Wildfires and climate justice: future wildfire events predicted to disproportionally impact socioeconomically vulnerable communities in North Carolina.

Wildfire events are becoming increasingly common across many areas of the United States, including North Carolina (NC). Wildfires can cause immediate damage to properties, and wildfire smoke conditions can harm the overall health of exposed communities. It is critical to identify communities at increased risk of wildfire events, particularly in areas with that have sociodemographic disparities and low socioeconomic status (SES) that may exacerbate incurred impacts of wildfire events. This study set out to: (1) characterize the distribution of wildfire risk across NC; (2) implement integrative cluster analyses to identify regions that contain communities with increased vulnerability to the impacts of wildfire events due to sociodemographic characteristics; (3) provide summary-level statistics of populations with highest wildfire risk, highlighting SES and housing cost factors; and (4) disseminate wildfire risk information via our online web application, ENVIROSCAN. Wildfire hazard potential (WHP) indices were organized at the census tract-level, and distributions were analyzed for spatial autocorrelation via global and local Moran's tests. Sociodemographic characteristics were analyzed via k-means analysis to identify clusters with distinct SES patterns to characterize regions of similar sociodemographic/socioeconomic disparities. These SES groupings were overlayed with housing and wildfire risk profiles to establish patterns of risk across NC. Resulting geospatial analyses identified areas largely in Southeastern NC with high risk of wildfires that were significantly correlated with neighboring regions with high WHP, highlighting adjacent regions of high risk for future wildfire events. Cluster-based analysis of SES factors resulted in three groups of regions categorized through distinct SES profiling; two of these clusters (Clusters 2 and 3) contained indicators of high SES vulnerability. Cluster 2 contained a higher percentage of younger (<5 years), non-white, Hispanic and/or Latino residents; while Cluster 3 had the highest mean WHP and was characterized by a higher percentage of non-white residents, poverty, and less than a high school education. Counties of particular SES and WHP-combined vulnerability include those with majority non-white residents, tribal communities, and below poverty level households largely located in Southeastern NC. WHP values per census tract were dispersed to the public via the ENVIROSCAN application, alongside other environmentally-relevant data.

Identifying and Responding to Lead in Drinking Water in a University Setting.

Lead is an established neurotoxicant, and it has known associations with adverse neurodevelopmental and reproductive outcomes. Exposure to lead at any level is unsafe, and the United States (US) has enacted various federal and state legislations to regulate lead levels in drinking water in K-12 schools and childcare facilities; however, no regulations exist for higher education settings. Upon the discovery of lead in drinking water fixtures in the University of North Carolina at Chapel Hill (UNC-CH) campus, a cross-campus water testing network and sampling plan was developed and deployed. The campaign was based on the US Environmental Protection Agency's (EPA) 3Ts (Training, Testing, and Taking Action) guidance. The seven-month campaign involved 5954 tests on 3825 drinking water fixtures across 265 buildings. A total of 502 (8.43%) tests showed lead above the limit of detection (1 part per billion, ppb), which represented 422 (11.03%) fixtures. Fewer than 1.5% of the tests were above the EPA action level for public water systems (15 ppb). In conclusion, systematic testing of all the fixtures across campus was required to identify localized contamination, and each entity in the cross-campus network undertook necessary roles to generate a successful testing campaign. UNC-CH established preventative measures to test drinking water fixtures every three years, which provide a framework for other higher education institutions in responding to lead contamination.

Epigenetic Responses to Nonchemical Stressors: Potential Molecular Links to Perinatal Health Outcomes.

PURPOSE OF REVIEW: We summarize the recent literature investigating exposure to four nonchemical stressors (financial stress, racism, psychosocial stress, and trauma) and DNA methylation, miRNA expression, and mRNA expression. We also highlight the relationships between these epigenetic changes and six critical perinatal outcomes (preterm birth, low birth weight, preeclampsia, gestational diabetes, childhood allergic disease, and childhood neurocognition). RECENT FINDINGS: Multiple studies have found financial stress, psychosocial stress, and trauma to be associated with DNA methylation and/or miRNA and mRNA expression. Fewer studies have investigated the effects of racism. The majority of studies assessed epigenetic or genomic changes in maternal blood, cord blood, or placenta. Several studies included multi-OMIC assessments in which DNA methylation and/or miRNA expression were associated with gene expression. There is strong evidence for the role of epigenetics in driving the health outcomes considered. A total of 22 biomarkers, including numerous HPA axis genes, were identified to be epigenetically altered by both stressors and outcomes. Epigenetic changes related to inflammation, the immune and endocrine systems, and cell growth and survival were highlighted across numerous studies. Maternal exposure to nonchemical stressors is associated with epigenetic and/or genomic changes in a tissue-specific manner among inflammatory, immune, endocrine, and cell growth-related pathways, which may act as mediating pathways to perinatal health outcomes. Future research can test the mediating role of the specific biomarkers identified as linked with both stressors and outcomes. Understanding underlying epigenetic mechanisms altered by nonchemical stressors can provide a better understanding of how chemical and nonchemical exposures interact.

