Risk of Death from Cardiovascular Disease Associated with Low-level Arsenic Exposure Among Long-term Smokers in a US Population-based Study

High levels of arsenic exposure have been associated with increases in cardiovascular disease risk. However, studies of arsenic’s effects at lower exposure levels are limited and few prospective studies exist in the United States using long-term arsenic exposure biomarkers. We conducted a prospective analysis of the association between toenail arsenic and cardiovascular disease mortality using longitudinal data collected on 3939 participants in the New Hampshire Skin Cancer Study. Using Cox proportional hazard models adjusted for potential confounders, we estimated hazard ratios and 95% confidence intervals associated with the risk of death from any cardiovascular disease, ischemic heart disease, and stroke, in relation to natural-log transformed toenail arsenic concentrations. In this US population, although we observed no overall association, arsenic exposure measured from toenail clipping samples was related to an increased risk of ischemic heart disease mortality among long-term smokers (as reported at baseline), with increased hazard ratios among individuals with ≥ 31 total smoking years (HR: 1.52, 95% CI: 1.02, 2.27), ≥ 30 pack-years (HR: 1.66, 95% CI: 1.12, 2.45), and among current smokers (HR: 1.69, 95% CI: 1.04, 2.75). These results are consistent with evidence from more highly exposed populations suggesting a synergistic relationship between arsenic exposure and smoking on health outcomes and support a role for lower-level arsenic exposure in ischemic heart disease mortality

Maternal Arsenic Exposure and Gestational Diabetes and Glucose Intolerance in the New Hampshire Birth Cohort Study

Background: Gestational diabetes mellitus (GDM) is a major pregnancy complication with detrimental effects for both mothers and their children. Accumulating evidence has suggested a potential role for arsenic (As) exposure in the development of GDM, but current studies have not assessed As exposure from water, urine or toenail samples. Methods: We investigated the association between As exposure and risk of glucose intolerance and GDM among 1151 women enrolled in the New Hampshire Birth Cohort Study. Arsenic was measured in home well water and via biomarkers (i.e., maternal urine collected ~24–28 weeks gestation and toenail clippings collected 2 weeks postpartum). Results: A total of 105 (9.1 %) of women were diagnosed with glucose intolerance and 14 (1.2 %) of women were diagnosed with GDM. A total of 10.3 % of women had water As levels above 10 μg/L, with a mean As level of 4.2. Each 5 μg/L increase in As concentration in home well water was associated with a ~10 % increased odds of GDM (OR: 1.1, 95 % CI 1.0, 1.2). A positive and statistically significant association also was observed between toenail As and GDM (OR: 4.5, 95 % CI 1.2, 16.6), but not urinary arsenic (OR: 0.8, 95 % CI 0.3, 2.4). In a stratified analysis, the association between water As and GDM and glucose intolerance was largely limited to obese women (OR: 1.7, 95 % CI 1.0, 2.8). Conclusions: Our findings support the role of As exposure via water from private wells in the incidence of GDM and that this association may be modified by body composition

Blood Pressure Changes in Relation to Arsenic Exposure in a U.S. Pregnancy Cohort

Background: Inorganic arsenic exposure has been related to the risk of increased blood pressure based largely on cross-sectional studies conducted in highly exposed populations. Pregnancy is a period of particular vulnerability to environmental insults. However, little is known about the cardiovascular impacts of arsenic exposure during pregnancy. Objectives: We evaluated the association between prenatal arsenic exposure and maternal blood pressure over the course of pregnancy in a U.S. population. Methods: The New Hampshire Birth Cohort Study is an ongoing prospective cohort study in which \u3e 10% of participant household wells exceed the arsenic maximum contaminant level of 10 μg/L established by the U.S. EPA. Total urinary arsenic measured at 24–28 weeks gestation was measured and used as a biomarker of exposure during pregnancy in 514 pregnant women, 18–45 years of age, who used a private well in their household. Outcomes were repeated blood pressure measurements (systolic, diastolic, and pulse pressure) recorded during pregnancy. Results: Using linear mixed effects models, we estimated that, on average, each 5-μg/L increase in urinary arsenic was associated with a 0.15-mmHg (95% CI: 0.02, 0.29; p = 0.022) increase in systolic blood pressure per month and a 0.14-mmHg (95% CI: 0.02, 0.25; p = 0.021) increase in pulse pressure per month over the course of pregnancy. Conclusions: In our U.S. cohort of pregnant women, arsenic exposure was associated with greater increases in blood pressure over the course of pregnancy. These findings may have important implications because even modest increases in blood pressure impact cardiovascular disease risk

