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Introduction: Identifying healthcare utilization and costs associated with active and passive smoking during pregnancy could help improve health management strategies., Aims and Methods: Data are from the Newborn Epigenetics STudy (NEST), a birth cohort enrolled from 2005 to 2011 in Durham and adjacent counties in North Carolina, United States. Participants included those for whom prenatal serum samples were assayed and for whom administrative data were obtainable (N = 1045). Zero-inflated poisson regression models were used to assess associations between cotinine, adjusted for covariates (eg, race and ethnicity, age at delivery, cohabitation status, and education), and health care utilization outcomes. Generalized linear regression models were used to estimate average total charges. Simulation models were conducted to determine the economic benefits of reducing secondhand smoke and smoking during pregnancy., Results: Increasing levels of cotinine were positively associated with parent's number of emergency department (ED) visits (coefficient[b] = 0.0012, standard error [SE] = 0.0002; p < .001), the number of ICU hours (b = 0.0079, SE = 0.0025; p = .002), time spent in the ICU (b = 0.0238, SE = 0.0020, p < .001), and the number of OP visits (b = 0.0003, SE = 0.0001; p < .001). For infants, higher cotinine levels were associated with higher number of ED (b = 0.0012, SE = 0.0004; p = .005), ICU (b = 0.0050, SE = 0.001; p < .001), and OP (b = 0.0006, SE = 0.0002; p < .001) visits and longer time spent in the ED (b = 0.0025, SE = 0.0003; p < .001), ICU (b = 0.0005, SE = 0.0001; p < .001), and IP (b = 0.0020, SE = 0.0002; p < .001). Simulation results showed that a 5% reduction in smoking would correspond to a potential median cost savings of $150 533 from ED visits of parents and infants., Conclusions: Our findings highlight the importance of smoke exposure cessation during pregnancy to reduce health care utilization and costs for both parents and infants., Implications: This study reinforces the importance of reducing smoking and secondhand smoke exposure during pregnancy. Focusing on expanding cessation services to this group could help reduce morbidities observed within this population. Furthermore, there is the potential for healthcare cost savings to healthcare systems, especially for those with high delivery numbers. These cost savings are represented by potential reductions in ED, OP, and ICU hours and visits., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Society for Research on Nicotine and Tobacco. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Objective: To describe the Coronovirus 19 (COVID-19) pandemic impact among mothers of young children (0-8 years) and assess prepandemic factors associated with greater pandemic impact and psychosocial distress., Methods: Mothers from 3 US birth cohorts (n = 301, mean child age 2.4 years) reported on demographics and psychosocial distress (anxiety, perceived stress, financial stress) before the pandemic (February 2015-February 2020). During the pandemic (July 2020-June 2021), they completed a supplemental survey about the impact of the pandemic on their families (Coronavirus Impact Scale) and psychosocial distress. Multivariable linear and ordinal logistic regression were used to evaluate prepandemic factors associated with pandemic impact overall and by domain., Results: Compared to prepandemic reports, maternal anxiety symptoms increased by 9.4%, perceived stress increased by 13.3%, and financial stress increased by 41.7%, of which all were statistically significant changes. Participants reported the most severe pandemic impact in family routines (72.4%), experiences of stress (40.2%), and social support (38.6%). Mothers with some college or a 4-year degree experienced higher overall pandemic impact compared to mothers with the least and highest education. Prepandemic distress was not associated with pandemic impact; however, midpandemic, all 3 distress measures were significantly positively associated with overall Coronavirus Impact Scale, with the largest effect size noted for perceived stress (B = 1.36, 95% CI: 0.90,1.82)., Conclusions: While, on average, mothers of young children experienced worsening psychosocial stress during the COVID-19 pandemic, prepandemic psychosocial stress alone was not prospectively associated with greater pandemic impact, suggesting that the COVID-19 pandemic may have both elaborated existing systemic social inequalities and created new burdens., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships, which may be considered as potential competing interests: Sara Johnson reports that financial support was provided by the National Institutes of Health. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Academic Pediatric Association. Published by Elsevier Inc. All rights reserved.)

Adverse childhood experiences (ACEs) contribute to numerous negative health outcomes across the life course and across generations. Here, we extend prior work by examining the association of maternal ACEs, and their interaction with financial stress and discrimination, with methylation status within eight differentially methylated regions (DMRs) in imprinted domains in newborns. ACEs, financial stress during pregnancy, and experience of discrimination were self-reported among 232 pregnant women. DNA methylation was assessed at PEG10 / SGCE, NNAT, IGF2, H19, PLAGL1 , PEG3 , MEG3-IG , and DLK1/MEG3 regulatory sequences using pyrosequencing. Using multivariable linear regression models, we found evidence to suggest that financial stress was associated with hypermethylation of MEG3-IG in non-Hispanic White newborns; discrimination was associated with hypermethylation of IGF2 and NNAT in Hispanic newborns, and with hypomethylation of PEG3 in non-Hispanic Black newborns. We also found evidence that maternal ACEs interacted with discrimination to predict offspring PLAGL1 altered DMR methylation, in addition to interactions between maternal ACEs score and discrimination predicting H19 and SGCE/PEG10 altered methylation in non-Hispanic White newborns. However, these interactions were not statistically significant after multiple testing corrections. Findings from this study suggest that maternal ACEs, discrimination, and financial stress are associated with newborn aberrant methylation in imprinted gene regions.

CpG site methylation patterns have potential to improve differentiation of high-grade screening-detected cervical abnormalities. We assessed CpG differential methylation (DM) and differential variability (DV) in high-grade (CIN2+) vs. low-grade (≤CIN1) lesions. In ≤CIN1 (n=117) and CIN2+ (n=31) samples, cervical sample DNA underwent testing with Illumina HumanMethylation arrays. We assessed DM and DV of CpG methylation M values among nine cervical cancer-associated genes. We fit CpG-specific linear models and estimated empirical Bayes standard errors and false discovery rates (FDR). An exploratory epigenome-wide association study (EWAS) aimed to detect novel DM and DV CpGs (FDR<0.05) and Gene Ontology (GO) term enrichment. Compared to ≤CIN1, CIN2+ exhibited greater methylation at CCNA1 Cluster 1 (M value difference 0.24; 95% CI 0.04, 0.43) and RARB Cluster 2 (0.16; 95% CI 0.05, 0.28), and lower methylation at CDH1 Cluster 1 (-0.15; 95% CI -0.26, -0.04). CIN2+ exhibited lower variability at CDH1 Cluster 2 (variation difference -0.24; 95% CI -0.41, -0.05) and FHIT Cluster 1 (-0.30; 95% CI -0.50, -0.09). EWAS detected 3,534 DM and 270 DV CpGs. Forty-four GO terms were enriched with DM CpGs related to transcriptional, structural, developmental, and neuronal processes. Methylation patterns may help triage screening-detected cervical abnormalities and inform US screening algorithms., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Tobacco retail outlet (TRO) density has been associated with increased cotinine levels in pregnant persons and their children. As such, the higher densities of TROs may represent higher levels of active smoking during pregnancy. The purpose of this study is to simulate the reduction in cotinine (a biomarker of smoke exposure) and health care utilization that could occur in pregnant persons under enactment of several candidate TRO reduction policy recommendations. Using existing retail outlet data from the state of North Carolina and from the Newborn Epigenetic Study (NEST), the present study created hypothetical policy-informed datasets of TROs that a) limited the number of TROs to the same density as the 2014 San Francisco (SF) policy (Policy 1), b) set the minimum distance to 500 feet between TROs from a school and from other TROs (Policy 2), c) restricted the types of TROs to exclude pharmacies (Policy 3), and d) a combination of Policies 1-3 (Policy 4). We estimated the effects of each policy individually and in a separate model with their combined effects in terms of the reduction on cotinine levels and health care utilization, as measured by number of visits to the emergency department (ED). We found that the hypothetical policies were likely to be effective in reducing maternal cotinine and ED visits, with the majority of the mothers in the dataset demonstrating reductions in these outcomes after implementation of the policies. We found that Policy 1 led to moderate reductions in TRO exposure for the majority of the sample as well as stratified by race/ethnicity. Additionally, Policy 4 had slightly larger estimated effects than Policy 1, but could be more onerous to implement in practice. Overall, we identified evidence supporting the efficacy of TRO reduction strategies that could impact smoke exposure during pregnancy in our diverse sample in North Carolina., (© 2024. The Author(s).)