Placental cellular composition and umbilical cord tissue metal(loid) concentrations: A descriptive molecular epidemiology study leveraging DNA methylation.

The placenta is a mixture of cell types, which may regulate maternal-fetal transfer of exogenous chemicals or become altered in response to exposures. We leveraged placental DNA methylation to characterize major constituent cell types and applied compositional data analysis to test associations with non-essential metal(loid)s measured in paired umbilical cord tissue (N = 158). Higher proportions of syncytiotrophoblasts were associated with lower arsenic, whereas higher proportions of Hofbauer cells were associated with higher cadmium concentrations in umbilical cords. These findings suggest that placental cellular composition influences amounts of metal(loid)s transferred to the fetus or that prenatal exposures alter the placental cellular makeup.

Toxic metal mixtures in private well water and increased risk for preterm birth in North Carolina.

BACKGROUND: Prenatal exposure to metals in private well water may increase the risk of preterm birth (PTB) (delivery < 37 weeks' gestation). In this study, we estimated associations between arsenic, manganese, lead, cadmium, chromium, copper, and zinc concentrations in private well water and PTB incidence in North Carolina (NC). METHODS: Birth certificates from 2003-2015 (n = 1,329,071) were obtained and pregnancies were assigned exposure using the mean concentration and the percentage of tests above the maximum contaminant level (MCL) for the census tract of each individuals' residence at the time of delivery using the NCWELL database (117,960 well water tests from 1998-2019). We evaluated associations between single metals and PTB using adjusted logistic regression models. Metals mixtures were assessed using quantile-based g-computation. RESULTS: Compared with those in other census tracts, individuals residing in tracts where > 25% of tests exceeded the MCL for lead (aOR 1.10, 95%CI 1.02,1.18) or cadmium (aOR 1.11, 95% CI 1.00,1.23) had an increased odds of PTB. Conversely, those residing in areas with > 25% MCL for zinc (aOR 0.77 (95% CI: 0.56,1.02) and copper (aOR 0.53 (95% CI: 0.13,1.34)) had a reduced odds of PTB. A quartile increase in the concentrations of a mixture of lead, cadmium, and chromium was associated with a small increased odds for PTB (aOR 1.02, 95% CI 1.01, 1.03). This metal mixture effect was most pronounced among American Indian individuals (aOR per quartile increase in all metals: 1.19 (95% CI 1.06,1.34)). CONCLUSIONS: In a large study population of over one million births, lead and cadmium were found to increase the risk of PTB individually and in a mixture, with additional mixtures-related impacts estimated from co-exposure with chromium. This study highlights critical racial and ethnic health disparities in relation to private well water thereby emphasizing the urgent need for improved private well water quality to protect vulnerable populations.

Accelerated epigenetic clock aging in maternal peripheral blood and preterm birth.

