Fine particulate matter (PM2.5) exposure is associated with increased risk of adverse cardiovascular health outcomes. Prior research shows that PM2.5 is disproportionately concentrated in communities of low socioeconomic status and with higher proportions of underrepresented ethnic and racial groups. However, little is known about the levels and trends in PM2.5 in American Indian (AI) communities. Prior work has estimated the risk of CVD outcomes from exposure to total PM2.5 and PM2.5 constituents in white, Black, Asian, and Hispanic populations; however, AI populations have been historically excluded from many of these studies. While certain behavioral and environmental CVD risk factors have been extensively studied in AI populations, the CVD health impacts of air pollution have not been previously characterized. In Chapter 2, we aimed to compare PM2.5 concentrations in AI- vs. non-AI-populated counties over time (2000 – 2018) in the contiguous US. We used a multi-criteria approach to classify counties as AI- or non-AI-populated. We ran linear mixed-effects models to estimate the difference in county-wide annual PM2.5 concentrations from monitoring sites and well-validated prediction models (measured and modeled PM2.5, respectively) in AI- vs. non-AI-populated counties, adjusting for population density and median household income. We estimated whether differences in AI- vs. non-AI-populated counties varied over time using interaction terms with calendar year. On average, adjusted measured PM2.5 concentrations in AI-populated counties were 0.79 μg/m3 (95%CI: 0.33, 1.26) lower than in non-AI-populated counties. However, this association was not constant over time; while in 2000, adjusted concentrations in AI-populated counties were 1.83 μg/m3 (95%CI: 1.53, 2.13) lower, by 2018, they were 0.84 μg/m3 (95%CI: 0.53, 1.15) higher than in non-AI-populated counties. Over the study period, measured PM2.5 mean concentrations in AI-populated counties decreased by 2.49 vs. 5.18 μg/m3 in non-AI-populated counties. Results were similar for satellite-based, modeled PM2.5. This study highlights disparities in PM2.5 trends between AI- and non-AI-populated counties over time, underscoring the need to strengthen air pollution regulations in tribal territories and areas where AI populations live. In Chapter 3, we further interrogate what components of PM2.5 could be contributing to the trends in total PM2.5. We estimated that adjusted concentrations of all six PM2.5 components in AI-populated counties were significantly lower than in non-AI-populated counties. However, component-specific trends varied over time. Sulfate and ammonium levels were significantly lower in AI- vs. non-AI-populated counties in 2000 but higher after 2011. Nitrate levels were consistently lower in AI- counties, while black carbon, organic matter, and soil levels showed inconsistent differences in AI- vs. non-AI-populated counties. This study highlights how differences in time trends of certain components by AI-populated county type, namely sulfate and ammonium, are driving steeper declines in total PM2.5 in non-AI vs. AI-populated counties, providing potential directives for air pollution regulations of key emissions sources on tribal and AI-populated lands. In Chapter 4, we estimated the effects of long-term PM2.5 exposure on CVD incidence, CVD mortality, and all-cause mortality in the Strong Heart Study (SHS), a longitudinal cohort of American Indian adults enrolled from centers in Arizona, Oklahoma, and North Dakota and South Dakota. We followed 2,115 participants from 2000–2019. Adjusted hazard ratios (95%CI) per 1μg/m3 increase in PM2.5 with CVD incidence, CVD mortality, and all-cause mortality were 1.09 (0.91, 1.30), 1.11 (0.91, 1.36), and 1.10 (0.96, 1.25), respectively. Center-specific models identified positive associations between PM2.5 and incident CHD (2.24 (1.40, 3.56)) and CVD (1.55 (1.05, 2.31)) in Arizona, marginally positive association between PM2.5 and CVD mortality in Oklahoma (1.29 (0.99, 1.68)), and null associations in North Dakota and South Dakota. This study assesses PM2.5 exposure and cardiovascular health effects in American Indian communities—addressing a critical gap in the representation of evidence in air pollution regulation. Further research on underlying mechanisms driving the unique associations observed across regions is needed.

