Burning questions: the effect of wildfire and non-willdfire PM2.5 exposure on cancer mortality now and into the future

A surge in climate-influenced wildfires has led to increased exposure to particulate matter ≤2.5 μm (PM2.5) from wildfire smoke. California, in particular, has seen a 172% increase in acres burned over the last quarter-century due to anthropogenic causes. This project seeks to bridge the knowledge gap on the direct effects of wildfire PM2.5 on cancer patients. Existing research indicates that ambient PM2.5 exposure is associated with heightened cancer mortality. However, the carcinogenic properties of smoke particles suggest that wildfire PM2.5 might be even more lethal. The scarcity of studies focusing on the relationship between wildfire smoke and cancer mortality, especially in the context of climate change adaptation, underscores the importance of this research. This pilot project proposes a comprehensive approach to study the impact of wildfire smoke on cancer mortality in California. Using open-source exposure data, the study will differentiate between the short- and long-term effects of PM2.5 from wildfire and non-wildfire sources (Aim 1a). This research aims to enhance our understanding of how wildfire smoke influences cancer mortality and to refine exposure assessment methodologies by considering clinically relevant exposure definitions that account for the fluctuating nature of wildfire exposure (Aim 1b). Furthermore, this project will evaluate the potential benefits of the California Wildfire Task Force's 2022 Strategic Plan, which seeks to amplify the use of "beneficial fire" to mitigate wildfire risks (Aim 2). By combining existing wildfire models under climate change with data from the study, the research will assess the potential impact of these strategies. This study will generate action-oriented knowledge on the mortality effects of wildfires that may guide climate change adaptation and health policy.

Understanding the relationship between the gut microbie, air pollution and diabetes risk

Type 2 diabetes (T2D) is a global public health burden. It is now recognized that the gut microbiome has an important role in T2D pathogenesis. There is also growing evidence that environmental exposures such as air pollution increases the risk of diabetes. Although several studies in China have investigated the relationship between air pollution exposures (from 3 to 5 days up to 2 years) and the gut microbiome, only two small studies of US overweight/obese adolescents and young adults have been conducted. Thus, little is known about the associations between air pollution and the gut microbiome among older US adults, and whether there are differences in associations by race, ethnicity, sex and between short- and long-term exposures. This proposal will leverage high quality epidemiologic resources of the Multiethnic Cohort (MEC) study, a well-established long-standing cohort, using existing gut microbiome, and air pollution data, in conjunction with diabetes surveillance over 20+ years of follow-up. To address gaps in previous studies, we propose 2 aims: In Aim 1, we will investigate the associations of air pollutants with the relative abundance and diversity of gut microbial communities among a multiethnic sample of 2,000 healthy adults in the California MEC (900 African American, 900 Latinos, 150 Japanese, 50 Whites), focusing on both short-term (12 months) and longer-term (spanning ~20 years) exposures to particulate matter (PM2.5, PM10, ultrafine particles) and gaseous pollutants (NOx, NO2, CO, ozone), and to assess whether there are racial and ethnic differences in the relationships between air pollutant exposures and the gut microbiome profile (composition and diversity). In Aim 2, in a case-control study of air pollution and diabetes (465 cases and 465 age, sex, race and ethnicity matched controls), we will identify gut microbiome profiles that either mediate or moderate associations between air pollution and diabetes.

SingleCell Epigenomics to Decode the Impact of Organophosphate Esters Exposure During LatePregnancy on Maternal Health

Organophosphate esters (OPEs), common flame retardants in products such as electronics and foam, have been increasingly found in environments, notably in pregnant women's urine and cord blood, indicating potential in utero transfer and associated adverse neurodevelopmental outcomes. These exposures are linked with risks like gestational diabetes mellitus, preterm birth and low birth weight. However, the biological effects of OPEs on maternal health remain unclear. Single-cell epigenomics sequencing offers insights into cellular-level impacts of OPE's cellular influence on maternal health during pregnancy. In our pilot study, we aim to delve deeper into OPEs' effects on maternal health by generating preliminary single- nuclear ATAC-seq data in 12,000-18,000 nuclei from blood samples from late pregnancy in the Maternal and Developmental Risks from Environmental and Social Stressors (MADRES) cohort. Our first aim is to profile the immune and inflammatory response to OPE exposures in late pregnancy by comparing open chromatin regions between pregnant women who are highly exposed and not exposed to OPEs. We will identify cell type-specific differentially accessible regions induced by OPEs and conduct enrichment analysis in biological pathways such as cancer, endocrine, and inflammatory responses. Our second aim is to develop predictive biomarker panels for maternal OPE exposure using machine learning models. This can pave the way for early detection of OPE xposure during pregnancy.

Gene-by-Environment effects on perivascular space development in childhood

Air pollution poses serious health risks to children, which can have lifespan consequences. Neuroimaging studies have uncovered links between fine particulate matter (PM2.5) and differences in brain structure and function in children. However, critical questions remain as to the potential impact on brain perivascular spaces (PVS), which is involved in the larger brain clearance system that is responsible for the drainage of neurotoxins from the Central Nervous System. Given the novelty of quantifying PVS in vivo, along with a rapidly evolving literature showing it is linked to various downstream physiological processes that have been linked to air pollution exposure, including neuroinflammation and oxidative stress, the current study will assess if prenatal and recent PM2.5 exposure is associated with developmental differences in PVS morphology in childhood.