BACKGROUND: Epigenetic clocks use CpG DNA methylation to estimate biological age. Acceleration is associated with cancer, heart disease, and shorter life span. Few studies evaluate DNA methylation age and pregnancy outcomes. AgeAccelGrim is a novel epigenetic clock that combines 7 DNA methylation components. OBJECTIVE: This study aimed to determine whether maternal biological aging (via AgeAccelGrim) is associated with early preterm birth. STUDY DESIGN: A prospective cohort of patients with singleton pregnancies and at high risk of spontaneous preterm birth delivering at a tertiary university hospital were included in this study. Genome-wide CpG methylation was measured using the Illumina EPIC BeadChip (Illumina, Inc, San Diego, CA) from maternal blood samples obtained at <28 weeks of gestation. AgeAccelGrim and its 7 DNA methylation components were estimated by the Horvath DNA methylation age online tool. Positive values are associated with accelerated biological aging, whereas negative values are associated with slower biological aging relative to each subject's age. The primary outcome was preterm birth at <34 weeks of gestation (any indication). The secondary outcomes were preterm birth at <37 and <28 weeks of gestation. AgeAccelGrim was analyzed as a continuous variable and in quartiles. Exploratory analyses evaluated each of the 7 DNA methylation components included in the composite AgeAccelGrim. Data were analyzed by chi-square test, t test, rank-sum test, logistic regression (controlling a priori for maternal age, cell counts, low socioeconomic status, and gestational age at the time of sample collection), and Kaplan-Meier survival analyses. The log-rank test was used to test the equality of the survival functions. RESULTS: Overall, 163 patients met the inclusion criteria. Of the patients, 48%, 39%, and 21% delivered at <37, <34, and <28 weeks of gestation, respectively. The median AgeAccelGrim was -0.35 years (interquartile range, -2.24 to 1.31) for those delivering at term. Those delivering preterm had higher AgeAccelGrim values that were inversely proportional to delivery gestational age (preterm birth at <37 weeks of gestation: +0.40 years [interquartile range: -1.21 to +2.28]; preterm birth at <34 weeks of gestation: +0.51 years [interquartile range: -1.05 to +2.67]; preterm birth at <28 weeks of gestation: +1.05 years [interquartile range: -0.72 to +2.72]). Estimated DNA methylation of the 7 epigenetic clock component values was increased among those with preterm birth at <34 weeks of gestation, although the differences were only significant for DNA methylation of plasminogen activation inhibitor 1. In regression models, AgeAcccelGrim was associated with an elevated risk of preterm birth with increasing magnitude for increasing severity of preterm birth. For each 1-year increase in the AgeAccelGrim value (ie, each 1-year increase in biological age compared with chronologic age), the adjusted odds of preterm birth were 11% (adjusted odds ratio, 1.11; 95% confidence interval, 1.00-1.24), 13% (adjusted odds ratio, 1.13; 95% confidence interval, 1.01-1.26), and 18% (adjusted odds ratio, 1.18; 95% confidence interval, 1.04-1.35) higher for preterm birth at <37, <34, and <28 weeks of gestation, respectively. Similarly, individuals with accelerated biological aging (≥75th percentile AgeAccelGrim) had more than double the odds of preterm birth at <34 weeks of gestation (adjusted odds ratio, 2.36; 95% confidence interval, 1.10-5.08) and more than triple the odds of preterm birth at <28 weeks of gestation (adjusted odds ratio, 3.89; 95% confidence interval, 1.61-9.38). The adjusted odds ratio for preterm birth at <37 weeks of gestation was 1.73 but spanned the null (adjusted odds ratio, 1.73; 95% confidence interval, 0.81-3.69). In Kaplan-Meier survival analyses, those in the highest AgeAccelGrim quartile delivered the earliest (log-rank P value of <.001). CONCLUSION: Accelerated biological aging was associated with preterm birth among high-risk patients. Future research confirming these findings and elucidating factors that slow biological aging may improve birth outcomes.

Prenatal Exposure to Toxic Metals and Neural Tube Defects: A Systematic Review of the Epidemiologic Evidence.

BACKGROUND: Neural tube defects (NTDs) affect >300,000 pregnancies worldwide annually. Few nongenetic factors, other than folate deficiency, have been identified that may provide intervenable solutions to reduce the burden of NTDs. Prenatal exposure to toxic metals [arsenic (As), cadmium (Cd), mercury (Hg), manganese (Mn) and lead (Pb)] may increase the risk of NTDs. Although a growing epidemiologic literature has examined associations, to our knowledge no systematic review has been conducted to date. OBJECTIVE: Through adaptation of the Navigation Guide systematic review methodology, we aimed to answer the question "does exposure to As, Cd, Hg, Mn, or Pb during gestation increase the risk of NTDs?" and to assess challenges to evaluating this question given the current evidence. METHODS: We selected available evidence on prenatal As, Cd, Hg, Mn, or Pb exposure and risk of specific NTDs (e.g., spina bifida, anencephaly) or all NTDs via a comprehensive search across MEDLINE, Embase, Web of Science, and TOXLINE databases and applied inclusion/exclusion criteria. We rated the quality and strength of the evidence for each metal. We applied a customized risk of bias protocol and evaluated the sufficiency of evidence of an effect of each metal on NTDs. RESULTS: We identified 30 studies that met our criteria. Risk of bias for confounding and selection was high in most studies, but low for missing data. We determined that, although the evidence was limited, the literature supported an association between prenatal exposure to Hg or Mn and increased risk of NTDs. For the remaining metals, the evidence was inadequate to establish or rule out an effect. CONCLUSION: The role of gestational As, Cd, or Pb exposure in the etiology of NTDs remains unclear and warrants further investigation in high-quality studies, with a particular focus on controlling confounding, mitigating selection bias, and improving exposure assessment. https://doi.org/10.1289/EHP11872.

