Grantee Research Project Results
Final Report: Center for Native American Environmental Health Equity Research
EPA Grant Number: R836157Center: Center for Native American Environmental Health Equity Research
Center Director: Lewis, Johnnye Lynn
Title: Center for Native American Environmental Health Equity Research
Investigators: Lewis, Johnnye Lynn , Gonzales, Melissa , Hudson, Laurie , Cerrato Corrales, Jose Manuel , MacKenzie, Debra Ann
Institution: University of New Mexico
EPA Project Officer: Callan, Richard
Project Period: July 1, 2015 through June 30, 2020 (Extended to June 30, 2021)
Project Amount: $1,500,000
RFA: NIH/EPA Centers of Excellence on Environmental Health Disparities Research (2015) RFA Text | Recipients Lists
Research Category: Human Health
Objective:
Mining in the United States has left a legacy of mine waste sites that may contain a mix of toxic metals including uranium, gold, silver, copper and lead, as well as arsenic, mercury, cadmium, and manganese. Disparities in exposure to these contaminants in tribal communities are compounded by a reliance on subsistence lifestyles and land and water use patterns. The Center responds directly to concerns of the community that chronic exposure to metal and metalloid mixtures contribute to negative health outcomes.
Experimental studies under controlled metal exposure conditions demonstrated distinct differences in response to specific metals based on cell type or tissue of origin. Uranium was toxic to normal human epidermal cells and kidney cells, but not to cells of the immune system. The ability of a specific metal (uranium, arsenic, manganese, vanadium, cobalt, cadmium) to cause toxicity, DNA damage and inhibition of DNA repair corresponded to the ability of a metal to promote oxidative stress in a particular cell type. Understanding oxidative stress as a possible underlying mechanism could help predict which mixed metals exposures may be more immunotoxic or immuno-disruptive. Given the substantial cell type difference in response, delineating the actions of uranium across different cell targets will be important for understanding the potential health effects of uranium exposures. Importantly, DNA damage, DNA repair and biomarkers of oxidative stress differed across the three tribes with different patterns of metal exposures. Because oxidative stress is an underlying factor in numerous chronic diseases, outcomes based on specific mixed metals exposure could help identify and prioritize remediation strategies for certain metal mixtures to advance Native environmental health equity.
In addition, we have examined whether environmental exposure to mixed metal contaminants lead to dysregulation of normal immune responses. Immune dysregulation can lead to inflammation and/or autoimmunity as well as increased susceptibility to infection and/or cancer. We demonstrated that metals exposures are associated with increases in biomarkers of autoimmunity, inflammation and alterations in immune cell phenotypes. Understanding how low-level exposures to environmental metals contribute to development of chronic diseases including metabolic disorders, cardiovascular disease, autoimmune disorders and cancers will help identify remediation and mitigation strategies with the goals to improve overall health within impacted tribal communities.
Research Project 1: Metals and metal mixtures in DNA damage and repair
The Native Environmental Health Equity Center seeks to address environmental health disparities and health concerns of three Native American communities (Navajo Nation, Cheyenne River Sioux Tribe and Crow Reservation) arising from exposure to mine waste metal mixtures. The communities are exposed to distinct metal mixtures with overlap in certain metals of primary concern: uranium (U), arsenic (As), manganese (Mn) and mercury (Hg). Each of the four metals identified by the tribal community partners share likely mechanisms of action such as generation of oxidative stress and disruption of zinc finger protein function. These shared mechanisms are predicted to amplify the toxicity of combined exposures compared to single metal exposure. The research in Research Project 1 is significant by providing important information to improve understanding of environmentally driven health disparities due to toxic metals exposures while being responsive to the concerns of the affected communities. Overall, the project represents transdisciplinary and translational research to advance understanding, mitigation and prevention of environmentally driven health disparities.
Specific Aim 1. Investigate the impact of specific metals and metal mixtures in human populations using biomarkers of toxicity including measures of oxidative stress, DNA damage and PARP activity. We will test a) DNA damage and repair capacity in peripheral blood mononuclear cells (PBMCs), b) target zinc finger protein PARP-1 activity in PBMCs, and c) measure biomarkers of oxidative stress and oxidative damage in PBMCs and urine from samples collected in the partner communities. The findings will be analyzed with respect to biomonitoring results conducted through the Environmental Monitoring and Interpretation Core. These studies will give us insights into the impact of metals and metal mixtures in the Native communities.