PFAS-accelerated diabetic kidney disease

Youth onset diabetes is a global epidemic. Young onset diabetes is a more extreme metabolic phenotype than adult-onset diabetes, including more rapid deterioration of pancreatic β-cell function. This increases the risk of diabetic kidney disease (DKD), and over 72% of adolescents with diabetes develop signs of early DKD in young adulthood. Because DKD is difficult to reverse, there is an urgent need to identify modifiable risk factors for DKD in youth. Per- and polyfluoroalkyl substances (PFAS) are a class of ubiquitous endocrine disrupting chemicals and are emerging environmental risk factors for diabetes and kidney disease. PFAS exposure has been linked to worse hyperglycemia and worse β-cell function, which could increase the risk of DKD later in life. Youth with diabetes may be particularly susceptible to the harmful effects of PFAS on both pancreatic β-cell function and kidney function. The goal of this project is to create the first ever mouse model of PFAS-accelerated DKD. This is a crucial step for defining the causative role of PFAS in driving DKD and will complement ongoing work examining clinical cohorts of youth with diabetes. Our overarching hypothesis is that PFAS exposure leads to proximal tubule dysfunction and increased albuminuria, both key factors for DKD. To test this hypothesis, we will treat juvenile diabetic mice with PFAS or vehicle and follow the progression of albuminuria over time. At the end of the experimental protocol, we will collect kidneys from these mice and perform single-nucleus RNA sequencing in order to identify the pathological gene expression patterns induced by PFAS within each cell population of the kidney.

Association between Per- and PolyfluorinatedSubstances in Drinking Water and County-level Incidence and Mortality of Cancer, Diabetes, CardiovascularDisease in the Contiguous United States Using a Multidisciplinary Approach

Per- and poly-fluoroalkyl substances (PFAS) threaten human health and are widely detected in the environment including drinking water. Unfortunately, recent monitoring efforts indicate that PFAS contamination in drinking water disproportionately affects neighborhoods with a high proportion of non-Hispanic Black and Latinx low- income populations. There is limited research on the health effect of PFAS at a national scale with a focus on racial/ethnic differences. In addition, limited research has been conducted to assess the association between PFAS in drinking water and mortality risk at a large scale. This project aims to evaluate the association between PFAS and incidence and mortality of cancer, diabetes, and cardiovascular disease at the county level in the contiguous United States and explore the effect measure modification by racial/ethnic composition of the county. Furthermore, the project will conduct a simulation-based cost-effectiveness analysis of removing PFAS in preventing incidence and deaths. The results of the project will be disseminated to community members through a proposed PFAS and human health working group involving academics, government agencies, and community groups. We will use publicly available datasets including US Geological Survey (USGS) and Environmental Protection Agency (EPA) to estimate PFAS in drinking water and the Centers for Disease Control and Prevention (CDC) to obtain incidence and mortality of cancer, diabetes, and cardiovascular disease between 2013 and 2019. We will use a simulation-based model to conduct a cost-effectiveness analysis. Findings from the project will add evidence to the impact of PFAS on human health and support policies in the removal of PFAS, especially in disadvantaged neighborhoods.

Extreme heat-related mortality: A mixture approach to study disparities through individual and neighborhood environment

Extreme heat is associated with elevated mortalities. With climate change intensifying temperatures and heat frequency in California, the projected mortality due to extreme temperatures will continue to increase. It is crucial to understand what population is vulnerable to heat-related health outcomes. Low socioeconomic status individuals, residents living in poor housing conditions, and members of disadvantaged neighborhoods may have a higher risk of mortality. However, previous studies using data at census tract level found weak to no effect measure modification to heat-related mortalities in California. Meanwhile, census tract level analysis may not be sufficient to reveal risk heterogeneity and therefore needs a smaller spatial scale. In addition, existing evidence of individual and neighborhood factors to heat mortality risks did not include healthcare access/usage indicators and often considers one variable at a time but not as a mixture. Environmental mixture modeling methods have been developed and used in epidemiological research, such as chemicals and genetics, but rarely applied to social vulnerability contexts. The proposed study will leverage resources from Los Angeles County accessor’s parcel data (n=2,421,858), census tract level neighborhood environment, and mortality from 2014 to 2019 from the California Department of Public Health (n=1,514,292) to address this knowledge gap. This proposal employs a mixture approach to investigate the vulnerability of heat-related mortality at the building and neighborhood levels. We propose to use three unsupervised mixture methods: K-means/K- prototype (partitional clustering), hierarchical clustering, and self-organizing maps (learning-based clustering neural networks), to understand mixture structures of effect modifiers. Aim 1 proposes to examine the relationship between clusters of neighborhood environment and extreme heat-related mortalities with a two- stage meta-regression method in California. Aim 2 proposes investigating whether mixtures of parcel-level housing factors and individual socioeconomic status modify the association between extreme heat andmortality using a time-stratified case-crossover study design in LA County, California.