Human cord plasma proteomic analysis reveals sexually dimorphic proteins associated with intrauterine growth restriction.

Intrauterine growth restriction (IUGR) is associated with increased risk of cardiometabolic disease later in life and has been shown to affect female and male offspring differently, but the mechanisms remain unclear. The purpose of this study was to identify proteomic differences and metabolic risk markers in IUGR male and female neonates when compared to appropriate for gestational age (AGA) babies that will provide a better understanding of IUGR pathogenesis and its associated risks. Our results revealed alterations in IUGR cord plasma proteomes with most of the differentially abundant proteins implicated in peroxisome pathways. This effect was evident in females but not in males. Furthermore, we observed that catalase activity, a peroxisomal enzyme, was significantly increased in females (p < 0.05) but unchanged in males. Finally, we identified risk proteins associated with obesity, type-2 diabetes, and glucose intolerance such as EGF containing fibulin extracellular matrix protein 1 (EFEMP1), proprotein convertase subtilisin/kexin type 9 (PCSK9) and transforming growth factor beta receptor 3 (TGFBR3) proteins unique to females while coagulation factor IX (C9) and retinol binding protein 4 (RBP4) are unique in males. In conclusion, IUGR may display sexual dimorphism which may be associated with differences in lifelong risk for cardiometabolic disease between males and females.

The effect of cesarean delivery on the neonatal gut microbiome in an under-resourced population in the Bronx, NY, USA.

BACKGROUND: Neonatal and early-life gut microbiome changes are associated with altered cardiometabolic and immune development. In this study, we explored Cesarean delivery effects on the gut microbiome in our high-risk, under-resourced Bronx, NY population. RESULTS: Fecal samples from the Bronx MomBa Health Study (Bronx MomBa Health Study) were categorized by delivery mode (vaginal/Cesarean) and analyzed via 16 S rRNA gene sequencing at four timepoints over the first two years of life. Bacteroidota organisms, which have been linked to decreased risk for obesity and type 2 diabetes, were relatively reduced by Cesarean delivery, while Firmicutes organisms were increased. Organisms belonging to the Enterococcus genus, which have been tied to aberrant immune cell development, were relatively increased in the Cesarean delivery microbiomes. CONCLUSION: Due to their far-reaching impact on cardiometabolic and immune functions, Cesarean deliveries in high-risk patient populations should be carefully considered.

Perinatal exposure to high dietary advanced glycation end products affects the reproductive system in female offspring in mice.

Maternal nutrition and the intrauterine environment are important in determining susceptibility to reproductive and metabolic disturbances. Advanced glycation end products (AGEs) are widely consumed in Western diet. The purpose of this study was to determine whether perinatal exposure to a high levels of dietary AGEs affect metabolic and reproductive parameters in female mice offspring. Female CD1 mice, 7 weeks old, were placed on either a diet low (L-AGE) or high (H-AGE) in AGEs before mating and then during pregnancy and lactation. All offspring were weaned onto the L-AGE diet and studied through to 16 weeks of age; they were counted and weighed at birth and then every week for a total of 11 weeks. Vaginal opening, litter size, growth curve, liver and abdominal fat weights, serum levels of anti-Mullerian hormone, leptin and adiponectin, as well as insulin and glucose tolerance tests were compared. Ovaries were harvested for follicular count and gene expression by real-time polymerase chain reaction. Compared to perinatal exposure to the L-AGE diet, perinatal exposure to the H-AGE diet caused lower body weight at birth, and adult offspring exhibited delayed growth, lower serum leptin and adiponectin levels, delayed vaginal opening, irregular oestrous cyclicity, arrested follicular development and significant alterations in the expression of genes involved in folliculogenesis (Amh and Amhr2) and steroidogenesis (Cyp19a1). These results indicate that perinatal exposure to a diet elevated in AGEs causes deficits in perinatal growth, pubertal onset, and reproductive organ development in female mice. Whether these findings translate to humans remains to be determined in future studies.

