Environmental metals and birth defects: New approaches to understanding the role of metals in congenital heart defects

Birth defects are a leading cause of infant mortality, and cardiac defects are among the most fatal. The majority of birth defects have no known cause whether environmental, genetic, or a combination of these factors. Toxic metals are likely contributors to birth defects in humans, yet the biological pathways that underlie these relationships remain largely unknown. The objective of this research was to assess the contributions of environmental metals to congenital heart defects using i) an ecologic study to evaluate the relationship between metals and birth defects in North Carolina and ii) an in vitro cardiomyocyte model to identify underlying metalaltered molecular pathways. This research evaluated the associations between arsenic, cadmium, manganese, and lead levels in private well water with the prevalence of specific birth defects using six years of data collected by the North Carolina Birth Defects Monitoring Program. Prevalence ratios (PR) with 95% confidence intervals (CI) were calculated to estimate the association between the prevalence of birth defects in census tracts with the highest average metal levels compared to the lowest average metal levels, adjusted for maternal age, race, and education status. We identified relationships between the highest category of arsenic exposure and the prevalence of conotruncal heart defects (PR: 1.3 95%CI: 0.9-1.8) as well as the highest category of manganese exposure and the prevalence of atrioventricular septal heart defects (PR: 1.8 95% CI: 1.1-3.1). The findings suggest an ecologic association between concentrations of metals in drinking water and the prevalence of specific birth defects. Next, we applied an in vitro approach to identify biological pathways that underlie metal-altered signaling in the heart. We exposed human-derived cardiomyocytes to low-level cadmium chloride (0.5 μM) and assessed changes in genome-wide microRNA (miRNA) and messenger RNA (mRNA) expression levels. We identified 8 miRNAs and 31 genes that were differentially expressed in cardiomyocytes exposed to cadmium compared to unexposed controls. A subset of 8 mRNAs were predicted targets of the cadmium-associated miRNAs. We identified miRNA-dependent signaling pathways that were enriched for gene expression, embryonic development, and organismal development. Taken together, the findings contribute to the understanding of potentially preventable environmentally-mediated birth defects.Doctor of Philosoph

Association of Manganese Biomarker Concentrations with Blood Pressure and Kidney Parameters among Healthy Adolescents: NHANES 2013–2018

Deficiency or excess exposure to manganese (Mn), an essential mineral, may have potentially adverse health effects. The kidneys are a major organ of Mn site-specific toxicity because of their unique role in filtration, metabolism, and excretion of xenobiotics. We hypothesized that Mn concentrations were associated with poorer blood pressure (BP) and kidney parameters such as estimated glomerular filtration rate (eGFR), blood urea nitrogen (BUN), and albumin creatinine ratio (ACR). We conducted a cross-sectional analysis of 1931 healthy U.S. adolescents aged 12–19 years participating in National Health and Nutrition Examination Survey cycles 2013–2014, 2015–2016, and 2017–2018. Blood and urine Mn concentrations were measured using inductively coupled plasma mass spectrometry. Systolic and diastolic BP were calculated as the average of available readings. eGFR was calculated from serum creatinine using the Bedside Schwartz equation. We performed multiple linear regression, adjusting for age, sex, body mass index, race/ethnicity, and poverty income ratio. We observed null relationships between blood Mn concentrations with eGFR, ACR, BUN, and BP. In a subset of 691 participants, we observed that a 10-fold increase in urine Mn was associated with a 16.4 mL/min higher eGFR (95% Confidence Interval: 11.1, 21.7). These exploratory findings should be interpreted cautiously and warrant investigation in longitudinal studies

Systems Biology and Birth Defects Prevention: Blockade of the Glucocorticoid Receptor Prevents Arsenic-Induced Birth Defects

Background: The biological mechanisms by which environmental metals are associated with birth defects are largely unknown. Systems biology–based approaches may help to identify key pathways that mediate metal-induced birth defects as well as potential targets for prevention

Toxic metal levels in children residing in a smelting craft village in Vietnam: a pilot biomonitoring study