Alzheimer's disease (AD) prevalence is twice as high in non-Hispanic Blacks (NHBs) as in non-Hispanic Whites (NHWs). The objective of this study was to determine whether aberrant methylation at imprint control regions (ICRs) is associated with AD. Differentially methylated regions (DMRs) were bioinformatically identified from whole-genome bisulfite sequenced DNA derived from brain tissue of 9 AD (5 NHBs and 4 NHWs) and 8 controls (4 NHBs and 4 NHWs). We identified DMRs located within 120 regions defined as candidate ICRs in the human imprintome ( https://genome.ucsc.edu/s/imprintome/hg38.AD.Brain&#95;track ). Eighty-one ICRs were differentially methylated in NHB-AD, and 27 ICRs were differentially methylated in NHW-AD, with two regions common to both populations that are proximal to the inflammasome gene, NLRP1, and a known imprinted gene, MEST/MESTIT1. These findings indicate that early developmental alterations in DNA methylation of regions regulating genomic imprinting may contribute to AD risk and that this epigenetic risk differs between NHBs and NHWs., (© 2024. The Author(s).)

Background: Poor birth outcomes such as preterm birth/delivery disproportionately affect African Americans compared to White individuals. Reasons for this disparity are likely multifactorial, and include prenatal psychosocial stressors, and attendant increased lipid peroxidation; however, empirical data linking psychosocial stressors during pregnancy to oxidative status are limited., Methods: We used established scales to measure five psychosocial stressors. Maternal adverse childhood experiences, financial stress, social support, anxiety, and depression were measured among 50 African American and White pregnant women enrolled in the Stress and Health in Pregnancy cohort. Liquid chromatography-tandem mass spectrometry was used to measure biomarkers of oxidative stress (four urinary F2-isoprostane isomers), to estimate oxidative status. Linear regression models were used to evaluate associations between psychosocial stressors, prenatal oxidative status and preterm birth., Results: After adjusting for maternal obesity, gestational diabetes, and cigarette smoking, African American women with higher oxidative status were more likely to report higher maternal adverse childhood experience scores (β = 0.16, se = 1.07, p-value = 0.024) and depression scores (β = 0.05, se = 0.02, p = 0.014). Higher oxidative status was also associated with lower gestational age at birth (β = -0.13, se = 0.06, p = 0.04) in this population. These associations were not apparent in Whites. However, none of the cross-product terms for race/ethnicity and social stressors reached statistical significance (p > 0.05)., Conclusion: While the small sample size limits inference, our novel data suggest that psychosocial stressors may contribute significantly to oxidative stress during pregnancy, and preterm birth or delivery African Americans. If replicated in larger studies, these findings would support oxidative stress reduction using established dietary or pharmacological approaches present a potential avenue to mitigate adverse effects of psychosocial stressors on birth outcomes., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Authors. Published by Elsevier Ltd.)

Maternal educational attainment (MEA) shapes offspring health through multiple potential pathways. Differential DNA methylation may provide a mechanistic understanding of these long-term associations. We aimed to quantify the associations of MEA with offspring DNA methylation levels at birth, in childhood and in adolescence. Using 37 studies from high-income countries, we performed meta-analysis of epigenome-wide association studies (EWAS) to quantify the associations of completed years of MEA at the time of pregnancy with offspring DNA methylation levels at birth (n = 9 881), in childhood (n = 2 017), and adolescence (n = 2 740), adjusting for relevant covariates. MEA was found to be associated with DNA methylation at 473 cytosine-phosphate-guanine sites at birth, one in childhood, and four in adolescence. We observed enrichment for findings from previous EWAS on maternal folate, vitamin-B 12 concentrations, maternal smoking, and pre-pregnancy BMI. The associations were directionally consistent with MEA being inversely associated with behaviours including smoking and BMI. Our findings form a bridge between socio-economic factors and biology and highlight potential pathways underlying effects of maternal education. The results broaden our understanding of bio-social associations linked to differential DNA methylation in multiple early stages of life. The data generated also offers an important resource to help a more precise understanding of the social determinants of health., (© 2023. The Author(s).)

Maternal exposure to childhood adversity is associated with detrimental health outcomes throughout the lifespan and may have implications for offspring. Evidence links maternal adverse childhood experiences (ACEs) to detrimental birth outcomes, yet the impact on the infant's epigenome is unclear. Moreover, maternal sleep habits during pregnancy may influence this association. Here, we explore whether restless sleep during pregnancy moderates the association between exposure to maternal childhood adversity and infant epigenetic age acceleration in 332 mother-infant dyads (56% female; 39% Black; 25% Hispanic). During the 2 nd trimester, mothers self-reported childhood adversity and past-week restless sleep; DNA methylation from umbilical vein endothelial cells was used to estimate five epigenetic clocks. Multivariable linear regression was used to test study hypotheses. Despite no evidence of main effects, there was evidence of an interaction between maternal ACEs and restless sleep in predicting infant epigenetic age acceleration using the EPIC Gestational Age clock. Only infants whose mothers reported exposure to both ACEs and restless sleep demonstrated accelerated epigenetic aging. Results provide preliminary evidence that maternal childhood adversity and sleep may influence the infant epigenome., Competing Interests: Conflict of Interest: The authors declare that they have no competing interests.

Background: Copper (Cu), an essential trace mineral regulating multiple actions of inflammation and oxidative stress, has been implicated in risk for preterm birth (PTB)., Objectives: This study aimed to determine the association of maternal Cu concentration during pregnancy with PTB risk and gestational duration in a large multicohort study including diverse populations., Methods: Maternal plasma or serum samples of 10,449 singleton live births were obtained from 18 geographically diverse study cohorts. Maternal Cu concentrations were determined using inductively coupled plasma mass spectrometry. The associations of maternal Cu with PTB and gestational duration were analyzed using logistic and linear regressions for each cohort. The estimates were then combined using meta-analysis. Associations between maternal Cu and acute-phase reactants (APRs) and infection status were analyzed in 1239 samples from the Malawi cohort., Results: The maternal prenatal Cu concentration in our study samples followed normal distribution with mean of 1.92 μg/mL and standard deviation of 0.43 μg/mL, and Cu concentrations increased with gestational age up to 20 wk. The random-effect meta-analysis across 18 cohorts revealed that 1 μg/mL increase in maternal Cu concentration was associated with higher risk of PTB with odds ratio of 1.30 (95% confidence interval [CI]: 1.08, 1.57) and shorter gestational duration of 1.64 d (95% CI: 0.56, 2.73). In the Malawi cohort, higher maternal Cu concentration, concentrations of multiple APRs, and infections (malaria and HIV) were correlated and associated with greater risk of PTB and shorter gestational duration., Conclusions: Our study supports robust negative association between maternal Cu and gestational duration and positive association with risk for PTB. Cu concentration was strongly correlated with APRs and infection status suggesting its potential role in inflammation, a pathway implicated in the mechanisms of PTB. Therefore, maternal Cu could be used as potential marker of integrated inflammatory pathways during pregnancy and risk for PTB., (Copyright © 2023. Published by Elsevier Inc.)