N-Acetylcysteine Resolves Placental Inflammatory-Vasculopathic Changes in Mice Consuming a High-Fat Diet.

The mechanism by which poor maternal nutrition can affect the long-term health of offspring is poorly understood. In mice, we previously found that maternal high-fat diet (HFD) exposure results in reduced fetal growth regardless of maternal genotype. We tested our hypothesis that maternal HFD-induced inflammation contributes to metabolic disease susceptibility of the offspring via alterations in the placenta. The effect of maternal genotype, diet, and treatment with the anti-inflammatory compound N-acetylcysteine (NAC) on placental morphologic features was investigated. Placentas from wild-type dams maintained on a HFD but not those heterozygous (+/-) for Glut4 (Slc2a4) on the same diet had an increase in decidual inflammation and vasculopathy occurring together. NAC administration resulted in amelioration of HFD-induced decidual vasculopathy independent of offspring genotype and sex. Consistent with these morphologic improvements, placentas from HFD dams treated with NAC had decreased mRNA and immunostaining of IL-1ß and monocyte chemoattractant protein-1, decreased mRNA of inflammatory genes, and increased mRNA of Vegfa. These results strongly suggest consumption of an HFD results in vascular changes in placenta reflected by alterations in expression of pivotal vascular developmental markers and inflammatory genes all of which are ameliorated by NAC. These placental changes play a key role in the increased programed metabolic disease of HFD-exposed offspring.

Loss of glucagon signaling alters white adipose tissue browning.

Various endocrine factors contribute to cold-induced white adipose tissue (WAT) browning, but glucagon has largely been ignored. The purpose of the current investigation was to determine if glucagon was required for the effects of cold on WAT browning. Utilizing whole-body glucagon receptor knockout (Gcgr-/-) mice and their wild-type (WT) littermate controls, we examined the response of inguinal WAT (iWAT) and interscapular brown adipose tissue (BAT) to an acute (48 h) cold stress or challenge with the ß3-adrenergic agonist CL316,243. The effects of glucagon alone on the induction of thermogenic genes in adipose tissue from C57BL6/J mice were also examined. Gcgr-/- mice displayed modest increases in indices of browning at room temperature while displaying a blunted induction of Ucp1, Cidea, and Ffg21 mRNA expression in iWAT following cold exposure. Similarly, cold induced increases in mitochondrial DNA copy number, and the protein content of mitochondrial respiratory chain complexes, UCP1, and PGC1α were attenuated in iWAT from Gcgr-/- mice. In BAT, the induction of thermogenic markers following cold exposure was reduced, but the effect was less pronounced than in iWAT. Glucagon treatment increased the expression of thermogenic genes in both iWAT and BAT of C57BL6/J mice. In response to CL316,243, circulating fatty acids, glycerol, and the phosphorylation of hormone-sensitive lipase were attenuated in iWAT of Gcgr-/- mice. We provide evidence that glucagon is sufficient for the induction of thermogenic genes in iWAT, and the absence of intact glucagon signaling blunts the cold-induced browning of WAT, possibly due, in part, to impaired adrenergic signaling.-Townsend, L. K., Medak, K. D., Knuth, C. M., Peppler, W. T., Charron, M. J., Wright, D. C. Loss of glucagon signaling alters white adipose tissue browning.

Anti-diabetic activity of insulin-degrading enzyme inhibitors mediated by multiple hormones.

