examined adult phenotype, hepatic transcriptome, and pancreatic β-islet function. In prenatal caloric-restricted rats with intrauterine growth restriction (IUGR) and postnatal exposure to high fat with fructose (HFhf) or high carbohydrate, we investigated male and female IUGR-HFhf and IUGR-high carbohydrate, vs HFhf and control offspring. Males more than females displayed adiposity, glucose intolerance, insulin resistance, hyperlipidemia, and hepatomegaly with hepatic steatosis. Male hepatic triglyceride synthesis, de novo lipogenesis genes increased, while female lipolysis, β-oxidation, fatty acid efflux, and FGF21 genes increased. IUGR-HFhf males demonstrated reduced β-islet insulin and humanin, and type 1 diabetes mellitus human amniotic fluid increased humanin. Humanin suppression disabled glucose stimulated insulin, ATP production, with apoptotic diminished β-islet viability. Humanin and FGF21 may reverse perinatal nutritional mismatched phenotype by restoring functional β islets and preventing metabolic dysfunction-associated steatotic liver disease and diabetes mellitus.

Introduction: Epidemiological studies have linked prenatal maternal diet to fetal growth, but whether diet affects placental outcomes is poorly understood.Methods: We collected past month dietary intake from 148 women in mid-pregnancy enrolled at University of California Los Angeles (UCLA) antenatal clinics from 2016 to 2019. We employed the food frequency Diet History Questionnaire II and generated the Healthy Eating Index-2015 (HEI-2015), the Alternate Healthy Eating Index for Pregnancy (AHEI-P), and the Alternate Mediterranean Diet (aMED). We conducted T-2-weighted magnetic resonance imaging (MRI) in mid-pregnancy (1st during 14-17 and 2nd during 19-24 gestational weeks) to evaluate placental volume (cm(3)) and we measured placenta weight (g) at delivery. We estimated change and 95 % confidence interval (CI) in placental volume and associations of placenta weight with all dietary index scores and diet items using linear regression models.Results: Placental volume in mid-pregnancy was associated with an 18.9 cm(3) (95 % CI 5.1, 32.8) increase per 100 gestational days in women with a higher HEI-2015 (>= median), with stronger results for placentas of male fetuses. We estimated positive associations between placental volume at the 1st and 2nd MRI and higher intake of vegetables, high-fat fish, dairy, and dietary intake of B vitamins. A higher aMED (>= median) score was associated with a 40.5 g (95 % CI 8.5, 72.5) increase in placenta weight at delivery, which was mainly related to protein intake.Discussion: Placental growth represented by volume in mid-pregnancy and weight at birth is influenced by the quality and content of the maternal diet.

In a prospective cohort of subjects who subsequently developed preeclampsia (PE, n = 14) versus remaining healthy (NORM, n = 12), early gestation circulating extracellular vesicles (EVs) containing a panel of microRNA signatures were characterized and their biological networks of targets deciphered. Multiple microRNAs of which some arose from the placenta (19MC and 14MC) demonstrated changes in association with advancing gestation, while others expressed were pathognomonic of the subsequent development of characteristic clinical features of PE which set in as a late-onset subtype. This panel of miRNAs demonstrated a predictability with an area under the curve of 0.96 using leave-one-out cross-validation training in a logistic regression model with elastic-net regularization and precautions against overfitting. In addition, this panel of miRNAs, some of which were previously detected in either placental tissue or as maternal cell-free non-coding transcripts, lent further validation to our EV studies and the observed association with PE. Further, the identified biological networks of targets of these detected miRNAs revealed biological functions related to vascular remodeling, cellular proliferation, growth, VEGF, EGF and the PIP3/Akt signaling pathways, all mediating key cellular functions. We conclude that we have demonstrated a proof-of-principle by detecting a panel of EV packaged miRNAs in the maternal circulation early in gestation with possibilities of biological function in the placenta and other maternal tissues, along with the probability of predicting the subsequent clinical appearance of PE, particularly the late-onset subtype.

Air pollution (AP) is detrimental to pregnancies including increasing risk factors of gestational diabetes mellitus. We hypothesized that exposure to AP causes cardiovascular and metabolic disruption thereby altering placental gene expression, which in turn affects the placental phenotype and thereby embryonic/fetal development. To test this hypothesis, we investigated the impact of intra-nasal instilled AP upon gestational day 16-19 maternal mouse cardiovascular and metabolic status, placental nutrient transporters, and placental-fetal size and morphology. To further unravel mechanisms, we also examined placental total DNA 5'-hydroxymethylation and bulk RNA sequenced gene expression profiles. AP exposed pregnant mice and fetuses were tachycardic with a reduction in maternal left ventricular fractional shortening and increased uterine artery with decreased umbilical artery systolic peak velocities. In addition, they were hyperglycemic, glucose intolerant and insulin resistant, with changes in placental glucose (Glut3) and fatty acid (Fatp1 & Cd36) transporters, and a spatial disruption of cells expressing Glut10 that imports L-dehydroascorbic acid in protecting against oxidative stress. Placentas revealed inflammatory cellular infiltration with associated cellular edema and necrosis, with dilated vascular spaces and hemorrhage. Placental and fetal body weights decreased in mid-gestation with a reduction in brain cortical thickness emerging in late gestation. Placental total DNA 5'-hydroxymethylation was 2.5-fold higher, with perturbed gene expression profiles involving key metabolic, inflammatory, transcriptional, cellular polarizing and processing genes and pathways. We conclude that gestational exposure to AP incites a maternal inflammatory response resulting in features mimicking maternal gestational diabetes mellitus with altered placental DNA 5'-hydroxymethylation, gene expression, and associated injury.