The purpose of this participatory action research study was to gain an awareness of the meanings of health for urban First Nations grandmothers, and how they promote it in their families and communities. Active participation of 7 urban First Nations grandmothers in the research process involved 4 group and 1 individual interview. Meanings of health included maintaining balance in all areas of life; physical, mental, emotional, and spiritual. Control imposed through the residential schools resulted in secrets kept, yet the survival and resiliency of the grandmothers were identified as part of being healthy. Personal health was linked with the health of their families and communities, and an awareness of living in two cultures vital in the intergenerational transmission of knowledge. Relationships with grandchildren were catalysts for change, and the grandmothers described working to “turn it around” throughout their challenges in health and life, as one strategy for health promotion. / ix, 146 leaves ; 29 cm

Societies that foster high quality social environments and integration produce healthier populations. The mechanisms underlying the protective effect of social integration appear to be through various forms of social support. In the Canadian Aboriginal context, few authors have explored the relationship between health and social support. This gap in understanding is significant because Aboriginal frameworks of health point to the salience of larger social structures (i.e., family), yet patterns of population health point to distinctly social causes of morbidity and mortality (e.g., violence, alcoholism). An interesting paradox emerges: patterns of Aboriginal health suggest that social support is not working to promote health. This dissertation explores this paradox through a mixed-methods approach to describe the value of social support for Aboriginal health, and to critically examine the social-structural processes and mechanisms through which social support influences Aboriginal health at the community level. / Principal components analyses of the 2001 Aboriginal Peoples Survey (APS) identified social support as a consistent dimension of Metis and Inuit health, and multivariable logistic regression modelling of the 2001 APS identified social support to be a significant determinant of thriving health among Indigenous men and women (e.g., those reporting their health as excellent/very good versus good/fair/poor). The results also indicate a distinct social gradient in thriving health status and social support among Aboriginal Canadians. / Narrative analyses of 26 interviews with Aboriginal Community Health Representatives point to two key explanations for the health-support paradox: (i) social support is not a widely accessible resource; and (ii) the negative health effects of social support can outweigh the positive ones. The formation of health behaviours and cultural norms - which underpin social supports - are inextricably tied to the poor material circumstances that characterize Canada's Aboriginal communities. The thesis concludes with a critical examination of the processes through which environmental dispossession has influenced the determinants of Aboriginal health, broadly speaking. Effects are most acute within the material and social environments of Aboriginal communities. More research attention should focus on identifying the pathways through which the physical, material and social environments interact to influence the health of Aboriginal Canadians.

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Cardiovascular disease remains the leading causing of death worldwide. American Indians experience an elevated prevelance of cardiovascular disease (CVD) and chronic metal exposures. Determining the impact of metal exposures on CVD can inform prevention and exposure reduction strategies. This dissertation will advance environmental monitoring and biological monitoring of lead, uranium, and selenium exposures using both established biomarkers and novel epigenetic biomarkers to determine the associations of metals with CVD, leveraging the Strong Heart Study (SHS), a prospective cohort of CVD and its risk factors among American Indian adults from tribes and communities in Arizona, Oklahoma, North Dakota, and South Dakota. In Chapter 1, we discuss lead, uranium, and selenium, sources of exposure, and relevance to cardiovascular disease. This includes an overview of metal toxicokinetics and how we can assess these contaminants in both established biomarkers, including blood and urine, as well as in epigenetic biomarkers. In Chapter 2, we estimated urinary uranium concentrations from data on uranium in water among Strong Heart Family Study participants. These estimates were derived from relationships between urinary uranium and water uranium assessed in Strong Heart Family Study (SHFS) participants (n=1,356). Predictions were made using generalized linear models and included demographic and clinical participant characteristics in addition to other metal contaminants measured in water and urine. The root mean square error (RMSE) of the prediction model was 1.01, and predicted urine uranium levels were comparable (median: 0.04 μg/g creatinine, 25th-75th: 0.02-0.08 μg/g creatinine) to urine uranium measured in the SHFS (0.04 μg/g creatinine, 0.02-0.07 μg/g creatinine). These findings emphasize the contribution of uranium in water to urine uranium (reflecting internal dose), and demonstrate the relevance of estimating metal contaminants in urine for the SHS to inform relationships with health effects. In Chapter 3, we evaluated whether urinary uranium concentrations were associated with measures of cardiac geometry and functioning among 1,332 American Indian youth and young adults from the SHFS. Transthoracic echocardiography and blood pressure was assessed at baseline (2001-2003) and a follow-up