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.

Meteorological data source comparison-a case study in geospatial modeling of potential environmental exposure to abandoned uranium mine sites in the Navajo Nation.

Meteorological (MET) data is a crucial input for environmental exposure models. While modeling exposure potential using geospatial technology is a common practice, existing studies infrequently evaluate the impact of input MET data on the level of uncertainty on output results. The objective of this study is to determine the effect of various MET data sources on the potential exposure susceptibility predictions. Three sources of wind data are compared: The North American Regional Reanalysis (NARR) database, meteorological aerodrome reports (METARs) from regional airports, and data from local MET weather stations. These data sources are used as inputs into a machine learning (ML) driven GIS Multi-Criteria Decision Analysis (GIS-MCDA) geospatial model to predict potential exposure to abandoned uranium mine sites in the Navajo Nation. Results indicate significant variations in results derived from different wind data sources. After validating the results from each source using the National Uranium Resource Evaluation (NURE) database in a geographically weighted regression (GWR), METARs data combined with the local MET weather station data showed the highest accuracy, with an average R2 of 0.74. We conclude that local direct measurement-based data (METARs and MET data) produce a more accurate prediction than the other sources evaluated in the study. This study has the potential to inform future data collection methods, leading to more accurate predictions and better-informed policy decisions surrounding environmental exposure susceptibility and risk assessment.

Chronic Community Exposure to Environmental Metal Mixtures Is Associated with Selected Cytokines in the Navajo Birth Cohort Study (NBCS).

Many tribal populations are characterized by health disparities, including higher rates of infection, metabolic syndrome, and cancer-all of which are mediated by the immune system. Members of the Navajo Nation have suffered chronic low-level exposure to metal mixtures from uranium mine wastes for decades. We suspect that such metal and metalloid exposures lead to adverse health effects via their modulation of immune system function. We examined the relationships between nine key metal and metalloid exposures (in blood and urine) with 11 circulating biomarkers (cytokines and CRP in serum) in 231 pregnant Navajo women participating in the Navajo Birth Cohort Study. Biomonitored levels of uranium and arsenic species were considerably higher in participants than NHANES averages. Each biomarker was associated with a unique set of exposures, and arsenic species were generally immunosuppressive (decreased cellular and humoral stimulating cytokines). Overall, our results suggest that environmental metal and metalloid exposures modulate immune status in pregnant Navajo women, which may impact long-term health outcomes in mothers and their children.

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.

Disparities in Risks of Inadequate and Excessive Intake of Micronutrients during Pregnancy.

BACKGROUND: Inadequate or excessive intake of micronutrients in pregnancy has potential to negatively impact maternal/offspring health outcomes. OBJECTIVE: The aim was to compare risks of inadequate or excessive micronutrient intake in diverse females with singleton pregnancies by strata of maternal age, race/ethnicity, education, and prepregnancy BMI. METHODS: Fifteen observational cohorts in the US Environmental influences on Child Health Outcomes (ECHO) Consortium assessed participant dietary intake with 24-h dietary recalls (n = 1910) or food-frequency questionnaires (n = 7891) from 1999-2019. We compared the distributions of usual intake of 19 micronutrients from food alone (15 cohorts; n = 9801) and food plus dietary supplements (10 cohorts with supplement data; n = 7082) to estimate the proportion with usual daily intakes below their age-specific daily Estimated Average Requirement (EAR), above their Adequate Intake (AI), and above their Tolerable Upper Intake Level (UL), overall and within sociodemographic and anthropometric subgroups. RESULTS: Risk of inadequate intake from food alone ranged from 0% to 87%, depending on the micronutrient and assessment methodology. When dietary supplements were included, some women were below the EAR for vitamin D (20-38%), vitamin E (17-22%), and magnesium (39-41%); some women were above the AI for vitamin K (63-75%), choline (7%), and potassium (37-53%); and some were above the UL for folic acid (32-51%), iron (39-40%), and zinc (19-20%). Highest risks for inadequate intakes were observed among participants with age 14-18 y (6 nutrients), non-White race or Hispanic ethnicity (10 nutrients), less than a high school education (9 nutrients), or obesity (9 nutrients). CONCLUSIONS: Improved diet quality is needed for most pregnant females. Even with dietary supplement use, >20% of participants were at risk of inadequate intake of ≥1 micronutrients, especially in some population subgroups. Pregnancy may be a window of opportunity to address disparities in micronutrient intake that could contribute to intergenerational health inequalities.

Mining and Environmental Health Disparities in Native American Communities.

PURPOSE OF REVIEW: More than a century of hard rock mining has left a legacy of >160,000 abandoned mines in the Western USA that are home to the majority of Native American lands. This article describes how abrogation of treaty rights, ineffective policies, lack of infrastructure, and a lack of research in Native communities converge to create chronic exposure, ill-defined risks, and tribal health concerns. RECENT FINDINGS: Recent results show that Native Americans living near abandoned uranium mines have an increased likelihood for kidney disease and hypertension, and an increased likelihood of developing multiple chronic diseases linked to their proximity to the mine waste and activities bringing them in contact with the waste. Biomonitoring confirms higher than expected exposure to uranium and associated metals in the waste in adults, neonates, and children in these communities. These sites will not be cleaned up for many generations making it critical to understand and prioritize exposure-toxicity relationships in Native populations to appropriately allocate limited resources to protect health. Recent initiatives, in partnership with Native communities, recognize these needs and support development of tribal research capacity to ensure that research respectful of tribal culture and policies can address concerns in the future. In addition, recognition of the risks posed by these abandoned sites should inform policy change to protect community health in the future.

A multifunctional androgen receptor screening assay using the high-throughput Hypercyt flow cytometry system.

The androgen receptor (AR) is a steroid hormone receptor which regulates transcription of androgen-sensitive genes and is responsible for the development and maintenance of male secondary sexual characteristics. Chemicals that interfere with AR activity may lead to pathological conditions in androgen-sensitive tissues. A variety of reporter systems have been developed, driven by androgen-sensitive promoters, which screen for chemicals that modulate androgenic activity. We have developed a flexible, high-throughput AR transcriptional activation assay, designated the Multifunctional Androgen Receptor Screening (MARS) assay, to facilitate the identification of novel modulators of AR transcriptional activity using flow cytometry. Androgen-independent human prostate cancer-derived PC3 cells were transiently cotransfected with an expression vector for the wild-type human AR and an androgen-sensitive promoter regulating the expression of destabilized enhanced GFP (dsEGFP). The transfected cells were stimulated with established androgenic and antiandrogenic compounds and assessed for increased or decreased dsEGFP expression. To screen for antagonists of AR transcription, the AR agonist R1881 was coadministered at submaximal concentrations with potential AR antagonists. The assay was formatted for high-throughput screening using the HyperCyt flow cytometry system. Agents with established androgenic and antiandrogenic activity were used for validation of the MARS assay. AR agonists were found to potently induce dsEGFP. Furthermore, AR agonists induced dsEGFP expression in a dose-dependent manner. Alternatively, AR antagonists blocked dsEGFP expression when coadministered with low-dose R1881, which also occurred in a dose-dependent manner. Modulators of AR transcriptional activity can be successfully identified by the MARS assay, utilizing a rapid, flexible, sensitive, and high-throughput format. Dose-response curves can be successfully generated for these compounds, allowing for an assessment of potency. Because of its simplicity and high-throughput compatibility, the MARS assay and HyperCyt system combined with flow cytometric analysis represents a valuable and novel addition to the current repertoire of AR transcriptional activation screening assays.