Preterm Birth and Metal Mixture Exposure among Pregnant Women from the Navajo Birth Cohort Study.

BACKGROUND: Preterm birth (PTB), defined as birth before 37 wk gestation, is associated with hypertension, diabetes, inadequate prenatal care, unemployment or poverty, and metal exposure. Indigenous individuals are more likely to have maternal risk factors associated with PTB compared with other populations in the United States; however, the role of environmental metals on PTB among pregnant Indigenous women remains uncertain. Previous research identified associations between PTB and individual metals, but there is limited investigation on metal mixtures and this birth outcome. OBJECTIVES: We used a mixtures analysis framework to investigate the association between metal mixtures and PTB among pregnant Indigenous women from the Navajo Birth Cohort Study (NBCS). METHODS: Maternal urine and blood samples were collected at the time of study enrollment and analyzed for metals by inductively coupled plasma dynamic reaction cell mass spectrometry. Bayesian Profile Regression was used to identify subgroups (clusters) of individuals with similar patterns of coexposure and to model association with PTB. RESULTS: Results indicated six subgroups of maternal participants with distinct exposure profiles, including one group with low exposure to all metals and one group with total arsenic, cadmium, lead, and uranium concentrations exceeding representative concentrations calculated from the National Health and Nutrition Examination Survey (NHANES). Compared with the reference group (i.e., the lowest exposure subgroup), the subgroup with the highest overall exposure had a relative risk of PTB of 2.9 times (95% credible interval: 1.1, 6.1). Exposures in this subgroup were also higher overall than NHANES median values for women 14-45 years of age. DISCUSSION: Given the wide range of exposures and elevated PTB risk for the most exposed subgroups in a relatively small study, follow-up investigation is recommended to evaluate associations between metal mixture profiles and other birth outcomes and to test hypothesized mechanisms of action for PTB and oxidative stress caused by environmental metals. https://doi.org/10.1289/EHP10361.

Environmental uranium exposures and cytokine profiles among mother-newborn baby pairs from the Navajo Βirth Cohort Study.

The Navajo Nation was heavily mined for uranium (U) during the cold-war leading to a legacy of >1100 abandoned U mining, milling and associated waste sites. The Navajo Birth Cohort Study was initiated to assess the effect of non-occupational legacy exposure to U during pregnancy on birth outcomes and child development. We report that 92% of babies with detectable urine U at birth were born from mothers who had urine U concentrations greater than national norms during pregnancy, indicative of prenatal exposure to U. To assess immune alterations associated with U exposure on both mothers and babies, we investigated associations between cytokine profiles and maternal U and associations of these measures with cytokine profiles in babies. Effect sizes for the differences in cytokine profiles were more evident among babies than mothers. Overall, there were seven cytokines (IFN-γ, IL-1ß, IL-2, IL-4, IL-10, GM-CSF, and TNF-α), for which the effect size for babies with higher than the national U concentrations was medium to large (ORs of 2.21 (1.08-4.52) through 1.71(0.76-3.83). In contrast, only three cytokines (IL-8, IL-12p70, and TNF-α) had effect sizes which almost reached medium strength (ORs of 1.64 (0.74-4.05) through 1.36 (0.65-2.87) in mothers with U above national norms. The effects of prenatal exposures to uranium and associated alterations in systemic immune responses resulting from U exposure could impact both maternal health as well as healthy child development through induction of inflammation, autoimmunity or other chronic diseases related to immune dysfunction that may affect long-term health.

The immunotoxicity of natural and depleted uranium: From cells to people.