RNASEL and MIR146A SNP-SNP Interaction as a Susceptibility Factor for Non-Melanoma Skin Cancer

Immunity and inflammatory pathways are important in the genesis of non-melanoma skin cancers (NMSC). Functional genetic variation in immune modulators has the potential to affect disease etiology. We investigated associations between common variants in two key regulators, MIR146A and RNASEL, and their relation to NMSCs. Using a large population-based case-control study of basal cell (BCC) and squamous cell carcinoma (SCC), we investigated the impact of MIR146A SNP rs2910164 on cancer risk, and interaction with a SNP in one of its putative targets (RNASEL, rs486907). To examine associations between genotype and BCC and SCC, occurrence odds ratios (OR) and 95% confidence intervals (95%CI) were calculated using unconditional logistic regression, accounting for multiple confounding factors. We did not observe an overall change in the odds ratios for SCC or BCC among individuals carrying either of the RNASEL or MIR146A variants compared with those who were wild type at these loci. However, there was a sex-specific association between BCC and MIR146A in women (ORGC = 0.73, [95%CI = 0.52–1.03]; ORCC = 0.29, [95% CI = 0.14–0.61], p-trend\u3c0.001), and a reduction in risk, albeit not statistically significant, associated with RNASEL and SCC in men (ORAG = 0.88, [95%CI = 0.65–1.19]; ORAA = 0.68, [95%CI = 0.43–1.08], p-trend = 0.10). Most striking was the strong interaction between the two genes. Among individuals carrying variant alleles of both rs2910164 and rs486907, we observed inverse relationships with SCC (ORSCC = 0.56, [95%CI = 0.38–0.81], p-interaction = 0.012) and BCC (ORBCC = 0.57, [95%CI = 0.40–0.80], p-interaction = 0.005). Our results suggest that genetic variation in immune and inflammatory regulators may influence susceptibility to NMSC, and novel SNP-SNP interaction for a microRNA and its target. These data suggest that RNASEL, an enzyme involved in RNA turnover, is controlled by miR-146a and may be important in NMSC etiology

Human Polyomaviruses and Incidence of Cutaneous Squamous Cell Carcinoma in the New Hampshire Skin Cancer Study

Squamous cell carcinoma (SCC) of the skin is a malignancy arising from epi- thelial keratinocytes. Experimental and epidemiologic evidence raise the possibility that human polyomaviruses (PyV) may be associated with the occurrence of SCC. To investigate whether the risk for SCC was associated with PyV infection, seropositivity to 10 PyV types was assessed following diagnosis in a population- based case–control study conducted in the United States. A total of 253 SCC cases and 460 age group and gender-matched controls were included. Antibody response against each PyV was measured using a multiplex serology-based glu- tathione S-transferase capture assay of recombinantly expressed VP1 capsid proteins. Odds ratios (OR) for SCC associated with seropositivity to each PyV type were estimated using logistic regression, with adjustment for potentially confounding factors. SCC cases were seropositive for a greater number of PyVs than controls (P = 0.049). Those who were JC seropositive had increased odds of SCC when compared to those who were JC seronegative (OR = 1.37, 95% CI: 0.98–1.90), with an increasing trend in SCC risk with increasing quartiles of seroreactivity (P for trend = 0.04). There were no clear associations between SCC risk and serostatus for other PyV types. This study provides limited evi- dence that infection with certain PyVs may be related to the occurrence of SCC in the general population of the United States