Specific Aim 2. Establish mechanism of specific metal disruption of zinc finger target proteins and potential metal interactions in generation of oxidative stress, DNA damage and PARP activity. We will use controlled in vitro and cell based assays to test a) metal binding and zinc displacement from zinc finger peptides using analytical techniques, b) metal binding, zinc displacement and PARP-1 function in protein isolated from cells exposed to concentrations of metals spanning the maximum contaminant level (MCL) values and measured exceedance levels found in the communities, c) impact of metals and metal combinations of oxidative stress and oxidative damage, d) effects of metals and metal combinations on cytotoxicity, DNA damage and DNA repair and e) determine whether zinc is protective against the effects of metals. These studies will provide mechanistic insights on the actions of metals and metal mixtures at concentrations relevant to the communities.
Results were disseminated to the communities at the Center Annual Meeting in October 2016 in Tachee, AZ, and in more detail to center members and the EAC the following day in Chinle, AZ.
A summary report that contained the comparative data for DNA damage and PARP activity was prepared and presented to the Crow community on October 1, 2019. Navajo specific DNA damage and PARP activity data was presented at the Navajo Nation Human Research Review Board Conference, October 16-17, 2019.
Research Project 2: Development of biomarkers of autoimmunity in three tribal communities exposed to mixed metal contaminants
Mining in the United States has left a legacy of >600,000 mine waste sites, many in the western US. These wastes may contain geologic mixtures of primary mining minerals: uranium (U), gold, silver, copper and lead, as well as those remaining after processing, including but not limited to, arsenic, mercury, cadmium, and manganese. Mining waste sites are often located on or contiguous to the watersheds of tribal lands (Lewis, Hoover and MacKenzie, 2019). Disparities in exposure are compounded by the fact that tribal populations are more likely to rely on subsistence lifestyles, with land and water use patterns leading to greater exposures to local contaminants. The objective of this project was to assess the relationship of metal exposures (determined through biomonitoring of blood and urine samples) with immunologic outcomes in individuals from Tribal communities who live in proximity to legacy mine waste. This objective responds directly to concerns of the community that chronic exposure to metal and metalloid mixtures contributes to development of disease. Our overarching hypothesis was that an increased body burden of metals due to environmental exposure to mixed metal contaminants within the Tribal communities can result in immune dysregulation and autoimmune responses, subsequently leading to disease development. For this project, we partnered with three Native American communities to address commonalities and differences through identification of unique but overlapping exposures with the assessed outcomes. We combined population studies with controlled experimental models to provide a better understanding of the mechanisms by which metal exposures alter immune function. This level of understanding is a crucial first step toward developing both risk reduction approaches and potential therapeutic strategies. Our research team, which included expertise in epidemiology, immunology, toxicology, mathematics and modeling, and environmental assessment addressed the following specific aims.
Aim 1: Determine whether exposure to metals or metal mixtures (measured through biomonitoring) increases the prevalence of anti-nuclear antibodies (ANA) in individuals from our three affected Tribal communities.
Aim 2: Determine whether exposures to metals or metals mixtures are associated with changes in cytokine profiles or T and B cell phenotypes in individuals from our three Tribal populations.
Aim 3: Determine the ability of metal mixtures relevant to our three participating Tribal communities to exacerbate or to induce autoimmune disease and immune dysregulation via a drinking water exposure in animal models.
Summary/Accomplishments (Outputs/Outcomes):
Research Project 1: Metals and metal mixtures in DNA damage and repair
Aim 1. We tested and compared technical approaches to identify the most robust methods to detect the impact of metals. PARP activity in participant PBMCs (as measured by its product poly(ADP) ribose (PAR)) was measured by flow cytometry, immuno-histochemical detection in cytospin cells and Elisa of lysates we find that the Elisa method provides the best dynamic range, sensitivity and reproducibility. We adopted the CometChip technology (Trevigen) for the comet assays. This is a high-throughput 96 well assay, which gives greater reproducibility, more single comets and increases the “n” for each participant in terms of cell number that can be reliably analyzed. We tested oxidative stress as measured by urinary F2 –isoprostanes by mass spectrometry in a subset of the Navajo participants (results discussed below). Although this is viewed as the “gold standard” for oxidative stress measurements, the costs exceed the project budgtet constraints and measurement of urinary 8-OHdG was used for subsequent analyses.