Background and Objectives: Breastfeeding during infancy is associated with healthier beverage consumption later in childhood, but little is known about this relation during infancy. This was a longitudinal study of breastfeeding and less healthy beverage consumption during the first year of life, in a birth cohort study conducted 2013-2018 in the Southeastern United States (n = 666)., Methods: We estimated monthly rates of 100% juice and sugar-sweetened beverage (SSB) consumption comparing infants who were exclusively or partially breastfed, versus those who were not, in multivariable adjusted models., Results: Mothers had a median age of 26.5 years, 71% identified as Black/African-American, and 61% reported household incomes <$20 000/year. The prevalence of any breastfeeding during the first month was 78.2% and 18.7% at month 12. By age 12 months, infants consumed juice a mean (SD) 9.1 (10.1) times per week and SSBs 3.6 (9.5) times per week. Breastfed infants had a 38% lower incidence rate of weekly juice consumption (95% CI 52%, 15%, p = 0.003) and a 57% lower incidence rate of weekly SSB consumption (95% CI 76%, 22%, p = 0.006), compared with infants who were not breastfed., Conclusions: Research on early-life correlates of dietary health should focus on the earliest beverages, given evidence that consumption of obesogenic beverages may begin prior to age 1 year., (© 2023 World Obesity Federation.)

Background/objectives: Murine models show that plastics, via their chemical constituents (e.g., phthalates), influence microbiota, metabolism, and growth. However, research on plastics in humans is lacking. Here, we examine how the frequency of plastic bottle exposure is associated with fecal microbiota, short-chain fatty acids (SCFAs), and anthropometry in the first year of life., Subjects/methods: In 442 infants from the prospective Nurture birth cohort, we examined the association of frequency of plastic bottle feeding at 3 months with anthropometric outcomes (skinfolds, length-for-age, and weight-for-length) at 12 months of age and growth trajectories between 3 and 12 months. Furthermore, in a subset of infants ( n = 70) that contributed fecal samples at 3 months and 12 months of age, we examined plastic bottle frequency in relation to fecal microbiota composition and diversity (measured by 16S rRNA gene sequencing of V4 region), and fecal SCFA concentrations (quantified using gas chromatography mass spectrometry)., Results: At 3 months, 67.6% of infants were plastic bottle fed at every feeding, 15.4% were exclusively breast milk fed, and 48.9% were exclusively formula fed. After adjustment for potential confounders, infants who were plastic bottle fed less than every feeding compared to those who were plastic bottle fed at every feeding at 3 months did not show differences in anthropometry over the first 12 months of life, save for lower length-for-age z-score at 12 months (adjusted β = -0.45, 95% CI: -0.76, -0.13). Infants who were plastic bottle fed less than every feeding versus every feeding had lower fecal microbiota alpha diversity at 3 months (mean difference for Shannon index: -0.59, 95% CI: -0.99, -0.20) and lower isovaleric acid concentration at 3 months (mean difference: -2.12 μmol/g, 95% CI: -3.64, -0.60), but these results were attenuated following adjustment for infant diet. Plastic bottle frequency was not strongly associated with microbiota diversity or SCFAs at 12 months after multivariable adjustment. Frequency of plastic bottle use was associated with differential abundance of some bacterial taxa, however, significance was not consistent between statistical approaches., Conclusions: Plastic bottle frequency at 3 months was not strongly associated with measures of adiposity or growth (save for length-for-age) over the first year of life, and while plastic bottle use was associated with some features of fecal microbiota and SCFAs in the first year, these findings were attenuated in multivariable models with infant diet. Future research is needed to assess health effects of exposure to other plastic-based products and objective measures of microplastics and plastic constituents like phthalates.

The etiology of childhood appetitive traits is poorly understood. Early-life epigenetic processes may be involved in the developmental programming of appetite regulation in childhood. One such process is DNA methylation (DNAm), whereby a methyl group is added to a specific part of DNA, where a cytosine base is next to a guanine base, a CpG site. We meta-analyzed epigenome-wide association studies (EWASs) of cord blood DNAm and early-childhood appetitive traits. Data were from two independent cohorts: the Generation R Study (n = 1,086, Rotterdam, the Netherlands) and the Healthy Start study (n = 236, Colorado, USA). DNAm at autosomal methylation sites in cord blood was measured using the Illumina Infinium HumanMethylation450 BeadChip. Parents reported on their child's food responsiveness, emotional undereating, satiety responsiveness and food fussiness using the Children's Eating Behaviour Questionnaire at age 4-5 years. Multiple regression models were used to examine the association of DNAm (predictor) at the individual site- and regional-level (using DMRff) with each appetitive trait (outcome), adjusting for covariates. Bonferroni-correction was applied to adjust for multiple testing. There were no associations of DNAm and any appetitive trait when examining individual CpG-sites. However, when examining multiple CpGs jointly in so-called differentially methylated regions, we identified 45 associations of DNAm with food responsiveness, 7 associations of DNAm with emotional undereating, 13 associations of DNAm with satiety responsiveness, and 9 associations of DNAm with food fussiness. This study shows that DNAm in the newborn may partially explain variation in appetitive traits expressed in early childhood and provides preliminary support for early programming of child appetitive traits through DNAm. Investigating differential DNAm associated with appetitive traits could be an important first step in identifying biological pathways underlying the development of these behaviors., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Methylation levels may be associated with and serve as markers to predict risk of progression of precancerous cervical lesions. We conducted an epigenome-wide association study (EWAS) of CpG methylation and progression to high-grade cervical intraepithelial neoplasia (CIN2 +) following an abnormal screening test., Methods: A prospective US cohort of 289 colposcopy patients with normal or CIN1 enrollment histology was assessed. Baseline cervical sample DNA was analyzed using Illumina HumanMethylation 450K (n = 76) or EPIC 850K (n = 213) arrays. Participants returned at provider-recommended intervals and were followed up to 5 years via medical records. We assessed continuous CpG M values for 9 cervical cancer-associated genes and time-to-progression to CIN2+. We estimated CpG-specific time-to-event ratios (TTER) and hazard ratios using adjusted, interval-censored Weibull accelerated failure time models. We also conducted an exploratory EWAS to identify novel CpGs with false discovery rate (FDR) < 0.05., Results: At enrollment, median age was 29.2 years; 64.0% were high-risk HPV-positive, and 54.3% were non-white. During follow-up (median 24.4 months), 15 participants progressed to CIN2+. Greater methylation levels were associated with a shorter time-to-CIN2+ for CADM1 cg03505501 (TTER = 0.28; 95%CI 0.12, 0.63; FDR = 0.03) and RARB Cluster 1 (TTER = 0.46; 95% CI 0.29, 0.71; FDR = 0.01). There was evidence of similar trends for DAPK1 cg14286732, PAX1 cg07213060, and PAX1 Cluster 1. The EWAS detected 336 novel progression-associated CpGs, including those located in CpG islands associated with genes FGF22, TOX, COL18A1, GPM6A, XAB2, TIMP2, GSPT1, NR4A2, and APBB1IP., Conclusions: Using prospective time-to-event data, we detected associations between CADM1-, DAPK1-, PAX1-, and RARB-related CpGs and cervical disease progression, and we identified novel progression-associated CpGs., Impact: Methylation levels at novel CpG sites may help identify individuals with ≤CIN1 histology at higher risk of progression to CIN2+ and inform risk-based cervical cancer screening guidelines., (© 2023. The Author(s).)