visit (2006-2009). We estimated mean differences in measures of cardiac geometry and functioning at baseline and follow-up using linear mixed effect models with random intercept and slope over time. In fully adjusted models, a log-doubling of urinary uranium was positively associated with left ventricular (LV) mass index (mean difference: 0.49 g/m2, 95% CI: 0.07-0.92 g/m2), left atrial systolic diameter (0.02 cm, 0.01-0.03 cm), and stroke volume (0.66 mL, 0.25-1.08 mL) at baseline. At follow-up, uranium was associated with increases in left atrial diameter (0.02 cm, 0.01-0.03 cm), pulse pressure (0.28 mmHg, 0.05-0.52 mmHg), and incident LV hypertrophy (OR: 1.25, 95% CI: 1.06, 1.48). These findings support the need to determine the potential long-term clinical and subclinical cardiovascular effects of chronic uranium exposure in the general population, and the need for future strategies to reduce exposure. In Chapter 4, we evaluated if blood lead was associated with CVD incidence and mortality in 1,818 adult American Indian participants. This study estimated the risk of incident CVD and CVD deaths in models adjusted for demographic, lifestyle, and cardiovascular risk factors. Blood lead levels in American Indian adults were associated with increased risk of CVD and coronary heart disease (CHD) incidence and mortality. The hazard ratio (HR) (95% CI) of mortality per change across the 80th-20th quantiles in blood lead was 1.15 (1.02-1.30) for CVD overall and 1.22 (1.08-1.37) for CHD. The corresponding HR was 1.11 (1.01-1.22) for incident CVD and 1.12 (1.00-1.25) for incident CHD. These findings contribute to the evidence of lead as a CVD risk factor at low levels and highlight the importance of further reducing lead exposure in communities across the United States, including American Indian communities. In Chapter 5, we leveraged novel epigenetic biomarkers of lead exposure to investigate their association with cardiovascular disease (CVD) incidence and mortality among 2,231 participants of the Strong Heart Study. Blood DNA methylation was measured using the Illumina MethylationEPIC BeadChip at baseline (1989-1991) and epigenetic biomarkers of lead levels in blood, patella, and tibia were estimated using previously developed biomarkers of DNA methylation at specific CpG sites. In adjusted models, the hazard ratio (HR) (95% CI) of CVD mortality per doubling increase in lead epigenetic biomarkers were 1.42 (1.07-1.87) for tibia lead, 1.22 (0.93-1.60) for patella lead, and 1.57 (1.16-2.11) for blood lead. The corresponding HRs for incident CVD were 0.99 (0.83-1.19), 1.07 (0.89-1.29), and 1.06 (0.87-1.30). The association between the tibia lead epigenetic biomarker and CVD mortality was modified by sex (interaction p-value: 0.014), with men at increased risk (HR: 1.42, 95% CI:1.17-1.72) compared to women (HR: 1.04, 95% CI:0.89-1.22). These findings support that epigenetic biomarkers of lead exposure may capture some of the disease risk associated with lead exposure. In Chapter 6, we investigated the association between urinary selenium levels and DNA methylation (DNAm) among 1,357 participants free of CVD and diabetes in the SHS. Selenium concentrations were measured in urine (collected in 1989-1991) using inductively coupled plasma mass spectrometry. DNAm in whole blood was measured cross-sectionally using the Illumina Methylation EPIC BeadChip (850K) Array. We used epigenome-wide robust linear regressions and elastic net to identify differentially methylated CpG sites associated with urinary selenium levels. Across 788,368 CpG sites, five differentially methylated positions (DMP) (cg00163554, cg18212762, cg25194720, cg11270656, cg00886293) were significantly associated with Se in linear regressions after accounting for multiple comparisons (false discovery rate p-value: 0.10). The top associated DMP (cg00163554) was annotated to the Disco Interacting Protein 2 Homolog C (DIP2C) gene, which relates to transcription factor binding. Future analyses should explore these relationships prospectively and investigate the potential role of differentially methylated sites with disease endpoints. In Chapter 7, we evaluated if declines in blood lead were associated with changes in systolic and diastolic blood pressure in adult American Indian participants from the SHFS (n=285). Using generalized estimating equations, a significant non-linear association between declines in blood lead and declines in systolic blood pressure was detected, with significant linear associations where blood lead decline was 1 µg/L or higher. These findings suggest the need to further study the cardiovascular impacts of reducing lead exposures and the importance of lead exposure prevention. In conclusion, we find that established biomarkers of metal exposure reflecting internal dose such as blood and urine, as well as epigenetic biomarkers of metals exposures, were associated with subclinical CVD and CVD incidence and mortality. Findings concerning blood lead emphasize that low levels of lead remain relevant for CVD, and declines in blood lead even when small (1.0-10.0 µg/L), were associated with reductions in systolic blood pressure. Novelly, we present that urinary uranium levels were adversely associated with measures of cardiac geometry and left ventricular functioning among American Indian adults, and that future attention must be paid to investigating associations with subclinical disease. We also find utility in using epigenetic biomarkers to capture CVD risk, as tibia and blood epigenetic biomarkers of lead, were associated with increased risk of CVD mortality, and urinary selenium was associated with distinct changes in DNAm. Although further work must further validate these epigenetic biomarkers in different populations, future work must continue to investigate these epigenetic biomarkers given their potential to capture CVD risk.