We worked with the Biostatistics Team to test statistical approaches most appropriate for Aim 1. Working with the Biostatistics Team we completed a study to assess potential relationships between exposure to uranium and arsenic and evidence for increased oxidative stress as measured by urinary F2 -isoprostanes in pregnant women enrolled in the Navajo Birth Cohort Study. Urinary arsenic and uranium, serum zinc and urinary F2 -isoprostanes were measured for each study participant at enrollment. Multivariable regression analysis indicated a significant association between arsenic exposure and the lipid peroxidation product 8-iso-prostaglandin F2α, controlling for zinc and trimester. No associations were detected with uranium despite evidence that median urinary uranium levels in the Navajo Birth Cohort samples were 2.3 times the median reported for women in the National Health and Nutrition Examination Survey (2011-12). Zinc was not found to have any causal mediation of the effects of the other metals on oxidative stress. The current work is consistent with other studies that have detected a relationship between arsenic and elevated oxidative stress. In contrast to arsenic, uranium did not appear to increase oxidative stress response in this study population.
Direct comparison of the prostaglandin ratio versus 8-iso-PGF2α alone as biomarkers of oxidative stress reveals the utility of the prostaglandin ratio for studies of populations with known underlying factors, such as pregnancy, that may affect oxidative stress measurements. (Dashner-Titus et al, Free Radic Biol Med. 2018 Apr 30;124:484-492.) Based on experiences using this environmental data set, the statistical team identified and compared methodologies. Utilizing two simulated data sets and applying the method to the real-life Navajo Birth Cohort Study (NBCS) dataset, we demonstrated good performance of a proposed two-step approach. Our simulation study indicated its effective variable dimension reduction and accurate identification of a parsimonious model compared to other methods: single-step adaptive lasso or two-step Classification and regression trees (CART) followed by adaptive lasso method. The two-step approach provides a robust way of analyzing the effects of chemical mixture exposures on health outcomes by combining the strengths of variable selection and adaptive shrinkage strategies. (Luo L et al, Environ Health. 2019 May 9;18(1):46).
We completed DNA damage, PARP activity measurements, 8-OHdG and urine metal biomonitoring by ICP-MS in Cheyenne River Sioux Tribe (CRST) participants, Navajo participants (50 men and 50 women for each community) and available Crow Tribe participant samples. Values obtained for for DNA damage, PARP activity and urinary 8-OHdG in CRST participant samples were significantly less than Navajo participant samples. DNA damage and repair values were similar for CRST and Crow participant samples despite a significant difference in oxidative stress as measured by urinary 8-OHdG. Significant differences in DNA damage between male and female participants were detected in the Navajo, but not the CRST cohorts. This may be due to pregnant status of the NBCS female population and will warrant further investigation. Final statistical analysis to establish potential relationships between these outcomes measures, urinary metals and serum zinc is pending and will be conducted in collaboration with the statistical team. We have prepared a “report back” document for metals levels for individual participants and aggregate data. These documents are in the final stages of review before we work with the CEC and RTC to properly communicate findings back to the communities.
Aim 2. The cell-based experimental studies demonstrated distinct differences in response to specific metals based on cell type. The initial focus was on uranium based on community concerns with arsenic as a well-studied control comparator metal. Low concentrations of uranium (as uranyl acetate; < 30 μM) were not cytotoxic to most human cells tested (Jurkat, THP-1, primary T-lymphocytes, HEK293, primary human airway epithelial cells) but were cytotoxic for primary human renal tubule epithelial cells and primary keratinocytes. In keratinocytes, concentrations of uranyl acetate in the low micromolar range inhibited the zinc finger DNA repair protein poly(ADP-ribose) polymerase (PARP)-1 and caused zinc loss from PARP-1 protein. Uranyl acetate exposure also stimulated an oxidative stress response and zinc loss from the zinc finger DNA repair proteins Xeroderma Pigmentosum, Complementation Group A (XPA) and aprataxin (APTX). In keeping with the observed inhibition of zinc finger function of DNA repair proteins, exposure to uranyl acetate enhanced retention of induced DNA damage. Co-incubation of uranyl acetate with zinc largely overcame the impact of uranium on PARP-1 activity and DNA damage. The findings are comparable to those reported in keratinocytes for arsenic and the work on uranium was published (Cooper et al, Toxicology and Applied Pharmacology 2016).