Background: Tobacco smoking during pregnancy is associated with metabolic dysfunction in children, but mechanistic insights remain limited. Hypomethylation of cg05575921 in the aryl hydrocarbon receptor repressor (AHRR) gene is associated with in utero tobacco smoke exposure. In this study, we evaluated whether AHRR hypomethylation mediates the association between maternal smoking and metabolic dysfunction in children., Methods: We assessed metabolic dysfunction using liver fat content (LFC), serum, and clinical data in children aged 7-12 years (n=78) followed since birth. Maternal smoking was self-reported at 12 weeks gestation. Methylation was measured by means of pyrosequencing at 3 sequential CpG sites, including cg05575921, at birth and at ages 7-12. Regression models were used to evaluate whether AHRR methylation mediated the association between maternal smoking and child metabolic dysfunction., Results: Average AHRR methylation at birth was significantly higher among children of nonsmoking mothers compared with children of mothers who smoked (69.8% ± 4.4% vs. 63.5% ± 5.5, p=0.0006). AHRR hypomethylation at birth was associated with higher liver fat content (p=0.01), triglycerides (p=0.01), and alanine aminotransferase levels (p=0.03), and lower HDL cholesterol (p=0.01) in childhood. AHRR hypomethylation significantly mediated associations between maternal smoking and liver fat content (indirect effect=0.213, p=0.018), triglycerides (indirect effect=0.297, p=0.044), and HDL cholesterol (indirect effect = -0.413, p=0.007). AHRR methylation in childhood (n=78) was no longer significantly associated with prenatal smoke exposure or child metabolic parameters (p>0.05)., Conclusions: AHRR hypomethylation significantly mediates the association between prenatal tobacco smoke exposure and features of childhood metabolic dysfunction, despite the lack of persistent hypomethylation of AHRR into childhood. Further studies are needed to replicate these findings and to explore their causal and long-term significance., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Association for the Study of Liver Diseases.)

Background: Seasonal variations in environmental exposures at birth or during gestation are associated with numerous adult traits and health outcomes later in life. Whether DNA methylation (DNAm) plays a role in the molecular mechanisms underlying the associations between birth season and lifelong phenotypes remains unclear., Methods: We carried out epigenome-wide meta-analyses within the Pregnancy And Childhood Epigenetic Consortium to identify associations of DNAm with birth season, both at differentially methylated probes (DMPs) and regions (DMRs). Associations were examined at two time points: at birth (21 cohorts, N = 9358) and in children aged 1-11 years (12 cohorts, N = 3610). We conducted meta-analyses to assess the impact of latitude on birth season-specific associations at both time points., Results: We identified associations between birth season and DNAm (False Discovery Rate-adjusted p values < 0.05) at two CpGs at birth (winter-born) and four in the childhood (summer-born) analyses when compared to children born in autumn. Furthermore, we identified twenty-six differentially methylated regions (DMR) at birth (winter-born: 8, spring-born: 15, summer-born: 3) and thirty-two in childhood (winter-born: 12, spring and summer: 10 each) meta-analyses with few overlapping DMRs between the birth seasons or the two time points. The DMRs were associated with genes of known functions in tumorigenesis, psychiatric/neurological disorders, inflammation, or immunity, amongst others. Latitude-stratified meta-analyses [higher (≥ 50°N), lower (< 50°N, northern hemisphere only)] revealed differences in associations between birth season and DNAm by birth latitude. DMR analysis implicated genes with previously reported links to schizophrenia (LAX1), skin disorders (PSORS1C, LTB4R), and airway inflammation including asthma (LTB4R), present only at birth in the higher latitudes (≥ 50°N)., Conclusions: In this large epigenome-wide meta-analysis study, we provide evidence for (i) associations between DNAm and season of birth that are unique for the seasons of the year (temporal effect) and (ii) latitude-dependent variations in the seasonal associations (spatial effect). DNAm could play a role in the molecular mechanisms underlying the effect of birth season on adult health outcomes., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Purpose: Investigate residential segregation and prenatal depression in a non-Hispanic (NH) Black and Hispanic North Carolina pregnancy cohort., Methods: Demographics, prenatal depression (Center for Epidemiological Studies Depression scale ≥16), and residence from the 2006-2009 Newborn Epigenetic Survey were linked to Census-tract levels of racial and economic segregation (Index of Concentration at the Extremes) from the American Community Survey 2005-2009 5-year estimates. Adjusted prevalence ratios (aPR) for prenatal depression compared living in Index of Concentration at the Extremes tertiles 1 and 2 (higher proportion NH Black or Hispanic and/or low income) to 3 (higher proportion NH white and/or high-income), accounting for neighborhood clustering, age, education, employment, parity, and marital status., Results: Among the 773 survey participants (482 NH Black and 291 Hispanic), 35.7% and 27.2% of NH Black and Hispanic participants had prenatal depression, respectively. For NH Black participants, depression prevalence was 17% lower for tertile 1 versus 3 for the NH Black/white (aPR=0.83; 95% CI=0.62-1.10), low/high income (aPR=0.83; 95% CI=0.62-1.11), and low-income NH Black/high-income NH white (aPR=0.82; 95% CI=0.61-1.09) measures. For Hispanic participants, estimates were weaker in the opposite direction for the Hispanic/NH white (aPR=1.02; 95% CI=0.71-1.47), low/high income (aPr=1.14; (95% CI=0.76-1.69), and low-income Hispanic/high-income NH white (aPR=1.12; 95% CI=0.78-1.60) measures., Conclusions: Residential segregation's impact on prenatal depression may differ by race/ethnicity and level of segregation, but findings are imprecise due to small sample sizes. Longitudinal research spanning greater geographic areas is needed., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Sarah C. Haight reports financial support was provided by National Institute of Child Health and Human Development. Sarah C. Haight, Chantel L. Martin, and Cathrine Hoyo report financial support was provided by National Institutes of Health., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: Despite many efforts, preterm birth (PTB) is poorly understood and remains a major public health problem in the United States. Toxicological work suggests gestational parent (GP) diet may modify the effect of ambient pollutants on birth outcomes. We assessed risk of PTB in humans in relation to fine particulate matter (PM 2.5 ), ozone (O 3 ), and nitrogen dioxide (NO 2 ) and variation by diet., Methods: 684 GP-singleton infant pairs in the Newborn Epigenetics Study prospective birth cohort were attributed ambient air pollutant exposures for each trimester based on residence. Total energy intake, percent of energy intake from saturated fat, and percent of energy intake from total fat were dichotomized at the 75th percentile. >We used log binomial regressions to estimate risk ratios (RR (95%CI)) for PTB by pollutant interquartile ranges, adjusting for GP age, pre-pregnancy body mass index, GP race/ethnicity, GP education, season of conception, household income, and each diet factor. We assessed departure from additivity using interaction contrast ratios (ICRs). We addressed missing covariate data with multiple imputation., Results: Point estimates suggest that O 3 may be inversely associated with PTB when exposure occurs in trimester 2 (min RR: 0.77, 95% CI: 0.39, 1.49), but may be harmful when exposure occurs in trimester 3 (max RR: 1.51, 95% CI: 0.62, 3.64). Additionally, PM 2.5 may be inversely associated with PTB when considered with total fat and saturated fat in trimester 2. Imprecise ICRs suggest departure from additivity (evidence of modification) with some pollutant-diet combinations., Conclusions: While confidence intervals are wide, we observed potential modification of pollutant associations by dietary factors. It is imperative that large cohorts collect the required data to examine this topic, as more power is necessary to investigate the nuances suggested by this work., (© 2023. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Objective: To assess the relationships of prenatal and childhood smoke exposure with specific neurodevelopmental and behavioral problems during early childhood., Study Design: A subsample (n = 386) of mother-child dyads from the Newborn Epigenetic Study (NEST) prebirth cohort participated in the study. Cotinine concentrations were used to objectively measure prenatal and childhood smoke exposure when youth were aged 3-13 years. Multivariable regression models were used to estimate associations of prenatal and childhood cotinine concentrations with performance on the National Institutes of Health (NIH) Toolbox and attention-deficit/hyperactivity disorder and behavioral symptoms, measured using the Behavior Assessment System for Children, 2nd edition (BASC-2)., Results: After adjusting for confounders, childhood cotinine concentrations were associated with poorer cognitive performance on tasks measuring cognitive flexibility (B = -1.29; P = .03), episodic memory (B = -0.97; P = .02), receptive language development (B = -0.58; P = .01), and inhibitory control and attention (B = -1.59; P = .006). Although childhood cotinine concentration was associated with higher levels of attention problems (B = 0.83; P = .004) on the BASC-2, after adjustment for confounders, the association is nonsignificant. Although associations for maternal cotinine concentrations were null, an interaction was detected between prenatal and childhood cotinine concentrations on the NIH Toolbox Picture Vocabulary Task (P = .02)., Conclusions: Our findings suggest that childhood tobacco smoke exposure may lead to poorer attention regulation and language acquisition, complex visual processing ability, and attention problems., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background: To examine whether financial stress during pregnancy mediates the association between maternal exposure to adverse childhood experiences (ACEs) and three birth outcomes (i.e., gestational age, birth weight, and admission to the neonatal intensive care unit [NICU])., Methods: Data were obtained from a prospective cohort study of pregnant women and their infants in Florida and North Carolina. Mothers (n = 531; M age at delivery = 29.8 years; 38% Black; 22% Hispanic) self-reported their exposure to childhood adversity and financial stress during pregnancy. Data on infant gestational age at birth, birth weight, and admission to the NICU were obtained from medical records within 7 days of delivery. Mediation analysis was used to test study hypotheses, adjusting for study cohort, maternal race, ethnicity, body mass index, and tobacco use during pregnancy., Results: There was evidence of an indirect association between maternal exposure to childhood adversity and infant gestational age at birth (b = -0.03, 95% CI = -0.06 - -0.01) and infant birth weight (b = -8.85, 95% CI = -18.60 - -1.28) such that higher maternal ACE score was associated with earlier gestational age and lower infant birth weight through increases in financial distress during pregnancy. There was no evidence of an indirect association between maternal exposure to childhood adversity and infant NICU admission (b = 0.01, 95% CI = -0.02-0.08)., Conclusions: Findings demonstrate one pathway linking maternal childhood adversity to a potentially preterm birth or shorter gestational age, in addition to low birth weight at delivery, and present an opportunity for targeted intervention to support expecting mothers who face financial stress., (© 2023. The Author(s).)

