Autoantibodies against apolipoprotein A-1 and cadmium: possible links to cardiovascular and liver diseases across multiple models

Abstract Aims Cadmium, an environmental pollutant from combustion, contributes to cardiovascular, autoimmune, and liver diseases even at low levels. Autoantibodies against apolipoprotein A1 (AAA1) known for their pro-atherogenic and pro-steatotic properties are common in the general population, though their origins remain unclear. This study explored potential links between cadmium exposure, AAA1, CVD risk factors and Metabolic Dysfunction-associated Steatotic Liver Disease (MASLD) risk scores using geospatial clustering, with further investigations performed in murine and cellular models. Methods Geospatial analyses were conducted on 6,361 participants from the CoLaus/PsyCoLaus cohort to examine dependence between serum AAA1, and urinary cadmium, SCORE2 CVD risk, and fatty liver index (FLI). Ten-week-old male C57BL/6J mice were fed a high-fat diet for ten weeks, with or without cadmium (10ppm) supplementation. At sacrifice, plasma and tissue samples were collected, and circulating AAA1 levels were measured. H0.04) and AAA1 were independently associated with higher cadmium level (p0.04). AAA1 hotspots significantly overlapped with cadmium and FLI hotspots, independent of SCORE2. Strongest correlations between cadmium and AAA1 were found near railways, with a 10-fold increase compared to global associations. Cadmium-treated mice presented higher AAA1 titers and liver fibrosis compared to control mice. Combined AAA1 and cadmium treatment of macrophages significantly increased lipid droplet content (p=0.02), IL-8 (p0.0001) and IL-13 (p=0.0004), key drivers in atherosclerosis and liver disease. Conclusions These geospatial footprints, supported by experimental findings, highlight a possible causal link between cadmium, AAA1, and MASLD in the general population. We hypothesize that environmental cadmium exposure may induce AAA1 in humans, though its role as an early marker of cadmium exposure and related health risks remains uncertain.