Benzo[a]pyrene exposure reduces cell-type diversity in lupus-prone mice

Abstract

Abstract Studies indicate that genetic factors only account for approximately thirty percent of all autoimmune diseases, while the rest of autoimmune pathogenesis is attributed to environmental factors including toxic chemicals, dietary components, and infections. To understand if and how toxic chemicals trigger autoimmunity, we investigated the effect of benzo[a]pyrene (BaP) exposure on the development of autoimmune phenotypes in the lupus-prone MRL/MpJ strain. Since BaP is a polycyclic aromatic hydrocarbon commonly found in byproducts of industrial incineration, motor vehicle emissions and cigarette smoke, we subjected mice to skin plus lung exposure to BaP over the course of 8 weeks before lupus onset. BaP treatment resulted in total body weight loss in male mice, while marginal changes in anti-dsDNA levels occurred. Multi-organ analyses of BaP-treated and control MRL mice suggested that kidney is a major organ directly affected by the metabolism of benzene-containing compounds, with increased expression of BaP-target genes including Cyp4b1 and Hao2. Intriguingly, spatial transcriptomic data showed that BaP caused drastic reduction in cell type diversity in both kidney and spleen of MRL mice. In addition, BaP exposure triggered C3 deposit in a more severe manner in the kidney of male MRL mice compared to female. Collectively, our results show that BaP exposure reduces cell type diversity in lupus-prone mice before disease onset, and stimulates sex-biased molecular pathways which may help explain the increased likelihood of end organ damage in males with lupus.