Benzo[a]pyrene Exposure Reduces Cell-Type Diversity and Stimulates Sex-Biased Damage Pathways in End Organs of Lupus-Prone Mice

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. To understand if and how environmental pollutants trigger autoimmunity, we investigated the effect of benzo[a]pyrene (BaP) exposure on the development of autoimmune phenotypes in the lupus-prone MRL strain. The exposure of MRL mice to BaP over the course of 8 weeks before lupus onset resulted in total body weight loss in males, while marginal changes in anti-dsDNA levels occurred. Multi-organ analyses of BaP-treated and control MRL mice suggested that the 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 a drastic reduction in cell-type diversity in both the kidneys and spleen of MRL mice. Further analysis of the molecular pathways affected suggested a sex-biased effect of BaP treatment, with the upregulated expression of angiogenesis genes in the lungs and an increased deposition of C3 in the kidneys of male mice. While SLE is more common in women, the disease is more severe in male patients, with an increased risk of disease progression to renal failure and lung cancer. Our results reveal sex-biased molecular pathways stimulated by BaP which may help explain the increased likelihood of end organ damage in males with lupus.