Environmental Exposures to PCDDs, PCDFs, and PCBs and Mechanism of Steatohepatitis in the Anniston Community Health Survey II

Abstract

PCDDs, PCDFs, and some PCBs activate the aryl hydrocarbon receptor (AhR); but non-dioxin like (NDL) PCBs do not. We previously reported a high prevalence of suspected nonalcoholic steatohepatitis (NASH) associated with PCB exposures in the Anniston Community Health Survey (ACHS). Here, we determine if dioxins and NDL PCB exposures were associated with serologic biomarkers of NASH in the subgroup of ACHS-II participants with suspected liver disease. The total dioxin toxic equivalency (TEQ) was determined by summing the TEQs for serum PCBs, PCDDs, and PCDFs using WHO toxic equivalency factors. Disease biomarkers were measured by ELISA or Milliplex. Subjects were categorized as having suspected liver disease if serum cytokeratin 18 was elevated. Linear regression models examined associations between TEQ or ΣNDL PCBs with NASH biomarkers in the suspected liver disease subgroup. In 345 adult participants, the prevalence of suspected liver disease was 62%. These subjects were at risk for NASH due to a high prevalence of overweight/obesity and diabetes. Suspected liver disease was significantly associated with male sex, non-Hispanic White race/ethnicity, increased liver enzymes, and a trend towards increased diabetes. Both TEQ and ΣNDL PCBs were associated with altered intermediary metabolism biomarkers (increased LDL, VLDL, phospholipids; and decreased HOMA-IR). TEQ was also associated with decreased HOMA-B. TEQ was associated with increased TNFα, IL-12 and CXCL11; while ΣNDL PCBs was associated with increased IL-13. Both TEQ and ΣNDL PCBs were positively associated with TGFβ. Neither exposure biomarker was positively associated with either CK18 or transaminases. In ACHS-II participants with suspected liver disease we found associations with altered biomarkers of liver intermediary metabolism, inflammation, fibrosis, and synthetic function; but not cell death. The potential role of the AhR, dioxins, and NDL PCBs in NASH progression warrants further investigation.