Prenatal metal mixtures and child blood pressure in the Rhea mother-child cohort in Greece

Background: Child blood pressure (BP) is predictive of future cardiovascular risk. Prenatal exposure to metals has been associated with higher BP in childhood, but most studies have evaluated elements individually and measured BP at a single time point. We investigated impacts of prenatal metal mixture exposures on longitudinal changes in BP during childhood and elevated BP at 11 years of age. Methods: The current study included 176 mother-child pairs from the Rhea Study in Heraklion, Greece and focused on eight elements (antimony, arsenic, cadmium, cobalt, lead, magnesium, molybdenum, selenium) measured in maternal urine samples collected during pregnancy (median gestational age at collection: 12 weeks). BP was measured at approximately 4, 6, and 11 years of age. Covariate-adjusted Bayesian Varying Coefficient Kernel Machine Regression and Bayesian Kernel Machine Regression (BKMR) were used to evaluate metal mixture impacts on baseline and longitudinal changes in BP (from ages 4 to 11) and the development of elevated BP at age 11, respectively. BKMR results were compared using static versus percentile-based cutoffs to define elevated BP. Results: Molybdenum and lead were the mixture components most consistently associated with BP. J-shaped relationships were observed between molybdenum and both systolic and diastolic BP at age 4. Similar associations were identified for both molybdenum and lead in relation to elevated BP at age 11. For molybdenum concentrations above the inflection points (~ 40–80 μg/L), positive associations with BP at age 4 were stronger at high levels of lead. Lead was positively associated with BP measures at age 4, but only at high levels of molybdenum. Potential interactions between molybdenum and lead were also identified for BP at age 11, but were sensitive to the cutoffs used to define elevated BP. Conclusions: Prenatal exposure to high levels of molybdenum and lead, particularly in combination, may contribute to higher BP at age 4. These early effects appear to persist throughout childhood, contributing to elevated BP in adolescence. Future studies are needed to identify the major sources of molybdenum and lead in this population

Association of cesarean delivery and formula supplementation with the intestinal microbiome of 6-week-old infants

Author Posting. © American Medical Association, 2016. This article is posted here by permission of American Medical Association for personal use, not for redistribution. The definitive version was published in JAMA Pediatrics 170 (2016): 212-219, doi:10.1001/jamapediatrics.2015.3732.The intestinal microbiome plays a critical role in infant development, and delivery mode and feeding method (breast milk vs formula) are determinants of its composition. However, the importance of delivery mode beyond the first days of life is unknown, and studies of associations between infant feeding and microbiome composition have been generally limited to comparisons between exclusively breastfed and formula-fed infants, with little consideration given to combination feeding of both breast milk and formula.This work was supported in part by grants from the National Institutes of Health (grants NIEHS P01ES022832, NIEHS P20ES018175, NIGMS P20GM104416, NLM K01LM011985, NLM R01LM009012, and NLM R01 LM010098) and the US Environmental Protection Agency (grants RD83459901 and RD83544201).2017-01-1

Physics-Informed Deep Learning to Reduce the Bias in Joint Prediction of Nitrogen Oxides

Atmospheric nitrogen oxides (NOx) primarily from fuel combustion have recognized acute and chronic health and environmental effects. Machine learning (ML) methods have significantly enhanced our capacity to predict NOx concentrations at ground-level with high spatiotemporal resolution but may suffer from high estimation bias since they lack physical and chemical knowledge about air pollution dynamics. Chemical transport models (CTMs) leverage this knowledge; however, accurate predictions of ground-level concentrations typically necessitate extensive post-calibration. Here, we present a physics-informed deep learning framework that encodes advection-diffusion mechanisms and fluid dynamics constraints to jointly predict NO2 and NOx and reduce ML model bias by 21-42%. Our approach captures fine-scale transport of NO2 and NOx, generates robust spatial extrapolation, and provides explicit uncertainty estimation. The framework fuses knowledge-driven physicochemical principles of CTMs with the predictive power of ML for air quality exposure, health, and policy applications. Our approach offers significant improvements over purely data-driven ML methods and has unprecedented bias reduction in joint NO2 and NOx prediction

