Toxic metals, epigenetics and risk of liver disease - PROJECT SUMMARY/ABSTRACT The prevalence of steatotic liver disease (SLD), commonly known as fatty liver disease, has increased significantly over the last several decades. SLD now affects approximately 80 million Americans with higher rates in Southern states. Over time, SLD can progress to steatohepatitis and fibrosis which increase the risk for cirrhosis and complications of end-stage liver disease including liver cancer. While some of the rise of SLD is driven by high rates of obesity, diabetes, alcohol use and metabolic syndrome, these established risk factors do not fully explain the observed increases nor the geographic variation. A potent yet understudied contributor is chronic exposure to environmental contaminants. Multiple chemical classes, including toxic metals, are ubiquitous in the U.S. population, with disproportionately higher exposures in rural areas and among socioeconomically disadvantaged groups of these geographic regions. Although toxic metals (e.g., cadmium, lead, arsenic, gadolinium) are hepatotoxic in model systems, we still lack consistent human data. This has been a major impediment for identifying mechanisms and for implementing clinic and public health policy. Conflicting human data could be due, in part, to unaccounted-for effects of co-exposure to multiple, including emerging toxic metals at concentrations experienced by the general population. Additionally, although clusters of conditions that include metabolic and liver injury are established risk factors of SLD, we still lack longitudinal data evaluating the contribution of these contaminants in progression. Most data are derived from cross-sectional studies yet half- lives of these chemicals in whole blood (the most common matrix for measurement) are ~35 days, impeding causal inference. Furthermore, although mounting data suggests that aberrant stable epigenetic profiles enhance the effects of toxic metal exposure, few epigenetic targets have been identified. To address these gaps, we will test the overarching hypothesis that environmentally relevant metal mixtures increase the risk of SLD and related metabolic and hepatic dysfunction, and that persistent, blood-based epigenetic signatures modulate this risk. To accomplish this, we will leverage a contemporary cohort (enrolled 2021-present) of otherwise healthy men and women aged 40-75 years from the Southeastern US on track to enrolling 6000 in the next two years. We will follow 1500-2000 participants for at least 5–10 years, measure 40 metals at enrollment and identify metal mixtures associated with hepatic steatosis and fibrosis using vibration-controlled transient elastography™-a handheld, ultrasound-based technique (Aim 1); and changes in precursor conditions over 5-10 years (Aim 2). We will determine the extent to which DNA methylation at >1,000 imprint control regions, measured at enrollment increases susceptibility to progression to hepatic fibrosis and steatosis and changes in metabolic dysfunction and liver injury markers. This work will generate critical longitudinal human data on real-world metal mixture exposures and the amplifying role of epigenetic susceptibility, providing an evidence base to inform policies aimed at preventing environmentally induced liver disease.