Despite decades of speculation that inhibiting endogenous insulin degradation might treat type-2 diabetes, and the identification of IDE (insulin-degrading enzyme) as a diabetes susceptibility gene, the relationship between the activity of the zinc metalloprotein IDE and glucose homeostasis remains unclear. Although Ide(-/-) mice have elevated insulin levels, they exhibit impaired, rather than improved, glucose tolerance that may arise from compensatory insulin signalling dysfunction. IDE inhibitors that are active in vivo are therefore needed to elucidate IDE's physiological roles and to determine its potential to serve as a target for the treatment of diabetes. Here we report the discovery of a physiologically active IDE inhibitor identified from a DNA-templated macrocycle library. An X-ray structure of the macrocycle bound to IDE reveals that it engages a binding pocket away from the catalytic site, which explains its remarkable selectivity. Treatment of lean and obese mice with this inhibitor shows that IDE regulates the abundance and signalling of glucagon and amylin, in addition to that of insulin. Under physiological conditions that augment insulin and amylin levels, such as oral glucose administration, acute IDE inhibition leads to substantially improved glucose tolerance and slower gastric emptying. These findings demonstrate the feasibility of modulating IDE activity as a new therapeutic strategy to treat type-2 diabetes and expand our understanding of the roles of IDE in glucose and hormone regulation.

Disruption of glucagon receptor signaling causes hyperaminoacidemia exposing a possible liver-alpha-cell axis.

Glucagon secreted from the pancreatic alpha-cells is essential for regulation of blood glucose levels. However, glucagon may play an equally important role in the regulation of amino acid metabolism by promoting ureagenesis. We hypothesized that disruption of glucagon receptor signaling would lead to an increased plasma concentration of amino acids, which in a feedback manner stimulates the secretion of glucagon, eventually associated with compensatory proliferation of the pancreatic alpha-cells. To address this, we performed plasma profiling of glucagon receptor knockout ( Gcgr-/-) mice and wild-type (WT) littermates using liquid chromatography-mass spectrometry (LC-MS)-based metabolomics, and tissue biopsies from the pancreas were analyzed for islet hormones and by histology. A principal component analysis of the plasma metabolome from Gcgr-/- and WT littermates indicated amino acids as the primary metabolic component distinguishing the two groups of mice. Apart from their hyperaminoacidemia, Gcgr-/- mice display hyperglucagonemia, increased pancreatic content of glucagon and somatostatin (but not insulin), and alpha-cell hyperplasia and hypertrophy compared with WT littermates. Incubating cultured α-TC1.9 cells with a mixture of amino acids (Vamin 1%) for 30 min and for up to 48 h led to increased glucagon concentrations (~6-fold) in the media and cell proliferation (~2-fold), respectively. In anesthetized mice, a glucagon receptor-specific antagonist (Novo Nordisk 25-2648, 100 mg/kg) reduced amino acid clearance. Our data support the notion that glucagon secretion and hepatic amino acid metabolism are linked in a close feedback loop, which operates independently of normal variations in glucose metabolism.

A High Fat Diet During Pregnancy and Lactation Induces Cardiac and Renal Abnormalities in GLUT4 +/- Male Mice.

BACKGROUND/AIMS: Altered nutrients during the in utero (IU) and/or lactation (L) period predispose offspring to cardio-renal diseases in adulthood. This study investigates the effect of a high fat diet (HFD) fed to female mice during IU/L on gene expression patterns associated with heart and kidney failure and hypertension in male offspring. METHODS: Female wild type (WT) mice were fed either a HFD or control chow (C) prior to mating with males with a genetic heterozygous deletion of GLUT4 (G4+/-, a model of peripheral insulin resistance and hypertension) and throughout IU/L. After weaning male offspring were placed on a standard rodent chow until 24 weeks of age. RESULTS: All offspring exposed to a maternal HFD showed increased heart and kidney weight and reduced cardiac insulin responsiveness. G4+/- offspring on a HFD displayed early hypertension associated with increased renal gene expression of renin and the AT1- receptors compared to G4+/- on a C diet. This group showed decreased cardiac expression of key genes involved in fatty acid oxidation compared to WT on a C diet. CONCLUSIONS: These results indicate an interaction between a HFD diet and genotype during early life development that can enhance susceptibility to cardio-renal diseases later in life.

Hyperglycemia in rodent models of type 2 diabetes requires insulin-resistant alpha cells.