Abstract Background In Vietnam, environmental pollution caused by small-scale domestic smelting of automobile batteries into lead ingot is a growing concern. The village of Nghia Lo is a smelting craft village located roughly 25 km southeast of Hanoi in the Red River Delta. Despite the concern of toxic metal exposure in the village, biomonitoring among susceptible populations, such as children, has not been previously conducted. The aim of this study was to determine the body burden of toxic metals in children residing in a smelting craft village. Methods Twenty children from Nghia Lo, Vietnam, ages 18 months to four years were selected for capillary whole blood and toenail biomonitoring. Whole blood lead levels (BLLs) were measured using a portable lead analyzer, and toenail levels of arsenic, cadmium, chromium, lead, manganese, and mercury were analyzed with inductively coupled plasma-mass spectrometry. Results The findings show that all of the 20 children had detectable BLLs, and every child had levels that exceeded the Centers for Disease Control and Prevention guideline level of 5 μg/dL. Eighty percent of tested subjects had BLLs higher than 10 μg/dL. Five children (25%) had BLLs greater than 45 μg/dL, the level of recommended medical intervention. In addition to blood lead, all of the children had detectable levels of arsenic, cadmium, chromium, lead, manganese, and mercury in toenail samples. Notably, average toenail lead, manganese, and mercury levels were 157 μg/g, 7.41 μg/g, and 2.63 μg/g respectively, well above levels previously reported in children. Significant Spearman’s rank correlations showed that there were relationships between blood and toenail lead levels (r = 0.65, p < 0.05), toenail levels of lead and cadmium (r = 0.66, p < 0.05), and toenail levels of manganese and chromium (r = 0.72, p < 0.001). Linear regression showed that reducing the distance to the nearest active smelter by half was associated with a 116% increase in BLL (p < 0.05). Conclusions The results suggest that children in battery recycling and smelting craft villages in Vietnam are co-exposed to toxic metals. There is an urgent need for mitigation to control metal exposure related to domestic smelting

Arsenic in North Carolina: Public Health Implications

Arsenic is a known human carcinogen and relevant environmental contaminant in drinking water systems. We set out to comprehensively examine statewide arsenic trends and identify areas of public health concern. Specifically, arsenic trends in North Carolina private wells were evaluated over an eleven-year period using the North Carolina Department of Health and Human Services (NCDHHS) database for private domestic well waters. We geocoded over 63,000 domestic well measurements by applying a novel geocoding algorithm and error validation scheme. Arsenic measurements and geographical coordinates for database entries were mapped using Geographic Information System (GIS) techniques. Furthermore, we employed a Bayesian Maximum Entropy (BME) geostatistical framework, which accounts for geocoding error to better estimate arsenic values across the state and identify trends for unmonitored locations. Of the approximately 63,000 monitored wells, 7,712 showed detectable arsenic concentrations that ranged between 1 and 806 μg/L. Additionally, 1,436 well samples exceeded the EPA drinking water standard. We reveal counties of concern and demonstrate a historical pattern of elevated arsenic in some counties, particularly those located along the Carolina terrane (Carolina slate belt). We analyzed these data in the context of populations using private well water and identify counties for targeted monitoring, such as Stanly and Union Counties. By spatiotemporally mapping these data, our BME estimate revealed arsenic trends at unmonitored locations within counties and better predicted well concentrations when compared to the classical kriging method. This study reveals relevant information on the location of arsenic-contaminated private domestic wells in North Carolina and indicates potential areas at increased risk for adverse health outcomes

A Comparison of the Effects of Child Management and Planned Activities Training in Five Parenting Environments

This study compared the effects of two procedures designed to enhance the extra training effects of behavioral parent training. Twenty parents of oppositional children were randomly assigned to either a child management training condition or a combined child management plus planned activities condition. A further 10 non-problem children and their parents served as a social validation group. Observations of both parent and child behavior were conducted in each of five home observation settings (breakfast time, kindy (kindergarten) or school exit, a structured playtime, bathtime, and bedtime). Both training procedures resulted in changes in both child oppositional and parent aversive behavior in all observation settings. In addition, desired positive parenting behaviors also improved in all settings. Treatment effects were maintained in all settings at 3-month follow-up. Comparisons between oppositional children following treatment and children in the social validation group showed that they each displayed similarly low levels of oppositional behavior in all settings. The implications of the results for facilitating generalized changes in behavioral parent training are discussed

Association between arsenic, cadmium, manganese, and lead levels in private wells and birth defects prevalence in North Carolina: a semi-ecologic study

Abstract: Background: Toxic metals including arsenic, cadmium, manganese, and lead are known human developmental toxicants that are able to cross the placental barrier from mother to fetus. In this population-based study, we assess the association between metal concentrations in private well water and birth defect prevalence in North Carolina. Methods: A semi-ecologic study was conducted including 20,151 infants born between 2003 and 2008 with selected birth defects (cases) identified by the North Carolina Birth Defects Monitoring Program, and 668,381 non-malformed infants (controls). Maternal residences at delivery and over 10,000 well locations measured for metals by the North Carolina Division of Public Health were geocoded. The average level of each metal was calculated among wells sampled within North Carolina census tracts. Individual exposure was assigned as the average metal level of the census tract that contained the geocoded maternal residence. Prevalence ratios (PR) with 95% confidence intervals (CI) were calculated to estimate the association between the prevalence of birth defects in the highest category (≥90th percentile) of average census tract metal levels and compared to the lowest category (≤50th percentile). Results: Statewide, private well metal levels exceeded the EPA Maximum Contaminant Level (MCL) or secondary MCL for arsenic, cadmium, manganese, and lead in 2.4, 0.1, 20.5, and 3.1 percent of wells tested. Elevated manganese levels were statistically significantly associated with a higher prevalence of conotruncal heart defects (PR: 1.6 95% CI: 1.1-2.5). Conclusions: These findings suggest an ecologic association between higher manganese concentrations in drinking water and the prevalence of conotruncal heart defects