A multi-omic approach identifies an autism spectrum disorder (ASD) regulatory complex of functional epimutations in placentas from children born preterm.

Children born preterm are at heightened risk of neurodevelopmental impairments, including Autism Spectrum Disorder (ASD). The placenta is a key regulator of neurodevelopmental processes, though the precise underlying molecular mechanisms remain unclear. Here, we employed a multi-omic approach to identify placental transcriptomic and epigenetic modifications related to ASD diagnosis at age 10, among children born preterm. Working with the extremely low gestational age (ELGAN) cohort, we hypothesized that a pro-inflammatory placental environment would be predictive of ASD diagnosis at age 10. Placental messenger RNA (mRNA) expression, CpG methylation, and microRNA (miRNA) expression were compared among 368 ELGANs (28 children diagnosed with ASD and 340 children without ASD). A total of 111 genes displayed expression levels in the placenta that were associated with ASD. Within these ASD-associated genes is an ASD regulatory complex comprising key genes that predicted ASD case status. Genes with expression that predicted ASD case status included Ewing Sarcoma Breakpoint Region 1 (EWSR1) (OR: 6.57 (95% CI: 2.34, 23.58)) and Bromodomain Adjacent To Zinc Finger Domain 2A (BAZ2A) (OR: 0.12 (95% CI: 0.03, 0.35)). Moreover, of the 111 ASD-associated genes, nine (8.1%) displayed associations with CpG methylation levels, while 14 (12.6%) displayed associations with miRNA expression levels. Among these, LRR Binding FLII Interacting Protein 1 (LRRFIP1) was identified as being under the control of both CpG methylation and miRNAs, displaying an OR of 0.42 (95% CI: 0.17, 0.95). This gene, as well as others identified as having functional epimutations, plays a critical role in immune system regulation and inflammatory response. In summary, a multi-omic approach was used to identify functional epimutations in the placenta that are associated with the development of ASD in children born preterm, highlighting future avenues for intervention.

Generation of the Chemical and Social Stressors Integration Technique (CASS-IT) to identify areas of holistic public health concern: An application to North Carolina.

Due to structural racism and income inequality, exposure to environmental chemicals is tightly linked to socioeconomic factors. In addition, exposure to psychosocial stressors, such as racial discrimination, as well as having limited resources, can increase susceptibility to environmentally induced disease. Yet, studies are often conducted separately in fields of social science and environmental science, reducing the potential for holistic risk estimates. To tackle this gap, we developed the Chemical and Social Stressors Integration Technique (CASS-IT) to integrate environmental chemical and social stressor datasets. The CASS-IT provides a framework to identify distinct geographic areas based on combinations of environmental chemical exposure, social vulnerability, and access to resources. It incorporates two data dimension reduction tools: k-means clustering and latent profile analysis. Here, the CASS-IT was applied to North Carolina (NC) as a case study. Environmental chemical data included toxic metals - arsenic, manganese, and lead - in private drinking well water. Social stressor data were captured by the CDC's social vulnerability index's four domains: socioeconomic status, household composition and disability, minority status and language, and housing type and transportation. Data on resources were derived from Federal Emergency Management Agency (FEMA's) Resilience and Analysis Planning Tool, which generated measures of health resources, social resources, and information resources. The results highlighted 31 NC counties where exposure to both toxic metals and social stressors are elevated, and health resources are minimal; these are counties in which environmental justice is of utmost concern. A census-tract level analysis was also conducted to demonstrate the utility of CASS-IT at different geographical scales. The tract-level analysis highlighted specific tracts within counties of concern that are particularly high priority. In future research, the CASS-IT can be used to analyze United States-wide environmental datasets providing guidance for targeted public health interventions and reducing environmental disparities.