In contrast, uranium did not promote an oxidative stress response in THP-1 (monocytic line) or Jurkat (T-cell) lines and distinct differences in cell sensitivity to metal cytotoxicity were observed. Concentration-dependent cytotoxicity occurred following exposure to arsenite, whereas cells remained viable after 48-hour treatment with up to 100 µM uranyl acetate despite uptake of uranium into cells. Proposed mechanisms of metal toxicity include generation of oxidative stress. Arsenite stimulated an oxidative stress response as detected by Nrf-2 nuclear accumulation and induction of the oxidative stress response genes HMOX-1 and NQO1. No evidence of oxidative stress was observed upon exposure with up to 30 µM uranyl acetate. Cellular oxidative stress can promote DNA damage and arsenite, but not uranium, stimulated DNA damage as measured by pH2AX. Arsenic enhanced the cytotoxic response to etoposide suggesting an inhibition of DNA repair, yet uranium did not modify the etoposide effect. Similarly, uranium did not inhibit Poly(ADP-Ribose) polymerase-1 activity. Because uranium reportedly stimulates oxidative stress, DNA damage and cytotoxicity in adherent epithelial cells, the current study suggests distinct cell type differences in response to uranium that may relate to generation of oxidative stress and associated downstream consequences. Delineating the actions of uranium across different cell targets will be important for understanding the potential health effects of uranium exposures.
We next tested manganese (Mn) because of its prevalence in the communities. The secondary drinking water standard for Mn is 50 ppb (~1 uM) and 100-fold greater levels have been detected in unregulated waters on Navajo lands. Mn level were readily detected in blood and urine within the Navajo Birth Cohort Study participants. Cell studies indicated that Mn alone is not cytotoxic to immune cells up to 100 uM, did not cause DNA damage or PARP inhibition, and did not promote an oxidative stress response. No additional change in toxicity was detected with metals in combination (As+U, As+Mn, U+Mn). Manganese to date has not displayed any activities pertinent to the research question or caused additive or synergistic interactions with arsenic or uranium. We continued testing of additional environmental metals (arsenic, uranium, cadmium, cobalt, vanadium, and manganese) that were found to be elevated in the blood and urine of NBCS participants singly and in combination. We detect varying cytotoxic effects of each metal; IC50 values were calculated after 48 hours with relative toxicity of As>V>Cd>Co>>U. The three most cytotoxic metals generated oxidative stress response as determined by DHE detection of reactive oxygen species and increased expression of the oxidative stress response gene HMOX1. The ROS generation by As, V and Cd was ablated by the presence of vitamin C as an antioxidant. We then tested metal combinations for interactions that would affect cell viability. Two-way ANOVAs were conducted to examine the effect of As with another metal on viability. Of the metals tested V and Cd were the only metal found to have a statistically significant interaction with As at 24 hours leading to increased cytotoxicity. At a 48h time point V, Cd, Co and Mn enhanced the cytotoxicity of 3 As when cells were treated in combination. The only metal that did not affect As toxicity was uranium. Selective interactions between metals were also observed for oxidative stress response. As, Cd and V all induced a robust induction of HMOX-1. The combination of Cd+As or Cd+V greatly enhanced HMOX-1 induction above values obtained with either metal alone, but there was no significant increase when As and V were combined. Because oxidative stress is an underlying factor in numerous chronic diseases, outcomes based on specific mixed metals exposure could help identify and prioritize remediation strategies for certain metal mixtures to advance Native environmental health equity. The work is based on understanding a possible underlying mechanism (ROS generation) that could help predict which mixed metals exposures may be more immunotoxic or immuno-disruptive.