Association between arsenic, cadmium, manganese, and lead levels in private wells and birth defects prevalence in North Carolina: a semi-ecologic study

Abstract: Background: Toxic metals including arsenic, cadmium, manganese, and lead are known human developmental toxicants that are able to cross the placental barrier from mother to fetus. In this population-based study, we assess the association between metal concentrations in private well water and birth defect prevalence in North Carolina. Methods: A semi-ecologic study was conducted including 20,151 infants born between 2003 and 2008 with selected birth defects (cases) identified by the North Carolina Birth Defects Monitoring Program, and 668,381 non-malformed infants (controls). Maternal residences at delivery and over 10,000 well locations measured for metals by the North Carolina Division of Public Health were geocoded. The average level of each metal was calculated among wells sampled within North Carolina census tracts. Individual exposure was assigned as the average metal level of the census tract that contained the geocoded maternal residence. Prevalence ratios (PR) with 95% confidence intervals (CI) were calculated to estimate the association between the prevalence of birth defects in the highest category (≥90th percentile) of average census tract metal levels and compared to the lowest category (≤50th percentile). Results: Statewide, private well metal levels exceeded the EPA Maximum Contaminant Level (MCL) or secondary MCL for arsenic, cadmium, manganese, and lead in 2.4, 0.1, 20.5, and 3.1 percent of wells tested. Elevated manganese levels were statistically significantly associated with a higher prevalence of conotruncal heart defects (PR: 1.6 95% CI: 1.1-2.5). Conclusions: These findings suggest an ecologic association between higher manganese concentrations in drinking water and the prevalence of conotruncal heart defects

An evaluation of metrics for assessing maternal exposure to agricultural pesticides

We evaluate the use of three different exposure metrics to estimate maternal agricultural pesticide exposure during pregnancy. Using a geographic information system-based method of pesticide exposure estimation, we combine data on crop density and specific pesticide application amounts/dates to create the three exposure metrics. For illustration purposes, we create each metric for a North Carolina cohort of pregnant women, 2003–2005, and analyze the risk of congenital anomaly development with a focus on metric comparisons. Based on the results, and the need to balance data collection efforts/computational efficiency with accuracy, the metric which estimates total chemical exposure using application dates based on crop-specific earliest planting and latest harvesting information is preferred. Benefits and drawbacks of each metric are discussed and recommendations for extending the analysis to other states are provided

Left atrial appendage closure with WATCHMAN in Asian patients: 2 year outcomes from the WASP registry

Background: Left atrial appendage closure is a non-pharmacological alternative for stroke prevention in high-risk non-valvular atrial fibrillation patients, but has not been widely studied in Asian patients. The prospective WASP registry assessed real-world outcomes for patients undergoing WATCHMAN implant in the Asia-Pacific region. Methods: Data were collected from consecutive patients across 9 centres. Major endpoints included procedural success, safety and long-term outcomes including occurrence of bleeding, stroke/transient ischaemic attack/systemic embolism and all-cause mortality. Results: Subjects (n = 201) had a mean age of 70.8 ± 9.4 years, high stroke risk (CHA2DS2-VASc: 3.9 ± 1.7), elevated bleeding risk (HAS-BLED: 2.1 ± 1.2) with 53% patients from Asian countries. Successful implantation occurred in 98.5% of patients; 7-day device/procedure-related SAE rate was 3.0%. After 2 years of follow-up, the rates of ischaemic stroke/TIA/SE and major bleeding were 1.9 and 2.2 per 100-PY, respectively, representing relative reductions of 77% and 49% versus expected rates per risk scores. The relative risk reductions versus expected rates were more pronounced in Asians vs. Non-Asians (89% vs 62%; 77% vs 14%). Other significant findings included larger mean LAA ostium diameter for Asians vs. Non-Asians (23.4 ± 4.1 mm vs. 21.2 ± 3.2 mm, p < 0.001) and hence requirement for larger median device size (27 mm for Asians, 24 mm for non-Asians [p < 0.0001]). Conclusion: Real-world experience of left atrial appendage closure with WATCHMAN has demonstrated low peri-procedural risk, and long-term efficacy for stroke and bleeding prevention in a primarily Asian cohort.Karen P. Phillips, Teguh Santoso, Prashanthan Sanders, Jeffrey Alison, Jason Leung Kwai Chan, Hui-Nam Pak, Mann Chandavimol, Kenneth M. Stein, Nicole Gordon, Omar Bin Razal