Metal mixtures modeling identifies birth weight-associated gene networks in the placentas of children born extremely preterm.

Prenatal exposure to toxic metals is linked to numerous adverse birth and later-in-life outcomes. These outcomes are tied to disrupted biological processes in fetal-derived tissues including the placenta and umbilical cord yet the precise pathways are understudied in these target tissues. We set out to examine the relationship between metal concentrations in umbilical cord and altered gene expression networks in placental tissue. These novel relationships were investigated in a subset of the Extremely Low Gestational Age Newborn (ELGAN) cohort (n = 226). Prenatal exposure to 11 metals/metalloids was measured using inductively coupled plasma tandem-mass spectrometry (ICP-MS/MS) in cord tissue, ensuring passage through the placental barrier. RNA-sequencing was used to quantify >37,000 mRNA transcripts. Differentially expressed genes (DEGs) were identified with respect to each metal. Weighted gene co-expression analysis identified gene networks modulated by metals. Two innovative mixtures modeling techniques, namely principal components analysis and quantile-based g-computation, were employed to identify genes/gene networks associated with multi-metal exposure. Individually, lead was associated with the strongest genomic response of 191 DEGs. Joint lead and cadmium exposure was related to 657 DEGs, including DNA Methyl Transferase 1 (DNMT1). These genes were enriched for the Eukaryotic Initiation Factor 2 (EIF2) pathway. Four gene networks, each containing genes within a Nuclear Factor kappa-light-chain-enhancer of Activated B Cells (NF-kB)-mediated network, were significantly increased in average expression level in relation to increases in all metal concentrations. All four of these metal mixture-associated gene networks were negatively correlated with important predictors of neonatal health including birth weight, placenta weight, and fetal growth. Bringing together novel methodologies from epidemiological mixtures analyses and toxicogenomics, applied to a unique cohort of extremely preterm children, the present study highlighted critical genes and pathways in the placenta dysregulated by prenatal metal mixtures. These represent potential mechanisms underlying the developmental origins of metal-induced disease.

CpG methylation patterns in placenta and neonatal blood are differentially associated with neonatal inflammation.

BACKGROUND: Infants born extremely premature are at increased risk for health complications later in life for which neonatal inflammation may be a contributing biological driver. Placental CpG methylation provides mechanistic information regarding the relationship between prenatal epigenetic programming, prematurity, neonatal inflammation, and later-in-life health. METHODS: We contrasted CpG methylation in the placenta and neonatal blood spots in relation to neonatal inflammation in the Extremely Low Gestational Age Newborn (ELGAN) cohort. Neonatal inflammation status was based on the expression of six inflammation-related proteins, assessed as (1) day-one inflammation (DOI) or (2) intermittent or sustained systemic inflammation (ISSI, inflammation on ≥2 days in the first 2 postnatal weeks). Epigenome-wide CpG methylation was assessed in 354 placental samples and 318 neonatal blood samples. RESULTS: Placental CpG methylation displayed the strongest association with ISSI (48 CpG sites) but was not associated with DOI. This was in contrast to CpG methylation in blood spots, which was associated with DOI (111 CpG sites) and not with ISSI (one CpG site). CONCLUSIONS: Placental CpG methylation was strongly associated with ISSI, a measure of inflammation previously linked to later-in-life cognitive impairment, while day-one neonatal blood methylation was associated with DOI. IMPACT: Neonatal inflammation increases the risk of adverse later-life outcomes, especially in infants born extremely preterm. CpG methylation in the placenta and neonatal blood spots were evaluated in relation to neonatal inflammation assessed via circulating proteins as either (i) day-one inflammation (DOI) or (ii) intermittent or sustained systemic inflammation (ISSI, inflammation on ≥2 days in the first 2 weeks). Tissue specificity was observed in epigenetic-inflammatory relationships: placental CpG methylation was associated with ISSI, neonatal blood CpG methylation was associated with DOI. Supporting the placental origins of disease framework, placental epigenetic patterns are associated with a propensity for ISSI in neonates.

Developing Toxic Metal Environmental Justice Indices (TM-EJIs) for Arsenic, Cadmium, Lead, and Manganese Contamination in Private Drinking Wells in North Carolina.