Purpose: Recent meta-analyses suggest the Metabolic Syndrome (MS) increases high-grade prostate cancer (PC), although studies are inconsistent and few black men were included. We investigated MS and PC diagnosis in black and white men undergoing prostate biopsy in an equal access healthcare system. We hypothesized MS would be linked with aggressive PC, regardless of race., Methods: Among men undergoing prostate biopsy at the Durham Veterans Affairs Hospital, medical record data abstraction of diagnosis or treatment for hypertension (≥ 130/85 mmHg), dyslipidemia (HDL < 40 mg/dL), hypertriglyceridemia (≥ 150 mg/dL), diabetes, hyperglycemia (fasting glucose ≥ 100 ml/dL), and central obesity (waist circumference ≥ 40 inches) were done. Biopsy grade group (GG) was categorized as low (GG1) or high (GG2-5). Multinomial logistic regression was used to examine MS (3-5 components) vs. no MS (0-2 components) and diagnosis of high grade and low grade vs. no PC, adjusting for potential confounders. Interactions between race and MS were also tested., Results: Of 1,051 men (57% black), 532 (51%) had MS. Men with MS were older, more likely to be non-black, and had a larger prostate volume (all p ≤ 0.011). On multivariable analysis, MS was associated with high-grade PC (OR = 1.73, 95% CI 1.21-2.48, p = 0.003), but not overall PC (OR = 1.17, 95% CI 0.88-1.57, p = 0.29) or low grade (OR = 0.87, 95% CI 0.62-1.21, p = 0.39). Results were similar in black and non-black men (all p-interactions > 0.25)., Conclusion: Our data suggest that metabolic dysregulation advances an aggressive PC diagnosis in both black and non-black men. If confirmed, prevention of MS could reduce the risk of developing aggressive PC, including black men at higher risk of PC mortality., (© 2022. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Epidural anesthesia is an effective pain relief modality, widely used for labor analgesia. Childhood asthma is one of the commonest chronic medical illnesses in the USA which places a significant burden on the health-care system. We recently demonstrated a negative association between the duration of epidural anesthesia and the development of childhood asthma; however, the underlying molecular mechanisms still remain unclear. In this study of 127 mother-child pairs comprised of 75 Non-Hispanic Black (NHB) and 52 Non-Hispanic White (NHW) from the Newborn Epigenetic Study, we tested the hypothesis that umbilical cord blood DNA methylation mediates the association between the duration of exposure to epidural anesthesia at delivery and the development of childhood asthma and whether this differed by race/ethnicity. In the mother-child pairs of NHB ancestry, the duration of exposure to epidural anesthesia was associated with a marginally lower risk of asthma (odds ratio = 0.88, 95% confidence interval = 0.76-1.01) for each 1-h increase in exposure to epidural anesthesia. Of the 20 CpGs in the NHB population showing the strongest mediation effect, 50% demonstrated an average mediation proportion of 52%, with directional consistency of direct and indirect effects. These top 20 CpGs mapped to 21 genes enriched for pathways engaged in antigen processing, antigen presentation, protein ubiquitination and regulatory networks related to the Major Histocompatibility Complex (MHC) class I complex and Nuclear Factor Kappa-B ( NFkB ) complex. Our findings suggest that DNA methylation in immune-related pathways contributes to the effects of the duration of exposure to epidural anesthesia on childhood asthma risk in NHB offspring., (© The Author(s) 2023. Published by Oxford University Press.)