Involvement of the Statistical Team: Dr. Li Luo is leading the analyses on the participant samples from Aim 1 and Mr. Daniel Beene manages all data, ensures the data consistency and prepares the metadata for the FAIR platform used by the team. Dr. Li Luo conducted analysis of the RNAseq data for the manuscript under review comparing arsenic, uranium or the combined metals on gene expression during T cell activation and Mr. Beene provided guidance for preparing and uploading the RNAseq dataset to repositories as required by NIH.
Research Project 2: Development of biomarkers of autoimmunity in three tribal communities exposed to mixed metal contaminants
Aim 1: Determine whether exposure to metals or metal mixtures (measured through biomonitoring) increases the prevalence of anti-nuclear antibodies (ANA) in individuals from our three affected Tribal communities. Detection of anti-nuclear antibodies can serve as a biomarker of autoimmune disease, often appearing decades before disease diagnosis. Overall, we have detected ANA at a prevalence higher than NHANES national averages. The specificity profiles against denatured DNA and other nuclear components (histone, native DNA, chromatin) in samples from our partnering tribal communities are consistent with those associated with environmentally induced autoimmune responses, illustrating the the need to include these important autoantigens frequently associated with environmental damage in our analysis that are not represented by the most common autoantigen panels.
Analysis of sera from 145 male and 141 female study participants from Navajo Nation, enrolled in the Navajo Birth Cohort Study (NBCS), which includes consent for immunologic evaluation, showed specificity for antibodies to denatured DNA at ~ 11%, twice the prevalence published for healthy adults. Although overall ANA positivity was around 11.3% among younger generation of Navajo men, antibodies to chromatin and native DNA, considered indicators of idiopathic autoimmune disease, were detected at low levels only in Navajo men, not in women. Our findings are notable in that development of autoantibodies is associated with aging and generally higher in women than in men. In the Navajo cohort, the 11.3% was similar for men and women, and the average age was 27, much younger than would be expected for detection of autoantibodies in the general population. We also observed significant positive associations between urine uranium levels and the presence of anti-nuclear antibodies (ANA) in Navajo male participants. This observation, combined with the association of ANA with uranium in males is suggestive that uranium exposure increases ANA in this population. Interestingly, preliminary data show that when mercury was included in the statistical modeling with uranium and arsenic in the analysis of Navajo Nation samples, there was increased risk for ANA in this population illustrating the importance of considering mixed metal exposures in the analysis.
Approximately 30% of participants (n=225; mean age 41 +/- 13 years) from our Cheyenne River Sioux cohort were positive for ANA, compared to the reported population positivity rate of 13.2% nationally. Autoantibodies with specificity for denatured DNA was detected at an 8-times higher rate than expected in healthy populations based on literature reports (4-5%). Other autoantibodies such as chromatin-specific and native DNA-specific autoantibodies were also increased (6 and 5 % detectable vs 0% expected in healthy people). Autoantibodies specific for thyroglobulin and thyroid peroxidase [TPO], were detected in 51.5% of CRST participants whereas in Europeans, 44% positivity for thyroid autoimmunity is common, again showing a higher than expected prevalence in the CRST cohort. As expected, age was a strong predictor of these autoantibodies. Urinary uranium levels were also found to be strong predictor of denatured DNA-specific autoantibodies in this cohort, a finding very similar to that we have found among older Navajo community members living in close proximity to abandoned uranium mine and mill sites in the Eastern Agency of Navajo Nation (Erdei et al., 2019). In CRST Tribal members, the detection of anti-denatured DNA autoantibody was associated with increased concentrations of serum Pb, while urinary As (III) and urinary MMA were associated with decreased anti-denatured DNA autoantibody detection. Anti-histone autoantibody response was predicted by several metal exposures. Positive estimates were found with urinary uranium, and serum Sb, Mn, and Mo exposures. These metals stayed in the final model, but were not significant predictors even though as univariate predictors they were all significant. Furthermore, in the same complex multivariable model, negative β estimates were obtained with serum Ba (p= 0.037), while serum Pb, Cd, Sn, Cu and Zn levels contributed to the model, but were not statistically significant predictors. Anti-thyroid-peroxidase specific autoimmune responses among CRST volunteers were positively associated with serum Sb concentrations (p- value was not significant) and negative estimates were obtained in the same model by serum Ba, and urinary As(V) concentration (p-values were non-significant).