Uranium is a naturally occurring element found in the environment as a mixture of isotopes with differing radioactive properties. Enrichment of mined material results in depleted uranium waste with substantially reduced radioactivity but retains the capacity for chemical toxicity. Uranium mine and milling waste are dispersed by wind and rain leading to environmental exposures through soil, air, and water contamination. Uranium exposure is associated with numerous adverse health outcomes in humans, yet there is limited understanding of the effects of depleted uranium on the immune system. The purpose of this review is to summarize findings on uranium immunotoxicity obtained from cell, rodent and human population studies. We also highlight how each model contributes to an understanding of mechanisms that lead to immunotoxicity and limitations inherent within each system. Information from population, animal, and laboratory studies will be needed to significantly expand our knowledge of the contributions of depleted uranium to immune dysregulation, which may then inform prevention or intervention measures for exposed communities.

Exposure to uranium and co-occurring metals among pregnant Navajo women.

Navajo Nation residents are at risk for exposure to uranium and other co-occurring metals found in abandoned mine waste. The Navajo Birth Cohort Study (NBCS) was initiated in 2010 to address community concerns regarding the impact of chronic environmental exposure to metals on pregnancy and birth outcomes. The objectives of this paper were to 1) evaluate maternal urine concentrations of key metals at enrollment and delivery from a pregnancy cohort; and 2) compare the NBCS to the US general population by comparing representative summary statistical values. Pregnant Navajo women (N = 783, age range 14-45 years) were recruited from hospital facilities on the Navajo Nation during prenatal visits and urine samples were collected by trained staff in pre-screened containers. The U.S. Centers for Disease Control and Prevention (CDC), National Center for Environmental Health's (NCEH) Division of Laboratory Sciences (DLS) analyzed urine samples for metals. Creatinine-corrected urine concentrations of cadmium decreased between enrollment (1st or 2nd trimester) and delivery (3rd trimester) while urine uranium concentrations were not observed to change. Median and 95th percentile values of maternal NBCS urine concentrations of uranium, manganese, cadmium, and lead exceeded respective percentiles for National Health and Nutrition Evaluation Survey (NHANES) percentiles for women (ages 14-45 either pregnant or not pregnant.) Median NBCS maternal urine uranium concentrations were 2.67 (enrollment) and 2.8 (delivery) times greater than the NHANES median concentration, indicating that pregnant Navajo women are exposed to metal mixtures and have higher uranium exposure compared to NHANES data for women. This demonstrates support for community concerns about uranium exposure and suggests a need for additional analyses to evaluate the impact of maternal metal mixtures exposure on birth outcomes.

Environmental risk mapping of potential abandoned uranium mine contamination on the Navajo Nation, USA, using a GIS-based multi-criteria decision analysis approach.

The Navajo Nation (NN), a sovereign indigenous tribal nation in the Southwestern United States, is home to 523 abandoned uranium mines (AUMs). Previous health studies have articulated numerous human health hazards associated with AUMs and multiple environmental mechanisms/pathways (e.g., air, water, and soil) for contaminant transport. Despite this evidence, the limited modeling of AUM contamination that exists relies solely on proximity to mines and only considers single rather than combined pathways from which the contamination is a product. In order to better understand the spatial dynamics of contaminant exposure across the NN, we adopted the following established geospatial and computational methods to develop a more sophisticated environmental risk map illustrating the potential for AUM contamination: GIS-based multi-criteria decision analysis (GIS-MCDA), fuzzy logic, and analytic hierarchy process (AHP). Eight criteria layers were selected for the GIS-MCDA model: proximity to AUMs, roadway proximity, drainage proximity, topographic landforms, wind index, topographic wind exposure, vegetation index, and groundwater contamination. Model sensitivity was evaluated using the one-at-a-time method, and statistical validation analysis was conducted using two separate environmental datasets. The sensitivity analysis indicated consistency and reliability of the model. Model results were strongly associated with environmental uranium concentrations. The model classifies 20.2% of the NN as high potential for AUM contamination while 65.7% and 14.1% of the region are at medium and low risk, respectively. This study is entirely a novel application and a crucial first step toward informing future epidemiologic studies and ongoing remediation efforts to reduce human exposure to AUM waste.