Imprinted genes - critical for growth, metabolism, and neuronal function - are expressed from one parental allele. Parent-of-origin-dependent CpG methylation regulates this expression at imprint control regions (ICRs). Since ICRs are established before tissue specification, these methylation marks are similar across cell types. Thus, they are attractive for investigating the developmental origins of adult diseases using accessible tissues, but remain unknown. We determined genome-wide candidate ICRs in humans by performing whole-genome bisulphite sequencing (WGBS) of DNA derived from the three germ layers and from gametes. We identified 1,488 hemi-methylated candidate ICRs, including 19 of 25 previously characterized ICRs (https://humanicr.org/). Gamete methylation approached 0% or 100% in 332 ICRs (178 paternally and 154 maternally methylated), supporting parent-of-origin-specific methylation, and 65% were in well-described CTCF-binding or DNaseI hypersensitive regions. This draft of the human imprintome will allow for the systematic determination of the role of early-acquired imprinting dysregulation in the pathogenesis of human diseases and developmental and behavioural disorders.

Sex-linked differences in mitochondrial ATP production, enzyme activities, and reactive oxygen species generation have been reported in multiple tissue and cell types. While the effects of reproductive hormones underlie many of these differences, regulation of sexually dimorphic mitochondrial function has not been fully characterized. We hypothesized that sex-specific DNA methylation contributes to sex-specific expression of nuclear genes that influence mitochondrial function. Herein, we analysed DNA methylation data specifically focused on nuclear-encoded mitochondrial genes in 191 males and 190 females. We found 596 differentially methylated sites (DMSs) (FDR p < 0.05), corresponding to 324 genes, with at least a 1% difference in methylation between sexes. To investigate the potential functional significance, we utilized gene expression microarray data. Of the 324 genes containing DMSs, 17 showed differences in gene expression by sex. Particularly striking was that ATP5G2 , encoding subunit C of ATP synthase, contains seven DMSs and exhibits a sex difference in expression (p = 0.04). Finally, we also found that alterations in DNA methylation associated with in utero tobacco smoke exposure were sex-specific in these nuclear-encoded mitochondrial genes. Interestingly, the level of sex differences in DNA methylation at nuclear-encoded mitochondrial genes and the level of methylation changes associated with smoke exposure were less prominent than that of other genes. This suggests more conservative regulation of DNA methylation at these nuclear-encoded mitochondrial genes as compared to others. Overall, our findings suggest that sex-specific DNA methylation may help establish sex differences in expression and function and that sex-specific alterations in DNA methylation in response to exposures could contribute to sex-variable toxicological responses.

Background: Psychosocial and physiologic stressors, such as depression and obesity, during pregnancy can have negative consequences, such as increased systemic inflammation, contributing to chronic disease for both mothers and their unborn children. These conditions disproportionately affect racial/ethnic minorities. The effects of recommended dietary patterns in mitigating the effects of these stressors remain understudied., Objectives: We aimed to evaluate the relations between maternal Mediterranean diet adherence (MDA) and maternal and offspring outcomes during the first decade of life in African Americans, Hispanics, and Whites., Methods: This study included 929 mother-child dyads from the NEST (Newborn Epigenetics STudy), a prospective cohort study. FFQs were used to estimate MDA in pregnant women. Weight and height were measured in children between birth and age 8 y. Multivariable linear regression models were used to examine associations between maternal MDA, inflammatory cytokines, and pregnancy and postnatal outcomes., Results: More than 55% of White women reported high MDA during the periconceptional period compared with 22% of Hispanic and 18% of African American women ( P  < 0.05). Higher MDA was associated with lower likelihood of depressive mood (β = -0.45; 95% CI: -0.90, -0.18; P  = 0.02) and prepregnancy obesity (β = -0.29; 95% CI: -0.57, -0.0002; P  = 0.05). Higher MDA was also associated with lower body size at birth, which was maintained to ages 3-5 and 6-8 y-this association was most apparent in White children (3-5 y: β = -2.9, P  = 0.02; 6-8 y: β = -3.99, P  = 0.01)., Conclusions: If replicated in larger studies, our data suggest that MDA provides a potent avenue by which effects of prenatal stressors on maternal and fetal outcomes can be mitigated to reduce ethnic disparities in childhood obesity., (© The Author(s) 2022. Published by Oxford University Press on behalf of the American Society for Nutrition.)

Introduction: Smoking and smoke exposure among pregnant women remain persistent public health issues. Recent estimates suggest that approximately one out of four nonsmokers have measurable levels of cotinine, a marker indicating regular exposure to secondhand smoke. Epidemiological research has attempted to pinpoint individual-level and neighborhood-level factors for smoking during pregnancy. However, most of these studies have relied upon self-reported measures of smoking., Aims and Methods: To more accurately assess smoke exposure resulting from both smoking and secondhand exposure in mothers during pregnancy, we used Bayesian regression models to estimate the association of cotinine levels with tobacco retail outlet (TRO) exposure and a neighborhood deprivation index (NDI) in six counties in North Carolina centered on Durham County., Results: Results showed a significant positive association between TRO exposure (β = 0.008, 95% credible interval (CI) = [0.003, 0.013]) and log cotinine after adjusting for individual covariates (eg, age, race/ethnicity, education, marital status). TRO exposure was not significant after including the NDI, which was significantly associated with log cotinine (β = 0.143, 95% CI = [0.030, 0.267]). However, in a low cotinine stratum (indicating secondhand smoke exposure), TRO exposure was significantly associated with log cotinine (β = 0.005, 95% CI = [0.001, 0.009]), while in a high cotinine stratum (indicating active smoking), the NDI was significantly associated with log cotinine (β = 0.176, 95% CI = [0.005, 0.372])., Conclusions: In summary, our findings add to the evidence that contextual factors are important for active smoking during pregnancy., Implications: In this study, we found several significant associations that suggest a more nuanced understanding of the potential influence of environmental- and individual-level factors for levels of prenatal smoke exposure. Results suggested a significant positive association between TRO exposure and cotinine levels, after adjusting for the individual factors such as race, education, and marital status. Individually, NDI was similarly positively associated with cotinine levels as well. However, when combining TRO exposure alongside NDI in the same model, TROs were no longer significantly associated with overall cotinine levels., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Society for Research on Nicotine and Tobacco. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Non-Alcoholic fatty liver disease (NAFLD) is the leading cause of chronic liver disease in children. Epigenetic alterations, such as through DNA methylation (DNAm), may link adverse childhood exposures and fatty liver and provide non-invasive methods for identifying children at high risk for NAFLD and associated metabolic dysfunction. We investigated the association between differential DNAm and liver fat content (LFC) and liver injury in pre-adolescent children. Leveraging data from the Newborn Epigenetics Study (NEST), we enrolled 90    mother-child dyads and used linear regression to identify CpG sites and differentially methylated regions (DMRs) in peripheral blood associated with LFC and alanine aminotransferase (ALT) levels in 7-12yo children. DNAm was measured using Infinium HumanMethylationEPIC BeadChips (Illumina). LFC and fibrosis were quantified by magnetic resonance imaging proton density fat fraction and elastography. Median LFC was 1.4% (range, 0.3-13.4%) and MRE was 2.5 kPa (range, 1.5-3.6kPa). Three children had LFC ≥ 5%, while six (7.6%) met our definition of NAFLD (LFC ≥ 3.7%). All children with NAFLD were obese and five were Black. LFC was associated with 88 DMRs and 106 CpGs (FDR<5%). The top two CpGs, cg25474373 and cg07264203, mapped to or near RFTN2 and PRICKLE2 genes. These two CpG sites were also significantly associated with a NAFLD diagnosis. As higher LFC associates with an adverse cardiometabolic profile already in childhood, altered DNAm may identify these children early in disease course for targeted intervention. Larger, longitudinal studies are needed to validate these findings and determine mechanistic relevance.