In our Crow cohort, 41 sera samples were tested for the same 6 antigens (denatured DNA, native DNA, histone, chromatin, thyroglobulin and thyroid peroxidase) in relation to metals exposures. Overall, the age distribution of participants was similar to CRST participants, *mean age 47 years), but lower autoimmune biomarker positivity rates were found, and no associations with age. Similar to CRST, however, female Crow participants showed a higher prevalence of both thyroid-specific autoantibodies. Urinary metals in Crow participants were generally low as well. Among Crow Nation sera, multivariable modeling showed that urinary Cs (p= 0.033) and serum copper (p-value ns) concentrations were negative predictors of anti-denatured DNA autoantibody detection. In the case of anti-native DNA levels, serum antimony (Sb) concentrations were found to be significant negative predictors (p= 0.026) while serum Sn and a toxic arsenic compound, urinary As (V) were both non-significant negative predictors. Anti-histone responses were found to be also negatively predicted by metal biomonitoring concentrations in a multivariable model; significantly by serum antimony (Sb) concentrations (p= 0.0021) and almost significantly by serum Sn concentrations (p= 0.058), while serum Ag concentrations were found to be negative predictor, but not statistically significant. It is also important to call attention to that even low level of As (V), was associated with serum specific autoantibody biomarkers.
The observed negative associations between specific autoantibody detection and metals biomonitoring concentrations are worth examining further as negative immunomodulation could be an indicator of complex immune suppression or immune dysregulation and suggest the need to establish prospective follow-up studies to clearly demarcate the threshold of immune-suppression and characterize in details the nature of the mixture interactions on the human autoimmune biomarker evaluation. Importantly, our data demonstrates that metals exposures are associated with changes in biomarkers of autoimmunity and may reflect ongoing immunologic alterations resulting from chronic lifetime exposure. While the NBCS samples had less overall detection of ANA, the participants were also significantly younger, making the finding of associations of autoantibodies with urine uranium concentrations in male participants concerning.
Aim 2: Determine whether exposures to metals or metals mixtures are associated with changes in cytokine profiles or T and B cell phenotypes in individuals from our three Tribal populations. Immunologic cytokines can serve as biomarkers of systemic inflammation and/or immune dysregulation. For this project we used a multiplex platform to analyze a panel of cytokines representing pro-inflammatory, anti-inflammatory and immune-modulatory cytokines and examined the relationship between cytokine expression and metals concentrations from samples taken at the same time point. In the Navajo Nation participants, we observed that while uranium was negatively related to inflammatory cytokines IL-12 and IFNg, we observed a strong and positive relationship with the hypersensitivity cytokine IL-17. This is consistent with findings of increased biomarkers of autoimmunity in Navajo participants associated with increased concentrations of urine uranium at the time of sampling. Higher levels of arsenic species corresponded with lower lymphocyte development cytokine IL-7, which is consistent with findings of decreases in total numbers of T cells in Navajo participants with higher concentrations of urine uranium at the time of sampling. Higher levels of arsenic were also associated with lower levels of cytokines involved in hypersensitivity and inflammation, including IL-17, IL-29, and CRP. Relationships of arsenic with IL-6 and IFNa depended on the specific species measured, reiterating the importance of measuring more than total arsenic in these samples. IL-6 was positively related to total arsenic, as was IFNa with DMA, however both IL-6 and IFNa were negatively related to As(III).
To address the impact of mixed-metal exposures, because many participants had multiple metals detected in their samples, we used a Bayesian clustering technique to assign study participants into groups based on their metals exposure profiles. Through this method, participants “clustered” into 6 groups based on whether their metals levels were in the first through 4th quartile for that metal. About ¼ of study participants were in the lowest quartile (group 1) and about the same proportion were in the highest exposure cluster (group 6). Strikingly, participants who fell into the three highest exposure clusters have elevated circulating levels of the inflammatory cytokine IFNγ. To investigate this further, Dr. Jennifer Ong conducted a BPR clustering analysis as part of her PhD dissertation work, using metals as predictors and cytokines as outcomes showed significantly higher INFγ levels (p = .005) in clusters with higher exposures, with all metals supporting the clustering having a mean in the third or fourth quantile, most notably As(III), As(V), DMA, and MMA. These data suggest that metals and metalloid exposure contribute to establishment of a chronic inflammatory process. Chronic inflammation is associated with cardiovascular disease, cancer, diabetes, chronic kidney disease, and other disorders known to contribute to health disparities in tribal communities.