Toxic metal exposure via private drinking wells is an environmental health challenge in North Carolina (NC). Policies tainted by environmental racism shape who has access to public water supplies, with Black People, Indigenous People, and People of Color (BIPOC) often excluded from municipal services. Thus, toxic metal exposure via private wells is an environmental justice (EJ) issue, and it is under-studied in NC. In this study, we developed four Toxic Metal Environmental Justice Indices (TM-EJIs) for inorganic arsenic (iAs), cadmium (Cd), lead (Pb), and manganese (Mn) to quantitatively identify areas of environmental injustice in NC. TM-EJIs were calculated at the census tract level (n = 2038) as the product of the following: (1) number of well water tests with concentrations exceeding national standards, (2) percentage of the low-income and minority population, and (3) population density. Mn had the greatest proportion (25.17%) of positive TM-EJIs, which are indicative of socioeconomically disadvantaged groups exposed to toxic metals. Positive TM-EJIs, particularly for Pb and Mn, were primarily located in eastern NC. These results highlight several new counties of concern and can be used by public health professionals and state environmental agencies to prioritize remediation efforts and efforts to reduce environmental injustices.

Prenatal exposure to multiple metallic and metalloid trace elements and the risk of bacterial sepsis in extremely low gestational age newborns: A prospective cohort study.

Background: Prenatal exposures to metallic and metalloid trace elements have been linked to altered immune function in animal studies, but few epidemiologic studies have investigated immunological effects in humans. We evaluated the risk of bacterial sepsis (an extreme immune response to bacterial infection) in relation to prenatal metal/metalloid exposures, individually and jointly, within a US-based cohort of infants born extremely preterm. Methods: We analyzed data from 269 participants in the US-based ELGAN cohort, which enrolled infants delivered at <28 weeks' gestation (2002-2004). Concentrations of 8 trace elements-including 4 non-essential and 4 essential-were measured using inductively coupled plasma tandem mass spectrometry in umbilical cord tissue, reflecting in utero fetal exposures. The infants were followed from birth to postnatal day 28 with bacterial blood culture results reported weekly to detect sepsis. Discrete-time hazard and quantile g-computation models were fit to estimate associations for individual trace elements and their mixtures with sepsis incidence. Results: Approximately 30% of the extremely preterm infants developed sepsis during the follow-up period (median follow-up: 2 weeks). After adjustment for potential confounders, no trace element was individually associated with sepsis risk. However, there was some evidence of a non-monotonic relationship for cadmium, with hazard ratios (HRs) for the second, third, and fourth (highest) quartiles being 1.13 (95% CI: 0.51-2.54), 1.94 (95% CI: 0.87-4.32), and 1.88 (95% CI: 0.90-3.93), respectively. The HRs for a quartile increase in concentrations of all 8 elements, all 4 non-essential elements, and all 4 essential elements were 0.92 (95% CI: 0.68-1.25), 1.19 (95% CI: 0.92-1.55), and 0.77 (95% CI: 0.57-1.06). Cadmium had the greatest positive contribution whereas arsenic, copper, and selenium had the greatest negative contributions to the mixture associations. Conclusions: We found some evidence that greater prenatal exposure to cadmium was associated with an increased the risk of bacterial sepsis in extremely preterm infants. However, this risk was counteracted by a combination of arsenic, copper, and selenium. Future studies are needed to confirm these findings and to evaluate the potential for nutritional interventions to prevent sepsis in high-risk infants.

The placenta epigenome-brain axis: placental epigenomic and transcriptomic responses that preprogram cognitive impairment.

Aim: The placenta-brain axis reflects a developmental linkage where disrupted placental function is associated with impaired neurodevelopment later in life. Placental gene expression and the expression of epigenetic modifiers such as miRNAs may be tied to these impairments and are understudied. Materials & methods: The expression levels of mRNAs (n = 37,268) and their targeting miRNAs (n = 2083) were assessed within placentas collected from the ELGAN study cohort (n = 386). The ELGAN adolescents were assessed for neurocognitive function at age 10 and the association with placental mRNA/miRNAs was determined. Results: Placental mRNAs related to inflammatory and apoptotic processes are under miRNA control and associated with cognitive impairment at age 10. Conclusion: Findings highlight key placenta epigenome-brain relationships that support the developmental origins of health and disease hypothesis.