Despite years of advisories against the behavior, smoking among pregnant women remains a persistent public health issue in the USA. Recent estimates suggest that 9.4% of women smoke before pregnancy and 7.1% during pregnancy in the USA. Epidemiological research has attempted to pinpoint individual-level and neighborhood-level factors for smoking during pregnancy, including educational attainment, employment status, housing conditions, poverty, and racial demographics. However, most of these studies have relied upon self-reported measures of smoking, which are subject to reporting bias. To more accurately and objectively assess smoke exposure in mothers during pregnancy, we used Bayesian index models to estimate a neighborhood deprivation index (NDI) for block groups in Durham County, North Carolina, and its association with cotinine, a marker of smoke exposure, in pregnant mothers (n = 887 enrolled 2005-2011). Results showed a significant positive association between NDI and log cotinine (beta = 0.20, 95% credible interval = [0.11, 0.29]) after adjusting for individual covariates (e.g., race/ethnicity and education). The two most important variables in the NDI according to the estimated index weights were percent females without a high school degree and percent Black population. At the individual level, Hispanic and other race/ethnicity were associated with lowered cotinine compared with non-Hispanic Whites. Higher education levels were also associated with lowered cotinine. In summary, our findings provide stronger evidence that the socio-geographic variables of educational attainment and neighborhood racial composition are important factors for smoking and secondhand smoke exposure during pregnancy and can be used to target intervention efforts., (© 2022. Society for Prevention Research.)

Children conceived with assisted reproductive technology (ART) have an increased risk of adverse outcomes, including congenital malformations and imprinted gene disorders. In a retrospective North Carolina-based-birth-cohort, we examined the effect of ovulation drugs and ART on CpG methylation in differentially methylated CpGs in known imprint control regions (ICRs). Nine ICRs containing 48 CpGs were assessed for methylation status by pyrosequencing in mixed leukocytes from cord blood. After restricting to non-smoking, college-educated participants who agreed to follow-up, ART-exposed ( n = 27), clomifene-only-exposed ( n = 22), and non-exposed ( n = 516) groups were defined. Associations of clomifene and ART with ICR CpG methylation were assessed with linear regression and stratifying by offspring sex. In males, ART was associated with hypomethylation of the PEG3 ICR [β(95% CI) = -1.46 (-2.81, -0.12)] and hypermethylation of the MEG3 ICR [3.71 (0.01, 7.40)]; clomifene-only was associated with hypomethylation of the NNAT ICR [-5.25 (-10.12, -0.38)]. In female offspring, ART was associated with hypomethylation of the IGF2 ICR [-3.67 (-6.79, -0.55)]. Aberrant methylation of these ICRs has been associated with cardiovascular disease and metabolic and behavioral outcomes in children. The results suggest that the increased risk of adverse outcomes in offspring conceived through ART may be due in part to altered methylation of ICRs. Larger studies utilizing epigenome-wide interrogation are warranted.

Liver cancer incidence has tripled since the early 1980s, making this disease one of the fastest rising types of cancer and the third leading cause of cancer-related deaths worldwide. In the US, incidence varies by geographic location and race, with the highest incidence in the southwestern and southeastern states and among racial minorities such as Hispanic and Black individuals. Prognosis is also poorer among these populations. The observed ethnic disparities do not fully reflect differences in the prevalence of risk factors, e.g., for cirrhosis that may progress to liver cancer or from genetic predisposition. Likely substantial contributors to risk are environmental factors, including chemical and non-chemical stressors; yet, the paucity of mechanistic insights impedes prevention efforts. Here, we review the current literature and evaluate challenges to reducing liver cancer disparities. We also discuss the hypothesis that epigenetic mediators may provide biomarkers for early detection to support interventions that reduce disparities., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Vidal, Moylan, Wilder, Grant, Murphy and Hoyo.)

Background: High-risk human papillomavirus (hrHPV) testing is utilized in primary cervical cancer screening, generally along with cytology, to triage abnormalities to colposcopy. Most screening-based hrHPV testing involves pooled detection of any hrHPV or of HPV16/18. Cervical neoplasia progression risks based on extended hrHPV genotyping-particularly non-16/18 hrHPV types-are not well characterized. HPV genotype-specific incidence of high-grade cervical intraepithelial neoplasia or more severe (CIN2+) following an abnormal screening result was examined., Methods: We assessed a US-based prospective, multiracial, clinical cohort of 343 colposcopy patients with normal histology (n = 226) or CIN1 (n = 117). Baseline cervical samples underwent HPV DNA genotyping, and participants were followed up to 5 years. Genotype-specific CIN2+ incidence rates (IR) were estimated with accelerated failure time models. Five-year CIN2+ risks were estimated nonparametrically for hierarchical hrHPV risk groups (HPV16; else HPV18/45; else HPV31/33/35/52/58; else HPV39/51/56/59/68)., Results: At enrollment, median participant age was 30.1 years; most (63%) were hrHPV-positive. Over follow-up, 24 participants progressed to CIN2+ (7.0%). CIN2+ IR among hrHPV-positive participants was 3.4/1,000 person-months. CIN2+ IRs were highest for HPV16 (8.3), HPV33 (7.8), and HPV58 (4.9). Five-year CIN2+ risk was higher for HPV16 (0.34) compared with HPV18/45 (0.12), HPV31/33/35/52/58 (0.12), and HPV39/51/56/59/68 (0.16) (P = 0.05)., Conclusions: Non-16/18 hrHPV types are associated with differential CIN2+ progression rates. HPV16, 33, and 58 exhibited the highest rates over 5 years. HPV risk groups warrant further investigation in diverse US populations., Impact: These novel data assessing extended HPV genotyping in a diverse clinical cohort can inform future directions to improve screening practices in the general population., (©2022 American Association for Cancer Research.)

Gestational exposure to police-reported crime is associated with adverse birth outcomes, but no previous research has evaluated the effects of gestational crime exposure on early childhood health or attempted to disentangle the health effects of neighborhood crime from the effects of neighborhood policing. Using data from 672 Newborn Epigenetics Study participants, we evaluate the effects of gestational exposure to violent crime and racialized drug policing on early childhood blood pressure. We demonstrate that violence and drug policing are consistently associated with increased blood pressure among children born to Black participants but not White or Latinx participants., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Background: Low food security during pregnancy can negatively affect women's physical and mental health. Although many women make a greater effort to eat a healthy diet during pregnancy, the influence of low food security during pregnancy on maternal diet is not well understood., Objective: This study aimed to assess the association between adult food security and maternal diet during pregnancy in a sample from North Carolina., Design: This was a cross-sectional, secondary data analysis of food security (marginal, low, and very low vs high) and maternal diet during pregnancy., Participants and Setting: This study included 468 predominantly Black/African American women during pregnancy from the Nurture cohort, enrolled through prenatal clinics in central North Carolina between 2013 and 2016., Main Outcome Measure: Diet quality was assessed using the Alternate Healthy Eating Index-Pregnancy and the Mediterranean Diet Score. Dietary intake from seven food groups included in the Alternate Healthy Eating Index-Pregnancy and/or Mediterranean Diet Score was assessed as well., Statistical Analysis Performed: Multiple linear regression models were used to examine the association between food security and diet quality and dietary intake during pregnancy, adjusting for race/ethnicity; participation in the Special Supplemental Nutrition Program for Women, Infants, and Children; education; prepregnancy body mass index; age; parity; and mean daily energy intake., Results: In this study, there was no association between maternal food security status and diet quality during pregnancy. However, researchers observed an association between low and marginal food security and greater intake of red and processed meats (marginal: β = 2.20 [P = 0.03]; low: β = 2.28 [P = 0.04]), as well as an association between very low food security and decreased vegetable consumption (β = -.43; P = 0.03)., Conclusions: Very low food security was associated with reduced vegetable intake. In addition, low and marginal food security were associated with greater red and processed meat intake. Future research should focus on nationally representative populations and include longitudinal assessments to allow for the study of the influence of food security on health during pregnancy., (Copyright © 2022 Academy of Nutrition and Dietetics. Published by Elsevier Inc. All rights reserved.)