Similarly to cytokine profiles, alterations in lymphocyte populations can also serve as biomarkers of immune dysregulation. We used flow cytometry to assess percentages of different lymphocyte populations (based on total immune cells in the sample measured by CD45 expression). Lymphocyte phenotyping for CRST samples (N=212) revealed that while increased natural killer cell percentages were significantly predicted by age, both female gender and total urinary arsenic exposures were significant predictors of decreased NK cell percentages. This was especially shown for arsenic V and DMA in urine. Increased percentages of HDLA DR activated T cells were also predicted significantly by increased urinary mercury levels, while urinary cadmium, and uranium stayed in the model but were not strong significant predictor factors. This is consistent with findings with samples from Navajo Nation participants (N= 250) where we observed decreases in total number of T cells and increases in NK cells with increased arsenic concentrations. Paradoxically, an increase in the total number of T cells and a decrease in NK cells was observed in participants with increased uranium concentration. We are continuing to investigate the metals induced alterations in lymphocyte phenotype (especially on NK cells) using experimental and animal models.
Aim 3: Determine the ability of metal mixtures relevant to our three participating Tribal communities to exacerbate or to induce autoimmune disease and immune dysregulation via a drinking water exposure in animal models. Combining population studies with controlled experimental models provided a better understanding of the mechanisms by which metal exposures alter immune function. A “lifetime” exposure model in mice was used to address immunologic alterations resulting from low-dose, chronic exposure to mixed metals in drinking water which represent the primary contaminants of concern on the Sioux, Navajo and Crow Reservations. To model “lifetime” exposure, beginning in utero, adult female C57BL/6N mice were exposed to drinking water (control or As+U+Mn or U+Mn water) for 7 days and then paired with male C3H/HeJ mice. Offspring continued to be exposed and were analyzed at 12 weeks. The most remarkable findings include significant changes observed in maturation and activation of T and/or B lymphocytic populations related to mixed metal exposure. The change in these populations could reflect a metals-induced immune dysregulation phenotype similar to that observed in our human population studies and as such warrant further investigation to better understand the impact of these changes on immune function. It will also be important to determine the role of mixed metal exposures and the mechanism by which this exposure alters immune responses.
Journal Articles: 13 Displayed | Download in RIS Format
Other center views: | All 89 publications | 13 publications in selected types | All 13 journal articles |
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Dasher-Titus EJ, Hoover J, Luo L, Lee J-H, Du R, Liu KJ, Traber MG, Ho E, Lewis J, Hudson LG. Metal exposure and oxidative stress markers in pregnant Navajo Birth Cohort Study participants. Free Radical Biology and Medicine 2018;124:484-492. |
R836157 (2018) R836157 (2019) |
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Doyle JT, Kindness L, Realbird J, Eggers MJ, Camper AK. Challenges and opportunities for tribal waters:addressing disparities in safe public drinking water on the Crow Reservation in Montana, USA. International Journal of Environmental Research and Public Health 2018;15(4):567. |
R836157 (2018) R836157 (2019) R835594 (2018) R835594 (Final) |
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Eggers MJ, Doyle JT, Lefthand MJ, Young SL, Moore-Nall AL, Kindness L, Other Medicine R, Ford TE, Dietrich E, Parker AE, Hoover JH, Camper AK. Community engaged cumulative risk assessment of exposure to inorganic well water contaminants, Crow Reservation, Montana. International Journal of Environmental Research and Public Health 2018;15(1):76. |
R836157 (2019) R835594 (2017) R835594 (2018) R835594 (Final) |
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Eggers MJ, Doyle JT, Lefthand MJ, Young SL, Moore-Nall AL, Kindness L, Other Medicine R, Ford TE, Dietrich E, Parker AE, Hoover JH, Camper AK. Community engaged cumulative risk assessment of exposure to inorganic well water contaminants, Crow Reservation, Montana. International Journal of Environmental Research and Public Health 2018;15(1):76 (34 pp.). |