To determine the role of glucagon action in diet-induced and genetic type 2 diabetes (T2D), we studied high-fat-diet-induced obese (DIO) and leptin receptor-defective (LepR(-/-)) rodents with and without glucagon receptors (GcgRs). DIO and LepR(-/-),GcgR(+/+) mice both developed hyperinsulinemia, increased liver sterol response element binding protein 1c, and obesity. DIO GcgR(+/+) mice developed mild T2D, whereas LepR(-/-),GcgR(+/+) mice developed severe T2D. High-fat-fed (HFF) glucagon receptor-null mice did not develop hyperinsulinemia, increased liver sterol response element binding protein 1c mRNA, or obesity. Insulin treatment of HFF GcgR(-/-) to simulate HFF-induced hyperinsulinemia caused obesity and mild T2D. LepR(-/-),GcgR(-/-) did not develop hyperinsulinemia or hyperglycemia. Adenoviral delivery of GcgR to GcgR(-/-),LepR(-/-) mice caused the severe hyperinsulinemia and hyperglycemia of LepR(-/-) mice to appear. Spontaneous disappearance of the GcgR transgene abolished the hyperinsulinemia and hyperglycemia. In conclusion, T2D hyperglycemia requires unsuppressible hyperglucagonemia from insulin-resistant α cells and is prevented by glucagon suppression or blockade.

DNA hypermethylation of CD3(+) T cells from cord blood of infants exposed to intrauterine growth restriction.

AIMS/HYPOTHESIS: Intrauterine growth restriction (IUGR) is associated with increased susceptibility to obesity, metabolic syndrome and type 2 diabetes. Although the mechanisms underlying the developmental origins of metabolic disease are poorly understood, evidence suggests that epigenomic alterations play a critical role. We sought to identify changes in DNA methylation patterns that are associated with IUGR in CD3(+) T cells purified from umbilical cord blood obtained from male newborns who were appropriate for gestational age (AGA) or who had been exposed to IUGR. METHODS: CD3(+) T cells were isolated from cord blood obtained from IUGR and AGA infants. The genome-wide methylation profile in eight AGA and seven IUGR samples was determined using the HELP tagging assay. Validation analysis using targeted bisulfite sequencing and bisulfite massARRAY was performed on the original cohort as well as biological replicates consisting of two AGA and four IUGR infants. The Segway algorithm was used to identify methylation changes within regulatory regions of the genome. RESULTS: A global shift towards hypermethylation in IUGR was seen compared with AGA (89.8% of 4,425 differentially methylated loci), targeted to regulatory regions of the genome, specifically promoters and enhancers. Pathway analysis identified dysregulation of pathways involved in metabolic disease (type 2 diabetes mellitus, insulin signalling, mitogen-activated protein kinase signalling) and T cell development, regulation and activation (T cell receptor signalling), as well as transcription factors (TCF3, LEF1 and NFATC) that regulate T cells. Furthermore, bump-hunting analysis revealed differentially methylated regions in PRDM16 and HLA-DPB1, genes important for adipose tissue differentiation, stem cell maintenance and function and T cell activation. CONCLUSIONS/INTERPRETATION: Our findings suggest that the alterations in methylation patterns observed in IUGR CD3(+) T cells may have functional consequences in targeted genes, regulatory regions and transcription factors. These may serve as biomarkers to identify those at 'high risk' for diminished attainment of full health potential who can benefit from early interventions. ACCESS TO RESEARCH MATERIALS: HELP tagging data: Gene Expression Omnibus database (GSE77268), scheduled to be released on 25 January 2019.

Ovarian kisspeptin expression is related to age and to monocyte chemoattractant protein-1.