Metastable epialleles (MEs) are genomic regions that are stochastically methylated prior to germ layer specification and exhibit high interindividual but low intra-individual variability across tissues. ME methylation is vulnerable to environmental stressors, including diet. Tobacco smoke (TS) exposure during pregnancy is associated with adverse impacts on fetal health and maternal micronutrient levels as well as altered methylation. Our objective was to determine if maternal smoke exposure impacts methylation at MEs. Consistent with prior studies, we observed reductions in one-carbon pathway micronutrients with gestational TS exposure, including maternal folate ( P  = 0.02) and vitamins B6 ( P  = 0.05) and B12 ( P  = 0.007). We examined putative MEs BOLA3, PAX8, and ZFYVE28 in cord blood specimens from 85 Newborn Epigenetics STudy participants. Gestational TS exposure was associated with elevated DNA methylation at PAX8 (+5.22% average methylation; 95% CI: 0.33% to 10.10%; P  = 0.037). In human conceptal kidney tissues, higher PAX8 transcription was associated with lower methylation ( R s  = 0.55; P  = 0.07), suggesting that the methylation levels established at MEs, and their environmentally induced perturbation, may have meaningful, tissue-specific functional consequences. This may be particularly important because PAX8 is implicated in several cancers, including pediatric kidney cancer. Our data are the first to indicate vulnerability of human ME methylation establishment to TS exposure, with a general trend of increasing levels of methylation at these loci. Further investigation is needed to determine how TS exposure-mediated changes in DNA methylation at MEs, and consequent expression levels, might affect smoking-related disease risk., (© The Author(s) 2022. Published by Oxford University Press.)

Background: Among children, sex-specific differences in disease prevalence, age of onset, and susceptibility have been observed in health conditions including asthma, immune response, metabolic health, some pediatric and adult cancers, and psychiatric disorders. Epigenetic modifications such as DNA methylation may play a role in the sexual differences observed in diseases and other physiological traits., Methods: We performed a meta-analysis of the association of sex and cord blood DNA methylation at over 450,000 CpG sites in 8438 newborns from 17 cohorts participating in the Pregnancy And Childhood Epigenetics (PACE) Consortium. We also examined associations of child sex with DNA methylation in older children ages 5.5-10 years from 8 cohorts (n = 4268)., Results: In newborn blood, sex was associated at Bonferroni level significance with differences in DNA methylation at 46,979 autosomal CpG sites (p < 1.3 × 10 -7 ) after adjusting for white blood cell proportions and batch. Most of those sites had lower methylation levels in males than in females. Of the differentially methylated CpG sites identified in newborn blood, 68% (31,727) met look-up level significance (p < 1.1 × 10 -6 ) in older children and had methylation differences in the same direction., Conclusions: This is a large-scale meta-analysis examining sex differences in DNA methylation in newborns and older children. Expanding upon previous studies, we replicated previous findings and identified additional autosomal sites with sex-specific differences in DNA methylation. Differentially methylated sites were enriched in genes involved in cancer, psychiatric disorders, and cardiovascular phenotypes., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

Maternal periconceptional diets have known associations with proper offspring neurodevelopment. Mechanisms for such associations include improper energy/nutrient balances between mother and fetus, as well as altered offspring epigenetics during development due to maternal nutrient and inflammatory status. Using a comprehensive food frequency questionnaire and assessing offspring temperament with the Infant-Toddler Social and Emotional Assessment ( n = 325, mean age = 13.9 months), we sought to test whether a maternal periconceptional diet characterized by high glycemic loading (MGL) would affect offspring temperament using adjusted ordinal regression. After limiting false discovery to 10%, offspring born to mothers in tertile 3 of glycemic loading (referent = tertile 1) were more likely to be in the next tertile of anxiety [OR (95% CI) = 4.51 (1.88-11.07)] and inhibition-related behaviors [OR (95% CI) = 3.42 (1.49-7.96)]. Male offspring were more likely to exhibit impulsive [OR (95% CI) = 5.55 (1.76-18.33)], anxiety [OR (95% CI) = 4.41 (1.33-15.30)], sleep dysregulation [OR (95% CI) = 4.14 (1.34-13.16)], empathy [6.68 (1.95-24.40)], and maladaptive behaviors [OR (95% CI) = 9.86 (2.81-37.18)], while females were more likely to exhibit increased anxiety-related behaviors [OR (95% CI) = 15.02 (3.14-84.27)]. These associations persisted when concurrently modeled with the maternal-Mediterranean dietary pattern. In a subset ( n = 142), we also found MGL associated with increased mean methylation of the imprint control region of SGCE/PEG10 . In conclusion, these findings highlight the importance of maternal dietary patterns on offspring neurodevelopment, offering avenues for prevention options for mothers.

Background: Selenium (Se), an essential trace mineral, has been implicated in preterm birth (PTB). We aimed to determine the association of maternal Se concentrations during pregnancy with PTB risk and gestational duration in a large number of samples collected from diverse populations., Methods: Gestational duration data and maternal plasma or serum samples of 9946 singleton live births were obtained from 17 geographically diverse study cohorts. Maternal Se concentrations were determined by inductively coupled plasma mass spectrometry analysis. The associations between maternal Se with PTB and gestational duration were analysed using logistic and linear regressions. The results were then combined using fixed-effect and random-effect meta-analysis., Findings: In all study samples, the Se concentrations followed a normal distribution with a mean of 93.8 ng/mL (SD: 28.5 ng/mL) but varied substantially across different sites. The fixed-effect meta-analysis across the 17 cohorts showed that Se was significantly associated with PTB and gestational duration with effect size estimates of an OR=0.95 (95% CI: 0.9 to 1.00) for PTB and 0.66 days (95% CI: 0.38 to 0.94) longer gestation per 15 ng/mL increase in Se concentration. However, there was a substantial heterogeneity among study cohorts and the random-effect meta-analysis did not achieve statistical significance. The largest effect sizes were observed in UK (Liverpool) cohort, and most significant associations were observed in samples from Malawi., Interpretation: While our study observed statistically significant associations between maternal Se concentration and PTB at some sites, this did not generalise across the entire cohort. Whether population-specific factors explain the heterogeneity of our findings warrants further investigation. Further evidence is needed to understand the biologic pathways, clinical efficacy and safety, before changes to antenatal nutritional recommendations for Se supplementation are considered., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY. Published by BMJ.)