R836157 (2018) |
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Girlamo C, Lin Y, Hoover J, Beene D, Woldeyohannes T, Liu Z, Campen M, MacKenzie D, Lewis J. Meteorological data source comparison-a case study in geospatial modeling of potential environmental exposure to abandoned uranium mine sites in the Navajo Nation. ENVIRONMENTAL MONITORING AND ASSESSMENT 2023;195(7):834 |
R836157 (2020) |
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Gonzales M, King E, Bobelu J, Ghahate DM, Madrid T, Lesansee S, Shah V. Perspectives on biological monitoring in environmental health research: a focus group study in a Native American community. International Journal of Environmental Research and Public Health 2018;15(6):1129 (8 pp.). |
R836157 (2018) R836157 (2019) |
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Harmon ME, Lewis J, Miller C, Hoover J, Ali AS, Shuey C, Cajero M, Lucas S, Zychowski K, Pacheco B, Erdei E, Ramone S, Nez T, Gonzales M, Campen MJ. Residential proximity to abandoned uranium mines and serum inflammatory potential in chronically exposed Navajo communities. Journal of Exposure Science & Environmental Epidemiology 2017;27(4):365-371. |
R836157 (2018) R836157 (2019) |
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Hoover JH, Coker E, Barney Y, Shuey C, Lewis J. Spatial clustering of metal and metalloid mixtures in unregulated water sources on the Navajo Nation – Arizona, New Mexico, and Utah, USA. Science of The Total Environment 2018;633:1667-1678. |
R836157 (2018) R836157 (2019) |
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Hoover J, Gonzales M, Shuey C, Barney Y, Lewis J. Elevated arsenic and uranium concentrations in unregulated water sources on the Navajo Nation, USA. Exposure and Health 2017;9(2):113-124. |
R836157 (2016) R836157 (2017) R836157 (2019) |
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Hoover J, Coker E, Erdei E, Luo L, MacKenzie D, Lewis J. Preterm Birth and Metal Mixture Exposure among Pregnant Women from the Navajo Birth Cohort Study. ENVIRONMENTAL HEALTH PERSPECTIVES 2023;131(12). |
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Lewis J, Hoover J, MacKenzie D. Mining and environmental health disparities in Native American communities. Current Environmental Health Reports 2017;4(2):130-141. |
R836157 (2017) R836157 (2019) |
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Rodriguez-Freire L, Avasarala S, Ali AS, Agnew D, Hoover JH, Artyushkova K, Latta DE, Peterson EJ, Lewis J, Crossey LJ, Brearley AJ, Cerrato JM. Post Gold King Mine spill investigation of metal stability in water and sediments of the Animas River watershed. Environmental Science & Technology 2016;50(21):11539-11548. |
R836157 (2016) R836157 (2017) R836157 (2019) |
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Saup CM, Williams KH, Rodríguez-Freire L, Cerrato JM, Johnston MD, Wilkins MJ. Anoxia stimulates microbially catalyzed metal release from Animas River sediments. Environmental Science: Processes & Impacts 2017;19(4):578-585. |
R836157 (2017) R836157 (2019) |
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Supplemental Keywords:
metals, DNA damage, DNA repair, oxidative stress, arsenic, uranium, manganese, vanadium, cobalt, cadmium, ANA, Immune activity, Native AmericanRelevant Websites:
The University of New Mexico Center for Native Environmental Health Equity Research Exit
The University of New Mexico Center for Native Environmental Health Equity Research Publications Exit
Progress and Final Reports:
Original Abstract Subprojects under this Center: (EPA does not fund or establish subprojects; EPA awards and manages the overall grant for this center).
R836157C001 Metals and metal mixtures in DNA damage and repair
R836157C002 Development of biomarkers of autoimmunity in 3 tribal communities exposed to mixed metal contaminants
The perspectives, information and conclusions conveyed in research project abstracts, progress reports, final reports, journal abstracts and journal publications convey the viewpoints of the principal investigator and may not represent the views and policies of ORD and EPA. Conclusions drawn by the principal investigators have not been reviewed by the Agency.
Project Research Results
- 2020 Progress Report
- 2019 Progress Report
- 2018 Progress Report
- 2017 Progress Report
- 2016 Progress Report
- Original Abstract
13 journal articles for this center