PURPOSE: The objective of this study was to test the hypothesis that ovarian kisspeptin (kiss1) and its receptor (kiss1r) expression are affected by age, obesity, and the age- and obesity-related chemokine monocyte chemoattractant protein-1 (MCP-1). METHODS: Ovaries from reproductive-aged and older C57BL/6J mice fed normal chow (NC) or high-fat (HF) diet, ovaries from age-matched young MCP-1 knockout and young control mice on NC, and finally, cumulus and mural granulosa cells (GCs) from women who underwent in vitro fertilization (IVF) were collected. Kiss1, kiss1r, anti-Mullerian hormone (AMH), and AMH receptor (AMHR-II) messenger RNA (mRNA) expression levels were quantified using real-time polymerase chain reaction (RT-PCR). RESULTS: In mouse ovaries, kiss1 and kiss1r mRNA levels were significantly higher in old compared to reproductive-aged mice, and diet-induced obesity did not alter kiss1 or kiss1r mRNA levels. Compared to young control mice, young MCP-1 knockout mice had significantly lower ovarian kiss1 mRNA but significantly higher AMH and AMHR-II mRNA levels. In human cumulus GCs, kiss1r mRNA levels were positively correlated with age but not with BMI. There was no expression of kiss1 mRNA in either cumulus or mural GCs. CONCLUSION: These data suggest a possible age-related physiologic role for the kisspeptinergic system in ovarian physiology. Additionally, the inflammatory MCP-1 may be associated with kiss1 and AMH genes, which are important in ovulation and folliculogenesis, respectively.

Animal models of in utero exposure to a high fat diet: a review.

The incidence of metabolic disease, including type 2 diabetes and obesity, has increased to epidemic levels in recent years. A growing body of evidence suggests that the intrauterine environment plays a key role in the development of metabolic disease in offspring. Among other perturbations in early life, alteration in the provision of nutrients has profound and lasting effects on the long term health and well being of offspring. Rodent and non-human primate models provide a means to understand the underlying mechanisms of this programming effect. These different models demonstrate converging effects of a maternal high fat diet on insulin and glucose metabolism, energy balance, cardiovascular function and adiposity in offspring. Furthermore, evidence suggests that the early life environment can result in epigenetic changes that set the stage for alterations in key pathways of metabolism that lead to type 2 diabetes or obesity. Identifying and understanding the causal factors responsible for this metabolic dysregulation is vital to curtailing these epidemics. This article is part of a Special Issue entitled: Modulation of Adipose Tissue in Health and Disease.

Metabolic manifestations of insulin deficiency do not occur without glucagon action.

To determine unambiguously if suppression of glucagon action will eliminate manifestations of diabetes, we expressed glucagon receptors in livers of glucagon receptor-null (GcgR(-/-)) mice before and after ß-cell destruction by high-dose streptozotocin. Wild type (WT) mice developed fatal diabetic ketoacidosis after streptozotocin, whereas GcgR(-/-) mice with similar ß-cell destruction remained clinically normal without hyperglycemia, impaired glucose tolerance, or hepatic glycogen depletion. Restoration of receptor expression using adenovirus containing the GcgR cDNA restored hepatic GcgR, phospho-cAMP response element binding protein (P-CREB), and phosphoenol pyruvate carboxykinase, markers of glucagon action, rose dramatically and severe hyperglycemia appeared. When GcgR mRNA spontaneously disappeared 7 d later, P-CREB declined and hyperglycemia disappeared. In conclusion, the metabolic manifestations of diabetes cannot occur without glucagon action and, once present, disappear promptly when glucagon action is abolished. Glucagon suppression should be a major therapeutic goal in diabetes.

Critical periods of increased fetal vulnerability to a maternal high fat diet.