Children born extremely preterm are at increased risk for neurodevelopmental impairments such as cerebral palsy, intellectual disability and autism. The biological processes that lead to these impairments likely begin before birth and involve altered placental function. In this study, the authors analyzed placental genomic and epigenomic data from children who were born extremely preterm in relation to cognitive assessments at 10 years of age. They examined the differences between the expression of placental genes and molecules that influence the expression of placental genes, comparing children who had impaired cognition at 10 years with children who did not. The results demonstrated elevated expression levels of genes involved in inflammatory processes and molecules that control the expression of these genes within the placentas of children who had impaired cognition at age 10.

Nitric oxide-related gene and microRNA expression in peripheral blood in pregnancy vary by self-reported race.

Adverse pregnancy outcomes disproportionately affect non-Hispanic (NH) Black patients in the United States. Structural racism has been associated with increased psychosocial distress and inflammation and may trigger oxidative stress. Thus, the nitric oxide (NO) pathway (involved in the regulation of inflammation and oxidative stress) may partly explain the underlying disparities in obstetric outcomes.Cohort study of 154 pregnant patients with high-risk obstetric histories; n = 212 mRNAs and n = 108 microRNAs (miRNAs) in the NO pathway were evaluated in circulating white blood cells. NO pathway mRNA and miRNA transcript counts were compared by self-reported race; NH Black patients were compared with women of other races/ethnicities. Finally, miRNA-mRNA expression levels were correlated.Twenty-two genes (q < 0.10) were differentially expressed in self-identified NH Black individuals. Superoxide dismutase 1 (SOD1), interleukin-8 (IL-8), dynein light chain LC8-type 1 (DYNLL1), glutathione peroxidase 4 (GPX4), and glutathione peroxidase 1 (GPX1) were the five most differentially expressed genes among NH Black patients compared to other patients. There were 63 significantly correlated miRNA-mRNA pairs (q < 0.10) demonstrating potential miRNA regulation of associated target mRNA expression. Ten miRNAs that were identified as members of significant miRNA-mRNA pairs were also differentially expressed among NH Black patients (q < 0.10).These findings support an association between NO pathway and inflammation and infection-related mRNA and miRNA expression in blood drawn during pregnancy and patient race/ethnicity. These findings may reflect key differences in the biology of inflammatory gene dysregulation that occurs in response to the stress of systemic racism and that underlies disparities in pregnancy outcomes.

Analysis of the novel NCWELL database highlights two decades of co-occurrence of toxic metals in North Carolina private well water: Public health and environmental justice implications.

Private well users are particularly vulnerable to metal exposure as they are not protected by the Safe Drinking Water Act. In North Carolina (NC), approximately 2.4 million individuals rely on private well water. In the present study, we constructed the NCWELL database: a comprehensive database of 117,960 geocoded well water tests over twenty-years in NC inclusive of 28 metals/metalloids. The NCWELL database was analyzed to identify areas of concern for single and co-occurring toxic metal contamination of private wells in NC. County-level population-at-risk rankings were calculated by combining toxic metal levels and the proportion of residents relying on well water. Additionally, k-means analysis was used to identify counties with critical co-occurrence of toxic metals. In the NCWELL database, inorganic arsenic (iAs) and lead (Pb) were detected above the EPA standards of 10 and 15 ppb in over 2500 and over 3000 tests, respectively. Shockingly, iAs was observed at levels up to 806 ppb and Pb at levels up to 105,440 ppb. Manganese (Mn) was detected above the EPA lifetime Health Advisory Limit in 4.9% and above the secondary Maximum Contaminant Level in 24.3% of all well water tests in NC, with a maximum concentration of 46,300 ppb reported. Mixtures-based analysis identified four distinct clusters of counties, one demonstrating high iAs and Mn and another with high Pb. Over the twenty-year period, metal levels remained high, indicative of sustained contamination in areas of concern. This study provides a novel database for researchers and concerned citizens in NC, demonstrates a methodology for identifying priority geographic regions for single and multiple contaminants, and has environmental justice implications in NC where metal exposure via private well water remains a serious public health concern.

Pre-pregnancy BMI-associated miRNA and mRNA expression signatures in the placenta highlight a sexually-dimorphic response to maternal underweight status.