Glucose is the primary energy source for most mammalian cells and its transport is affected by a family of facilitative glucose transporters (GLUTs) encoded by the SLC2 gene. GLUT1 and GLUT3, highly expressed isoforms in the blood–brain barrier and neuronal membranes, respectively, are associated with multiple neurodevelopmental disorders including epilepsy, dyslexia, ADHD, and autism spectrum disorder (ASD). Dietary therapies, such as the ketogenic diet, are widely accepted treatments for patients with the GLUT1 deficiency syndrome, while ameliorating certain symptoms associated with GLUT3 deficiency in animal models. A ketogenic diet, high-fat diet, and calorie/energy restriction during prenatal and postnatal stages can also alter the placental and brain GLUTs expression with long-term consequences on neurobehavior. This review focuses primarily on the role of diet/energy perturbations upon GLUT isoform-mediated emergence of neurodevelopmental and neurodegenerative disorders.

Air pollution is detrimental to pregnancy adversely affecting maternal and child health. Our objective was to unravel epigenetic mechanisms mediating the effect of pre-conception, periconception, and gestational exposure to inhaled air pollutants (AP) upon the maternal and placental-fetal phenotype and explore the benefit of an omega-3 rich dietary intervention. To this end, we investigated intra-nasal instilled AP during 8 weeks of preconception, periconception, and gestation (G; D0 to 18) upon GD16-19 maternal mouse metabolic status, placental nutrient transporters, placental-fetal size, and placental morphology. Pre-pregnant mice were glucose intolerant and insulin resistant, while pregnant mice were glucose intolerant but displayed no major placental macro-nutrient transporter changes, except for an increase in CD36. Placentas revealed inflammatory cellular infiltration with cellular edema, necrosis, hemorrhage, and an increase in fetal body weight. Upon examination of placental genome-wide epigenetic processes of DNA sequence specific 5’-hydroxymethylation (5’-hmC) and 5’-methylation (5’-mC) upon RNA sequenced gene expression profiles, revealed changes in key metabolic, inflammatory, transcriptional, and cellular processing genes and pathways. An omega-3 rich anti-inflammatory diet from preconception (8 weeks) through periconception and gestation (GD0-18), ameliorated all these maternal and placental-fetal adverse effects. We conclude that pre-conceptional, periconceptional and gestational exposures to AP incite a maternal inflammatory response resulting in features of pre-existing maternal diabetes mellitus with injury to the placental-fetal unit. DNA 5’-mC more than 5’-hmC mediated AP induced maternal inflammatory and metabolic dysregulation which together alter placental gene expression and phenotype. A dietary intervention partially reversing these adversities provides possibilities for a novel nutrigenomic therapeutic strategy.

IMPACT:The pediatric subspecialty workforce is challenged by shortages and geographic maldistribution of subspecialists. We invited leaders in pediatrics to discuss how the field's vitality and survival can be secured. These leaders presented their own opinions and not the opinion of the society or organization that they are presenting. Early exposure of future trainees to pediatrics and advocacy for improved reimbursement structures, loan repayment, and funded programs for physician scientists will enhance the recruitment and retention of pediatric subspecialists to guarantee advancement of knowledge and the appropriate care of children with chronic and complex diseases.

Objective The aim of Placental Assessment in Response to Environmental Pollution Study (PARENTs) was to determine whether imaging of the placenta by novel multiparametric magnetic resonance imaging (MRI) techniques in early pregnancy could help predict adverse pregnancy outcomes (APOs) due to ischemic placental disease (IPD). Additionally, we sought to determine maternal characteristics and environmental risk factors that contribute to IPD and secondary APOs. Study Design Potential patients in their first trimester of pregnancy, who agreed to MRI of the placenta and measures of assessment of environmental pollution, were recruited into PARENTs, a prospective population-based cohort study. Participants were seen at three study visits during pregnancy and again at their delivery from 2015 to 2019. We collected data from interviews, chart abstractions, and imaging. Maternal biospecimens (serum, plasma, and urine) at antepartum study visits and delivery specimens (placenta, cord, and maternal blood) were collected, processed, and stored. The primary outcome was a composite of IPD, which included any of the following: placental abruption, hypertensive disease of pregnancy, fetal growth restriction, or a newborn of small for gestational age. Results In this pilot cohort, of the 190 patients who completed pregnancy to viable delivery, 50 (26%) developed IPD. Among demographic characteristics, having a history of prior IPD in multiparous women was associated with the development of IPD. In the multiple novel perfusion measurements taken of the in vivo placenta using MRI, decreased high placental blood flow (mL/100 g/min) in early pregnancy (between 14 and 16 weeks) was found to be significantly associated with the later development of IPD. Conclusion Successful recruitment of the PARENTs prospective cohort demonstrated the feasibility and acceptability of the use of MRI in human pregnancy to study the placenta in vivo and at the same time collect environmental exposure data. Analysis is ongoing and we hope these methods will assist researchers in the design of prospective imaging studies of pregnancy. Key Points