Estimated Exposure to Arsenic in Breastfed and Formula-Fed Infants in a United States Cohort

Background: Previous studies indicate that concentrations of arsenic in breast milk are relatively low even in areas with high drinking-water arsenic. However, it is uncertain whether breastfeeding leads to reduced infant exposure to arsenic in regions with lower arsenic concentrations. Objective: We estimated the relative contributions of breast milk and formula to arsenic exposure during early infancy in a U.S. population. Methods: We measured arsenic in home tap water (n = 874), urine from 6-week-old infants (n = 72), and breast milk from mothers (n = 9) enrolled in the New Hampshire Birth Cohort Study (NHBCS) using inductively coupled plasma mass spectrometry. Using data from a 3-day food diary, we compared urinary arsenic across infant feeding types and developed predictive exposure models to estimate daily arsenic intake from breast milk and formula. Results: Urinary arsenic concentrations were generally low (median, 0.17 μg/L; maximum, 2.9 μg/L) but 7.5 times higher for infants fed exclusively with formula than for infants fed exclusively with breast milk (β = 2.02; 95% CI: 1.21, 2.83; p \u3c 0.0001, adjusted for specific gravity). Similarly, the median estimated daily arsenic intake by NHBCS infants was 5.5 times higher for formula-fed infants (0.22 μg/kg/day) than for breastfed infants (0.04 μg/kg/day). Given median arsenic concentrations measured in NHBCS tap water and previously published for formula powder, formula powder was estimated to account for ~ 70% of median exposure among formula-fed NHBCS infants. Conclusions: Our findings suggest that breastfed infants have lower arsenic exposure than formula-fed infants, and that both formula powder and drinking water can be sources of exposure for U.S. infants

Maternal and infant inflammatory markers in relation to prenatal arsenic exposure in a U.S. pregnancy cohort.

INTRODUCTION: Accumulating evidence indicates that arsenic (As), a potent environmental toxicant, may increase cardiovascular disease risk and adversely affect endothelial function at high levels of exposure. Pregnancy is a vulnerable time for both mother and child; however, studies examining the association between prenatal As exposure and plasma biomarkers of inflammation and endothelial function in mothers and newborns are lacking. METHODS: We examined maternal urinary As levels at gestational weeks 24-28 and levels of inflammatory biomarkers in plasma from 563 pregnant women and 500 infants' cord blood. We assessed a multiplexed panel of circulating inflammatory and endothelial function markers, including tumor necrosis factor alpha (TNFα), monocyte chemoattractant protein 1 (MCP1), intercellular adhesion molecule (ICAM1) and vascular cell adhesion molecule (VCAM1). RESULTS: Compared with the bottom tertile, the highest tertile of maternal urinary As during pregnancy was associated with a 145.2ng/ml (95% CI 4.1, 286.3; p=0.04) increase in cord blood ICAM1 and 557.3ng/ml (95% CI -56.4, 1171.1; p=0.09) increase in cord blood VCAM1. Among mothers, the highest tertile of maternal urinary As during pregnancy was related to a 141.8ng/ml (95% CI 26.1, 257.5; p=0.02) increase maternal plasma VCAM1 levels. Urinary As was unrelated to MCP1 or TNFα in maternal plasma and cord blood. In structural equation models, the association between maternal urinary As and infant VCAM was mediated by maternal levels of VCAM (βmediation: 0.024, 95% CI: 0.002, 0.050). CONCLUSION: Our observations indicate that As exposure during pregnancy may affect markers of vascular health and endothelial function in both pregnant women and children, and suggest further investigation of the potential impacts on cardiovascular health in these susceptible populations