Elevated autoimmunity in residents living near abandoned uranium mine sites on the Navajo Nation.

Specific autoantibodies were assessed among residents of the Navajo Nation in New Mexico chronically exposed to metal mixtures from uranium mine wastes and in drinking water supplies. Age and the extent of exposure to legacy waste from 100 abandoned uranium mine and mill sites were associated with antibodies to denatured DNA, previously known to be an early indicator of medication-induced autoimmunity. Surprisingly, autoantibodies to native DNA and/or chromatin were also linked to environmental exposure, specifically uranium consumption through drinking water for both men and women, while urinary arsenic was negatively associated with these autoantibodies in women. These findings suggest that contaminants derived from uranium mine waste enhanced development of autoantibodies in some individuals, while arsenic may be globally immunosuppressive with gender-specific effects. Specific autoantibodies may be a sensitive indicator of immune perturbation by environmental toxicants, an adverse effect not considered in current drinking water standards or regulatory risk assessment evaluations.

Arsenic association with circulating oxidized low-density lipoprotein in a Native American community.

More than 500 abandoned uranium (U) mines within the Navajo Nation contribute U, arsenic (As) and other metals to groundwater, soil and potentially air through airborne transport. The adverse cardiovascular health effects attributed to cumulative exposure to these metals remains uncertain. The aim of this study was to examine whether environmental exposure to these metals may promote or exacerbate the oxidation of low-density lipoprotein (LDL) cholesterol in this Native American population. The correlation of cardiovascular biomarkers (oxidized LDL (oxLDL) and C-reactive protein (CRP)) from a Navajo cohort (n = 252) with mean annual As and U intakes from water and urine metals was estimated using linear regression. Proof-of-concept assays were performed to investigate whether As and U directly oxidize human LDL. Mean annual As intake from water was positively and significantly associated with oxLDL, but not CRP in this study population, while U intake estimates were negatively associated with oxLDL. In an acellular system, As, but not U, directly oxidized the apolipoprotein B-100 component of purified human LDL. Neither metal promoted lipid peroxidation of the LDL particle. Both the population and lab results are consistent with the hypothesis that As promotes oxidation of LDL, a crucial step in vascular inflammation and chronic vascular disease. Conversely, for outcomes related to U, negative associations were observed between U intake and oxLDL, and U only minimally altered human LDL in direct exposure experiments. Only urine U was correlated with CRP, whereas no other metals in water or urine were apparently reliable predictors of this inflammatory marker.

Residential proximity to abandoned uranium mines and serum inflammatory potential in chronically exposed Navajo communities.

Members of the Navajo Nation, who possess a high prevalence of cardiometabolic disease, reside near hundreds of local abandoned uranium mines (AUM), which contribute uranium, arsenic and other metals to the soil, water and air. We recently reported that hypertension is associated with mine waste exposures in this population. Inflammation is a major player in the development of numerous vascular ailments. Our previous work establishing that specific transcriptional responses of cultured endothelial cells treated with human serum can reveal relative circulating inflammatory potential in a manner responsive to pollutant exposures, providing a model to assess responses associated with exposure to these waste materials in this population. To investigate a potential link between exposures to AUM and serum inflammatory potential in affected communities, primary human coronary artery endothelial cells were treated for 4 h with serum provided by Navajo study participants (n=145). Endothelial transcriptional responses of intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1) and chemokine ligand 2 (CCL2) were measured. These transcriptional responses were then linked to AUM exposure metrics, including surface area-weighted AUM proximity and estimated oral intake of metals. AUM proximity strongly predicted endothelial transcriptional responses to serum including CCL2, VCAM-1 and ICAM-1 (P<0.0001 for each), whereas annual water intakes of arsenic and uranium did not, even after controlling for all major effect modifiers. Inflammatory potential associated with proximity to AUMs, but not oral intake of specific metals, additionally suggests a role for inhalation exposure as a contributor to cardiovascular disease.