BACKGROUND: Fetal adaptations to high fat (HF) diet in utero (IU) that may predispose to Metabolic Syndrome (MetS) in adulthood include changes in fetal hepatic gene expression. Studies were performed to determine whether maternal exposure to HF diet at different stages during pregnancy had different effects on the fetus, including hepatic gene expression. METHODS: Female wild type mice were fed either a HF or breeding chow (C) for 2 wks prior to mating. The experimental groups were composed of embryonic day (e) 18.5 fetuses obtained from WT female mice that were fed HF (HF, 35.5% fat) or breeding chow (C, 9.5% fat) for 2 wk before mating until e9.5 of pregnancy (periconception-midpregnancy). At e9.5 dams were switched to the opposite diet (C-HF or HF-C). RESULTS: Exposure to HF diet throughout pregnancy reduced maternal weight gain compared to C diet (p < 0.02 HF vs. C). HF-C dams had significantly decreased adiponectin levels and litter size when compared to C-HF (p < 0.02 HF-C vs C-HF). Independent of the timing of exposure to HF, fetal weight and length were significantly decreased when compared to C diet (HF, C-HF and HF-C vs. C p < 0.02). HF diet during the second half of pregnancy increased expression of genes in the fetal liver associated with fetal growth (C-HF vs C p < 0.001), glucose production (C-HF vs C p < 0.04), oxidative stress and inflammation (C-HF vs C p < 0.01) compared to C diet. CONCLUSIONS: This model defines that there are critical periods during gestation in which the fetus is actively shaped by the environment. Early exposure to a HF diet determines litter size while exposure to HF during the second half of pregnancy leads to dysregulation of expression of key genes responsible for fetal growth, hepatic glucose production and oxidative stress. These findings underscore the importance of future studies designed to clarify how these critical periods may influence future risk of developing MetS later in life.

In utero exposure to a maternal high-fat diet alters the epigenetic histone code in a murine model.

OBJECTIVE: Data from animal models show that in utero exposure to a maternal high-fat diet (HFD) renders susceptibility of these offspring to the adult onset of metabolic syndrome. We and others have previously shown that epigenetic modifications to histones may serve as a molecular memory of the in utero exposure, rendering the risk of adult disease. Because mice heterozygous for the Glut4 gene (insulin sensitive glucose transporter) born to wild-type (WT) mothers demonstrate exacterbated metabolic syndrome when exposed to an HFD in utero, we sought to analyze the genome-wide epigenetic changes that occur in the fetal liver in susceptible offspring. STUDY DESIGN: WT and Glut4(+/-) (G4(+/-)) offspring of WT mothers that were exposed either to a control or an HFD in utero were studied. Immunoblotting was used to measure hepatic histone modifications of fetal and 5-week animals. Chromatin immunoprecipitation (ChIP) followed by hybridization to chip arrays (ChIP-on-chip) was used to detect genome-wide changes of histone modifications with HFD exposure. RESULTS: We found that levels of hepatic H3K14ac and H3K9me3 significantly increased with HFD exposure in WT and G4(+/-) fetal and 5-week offspring. Pathway analysis of our ChIP-on-chip data revealed differential H3K14ac and H3K9me3 enrichment along pathways that regulate lipid metabolism, specifically in the promoter regions of Pparg, Ppara, Rxra, and Rora. CONCLUSION: We conclude that HFD exposure in utero is associated with functional alterations to fetal hepatic histone modifications in both WT and G4(+/-) offspring, some of which persist up to 5 weeks of age.

Downregulation of the kidney glucagon receptor, essential for renal function and systemic homeostasis, contributes to chronic kidney disease.

The glucagon receptor (GCGR) in the kidney is expressed in nephron tubules. In humans and animal models with chronic kidney disease, renal GCGR expression is reduced. However, the role of kidney GCGR in normal renal function and in disease development has not been addressed. Here, we examined its role by analyzing mice with constitutive or conditional kidney-specific loss of the Gcgr. Adult renal Gcgr knockout mice exhibit metabolic dysregulation and a functional impairment of the kidneys. These mice exhibit hyperaminoacidemia associated with reduced kidney glucose output, oxidative stress, enhanced inflammasome activity, and excess lipid accumulation in the kidney. Upon a lipid challenge, they display maladaptive responses with acute hypertriglyceridemia and chronic proinflammatory and profibrotic activation. In aged mice, kidney Gcgr ablation elicits widespread renal deposition of collagen and fibronectin, indicative of fibrosis. Taken together, our findings demonstrate an essential role of the renal GCGR in normal kidney metabolic and homeostatic functions. Importantly, mice deficient for kidney Gcgr recapitulate some of the key pathophysiological features of chronic kidney disease.

Leptin therapy in insulin-deficient type I diabetes.