Pre-pregnancy body mass index (BMI) is associated with adverse pregnancy and neonatal health outcomes, with differences in risk observed between sexes. Given that the placenta is a sexually dimorphic organ and critical regulator of development, examining differences in placental mRNA and miRNA expression in relation to pre-pregnancy BMI may provide insight into responses to maternal BMI in utero. Here, genome-wide mRNA and miRNA expression levels were assessed in the placentas of infants born extremely preterm. Differences in expression were evaluated according to pre-pregnancy BMI status (1) overall and (2) in male and female placentas separately. Overall, 719 mRNAs were differentially expressed in relation to underweight status. Unexpectedly, no genes were differentially expressed in relation to overweight or obese status. In male placentas, 572 mRNAs were associated with underweight status, with 503 (70%) overlapping genes identified overall. Notably, 43/572 (8%) of the mRNAs associated with underweight status in male placentas were also gene targets of two miRNAs (miR-4057 and miR-128-1-5p) associated with underweight status in male placentas. Pathways regulating placental nutrient metabolism and angiogenesis were among those enriched in mRNAs associated with underweight status in males. This study is among the first to highlight a sexually dimorphic response to low pre-pregnancy BMI in the placenta.

Comparing the Predictivity of Human Placental Gene, microRNA, and CpG Methylation Signatures in Relation to Perinatal Outcomes.

Molecular signatures are being increasingly integrated into predictive biology applications. However, there are limited studies comparing the overall predictivity of transcriptomic versus epigenomic signatures in relation to perinatal outcomes. This study set out to evaluate mRNA and microRNA (miRNA) expression and cytosine-guanine dinucleotide (CpG) methylation signatures in human placental tissues and relate these to perinatal outcomes known to influence maternal/fetal health; namely, birth weight, placenta weight, placental damage, and placental inflammation. The following hypotheses were tested: (1) different molecular signatures will demonstrate varying levels of predictivity towards perinatal outcomes, and (2) these signatures will show disruptions from an example exposure (ie, cadmium) known to elicit perinatal toxicity. Multi-omic placental profiles from 390 infants in the Extremely Low Gestational Age Newborns cohort were used to develop molecular signatures that predict each perinatal outcome. Epigenomic signatures (ie, miRNA and CpG methylation) consistently demonstrated the highest levels of predictivity, with model performance metrics including R2 (predicted vs observed) values of 0.36-0.57 for continuous outcomes and balanced accuracy values of 0.49-0.77 for categorical outcomes. Top-ranking predictors included miRNAs involved in injury and inflammation. To demonstrate the utility of these predictive signatures in screening of potentially harmful exogenous insults, top-ranking miRNA predictors were analyzed in a separate pregnancy cohort and related to cadmium. Key predictive miRNAs demonstrated altered expression in association with cadmium exposure, including miR-210, known to impact placental cell growth, blood vessel development, and fetal weight. These findings inform future predictive biology applications, where additional benefit will be gained by including epigenetic markers.

Development of the genomic inflammatory index (GII) to assess key maternal antecedents associated with placental inflammation.

INTRODUCTION: Placental inflammation is associated with a variety of adverse health outcomes, including poor pregnancy outcomes as well as later in life health. The current clinical methodologies for evaluating placental histology for inflammation are limited in their sensitivity. The objective of this study was to develop a genomic inflammatory index (GII) that can be utilized as a biomarker to effectively quantify and evaluate placental inflammation. METHODS: RNA-sequencing of n = 386 placentas from the Extremely Low Gestational Age Newborn (ELGAN) cohort was conducted. Transcriptional data for a biologically-targeted set of 14 genes, selected for their established role in pro-inflammatory signaling pathways, were aggregated to construct the GII. Multiple linear regression models were used to examine relationships between 47 perinatal factors and the GII. RESULTS: The GII demonstrated a nine-fold difference across subjects and displayed positive trends with other indicators of placental inflammation. Significant differences in the GII were observed for race where women who self-identified as Black displayed higher levels of placental inflammation than those who self-identified as White women (p < 0.001). Additionally, married Black women showed reduced placental inflammation compared to those who were unmarried (beta value: 0.828, p-value: 0.032). Placentas from women who were treated with steroids during the delivery of the infant displayed higher GII levels than those who were not (p = 0.023). DISCUSSION: Overall, the GII demonstrated an association between various perinatal factors and placental inflammation. It is anticipated that the GII will provide a novel genomics tool for quantifying placental inflammation, allowing for further investigation of causes, and ultimately the prevention, of inflammation in the placenta.