In nonobese diabetic mice with uncontrolled type 1 diabetes, leptin therapy alone or combined with low-dose insulin reverses the catabolic state through suppression of hyperglucagonemia. Additionally, it mimics the anabolic actions of insulin monotherapy and normalizes hemoglobin A1c with far less glucose variability. We show that leptin therapy, like insulin, normalizes the levels of a wide array of hepatic intermediary metabolites in multiple chemical classes, including acylcarnitines, organic acids (tricarboxylic acid cycle intermediates), amino acids, and acyl CoAs. In contrast to insulin monotherapy, however, leptin lowers both lipogenic and cholesterologenic transcription factors and enzymes and reduces plasma and tissue lipids. The results imply that leptin administration may have multiple short- and long-term advantages over insulin monotherapy for type 1 diabetes.

Association of parent-child interactions with parental psychological distress and resilience during the COVID-19 pandemic.

Introduction: The effects of psychological distress/resilience on parent-child engagement (e.g., family dinners, reading) during the COVID-19 pandemic have not been well studied. Among very young children from underrepresented backgrounds enrolled in the ongoing longitudinal Bronx Mother Baby Health Study of healthy term infants, we (1) examined associations between exposures to COVID-19-related events, demographic factors and parental psychological distress and resilience; and (2) correlated these factors with parent-child engagement activities. Methods: Between June 2020-August 2021, parents of 105 Bronx Mother Baby Health Study participants aged birth-25 months completed questionnaires related to exposures to COVID-19-related events, frequency of positive parent-child engagement activities, food and housing insecurity, and parental psychological distress and resilience. Families were also asked open ended questions about the pandemic's impact. Results: 29.8% and 47.6% of parents reported food and housing insecurity, respectively. Greater exposures to COVID-19-related events were associated with increased parental psychological distress. Positive parent-child interactions were associated with demographic factors and higher levels of maternal education, but not with exposures to COVID-19-related events. Discussion: This study adds to a growing body of literature on the negative impacts of COVID-19 exposures and psychosocial stressors on families during the pandemic, supporting the need for enhanced mental health resources and social supports for families.

Corrigendum: Association of parent-child interactions with parental psychological distress and resilience during the COVID-19 pandemic.

[This corrects the article DOI: 10.3389/fped.2023.1150216.].

SARS-CoV-2 Infection in Unvaccinated High-Risk Pregnant Women in the Bronx, NY, USA Is Associated with Decreased Apgar Scores and Placental Villous Infarcts.

Babies born to severe acute respiratory syndrome corona virus-2 (SARS-CoV-2)-infected mothers are at greater risk for perinatal morbidity and more likely to receive a neurodevelopmental diagnosis in the first year of life. However, the effect of maternal infection on placental function and neonatal outcomes varies depending upon the patient population. We set out to test our hypothesis that maternal SARS-CoV-2 infection in our underserved, socioeconomically disadvantaged, mostly unvaccinated, predominantly African American and Latina population in the Bronx, NY would have effects evident at birth. Under IRB approval, 56 SARS-CoV-2-positive patients infected during the "first wave" of the pandemic with alpha and beta strains of the virus, 48 patients infected during the "second wave" of the pandemic with delta and omicron strains and 61 negative third-trimester high-risk patients were randomly selected from Montefiore Medical Center (MMC), Bronx, NY. In addition, two positive cases from Yale New Haven Hospital, CT were included as controls. All 104 placentas delivered by SARS-CoV-2-positive mothers were uninfected by the virus, based on immunohistochemistry, in situ hybridization, and qPCR analysis. However, placental villous infarcts were significantly increased in first-wave cases compared to second-wave cases or negative controls. Significantly lower Apgar scores at 1 min and 5 min were observed in neonates born to infected mothers with severe symptoms. These findings suggest that even without entering the placenta, SARS-CoV-2 can affect various systemic pathways, culminating in altered placental development and function, which may adversely affect the fetus, especially in a high-risk patient population such as ours. These results underline the importance of vaccination among pregnant women, particularly in low-resource areas.