Single-Cell Multi-Omics Profiling of Immune Cells Isolated from Atherosclerotic Plaques in Male ApoE Knockout Mice Exposed to Arsenic.

Abstract

Background: Millions worldwide are exposed to elevated levels of arsenic that significantly increase their risk of developing atherosclerosis, a pathology primarily driven by immune cells. While the impact of arsenic on immune cell populations in atherosclerotic plaques has been broadly characterized, cellular heterogeneity is a substantial barrier to in-depth examinations of the cellular dynamics for varying immune cell populations.

Objectives: This study aimed to conduct single-cell multi-omics profiling of atherosclerotic plaques in apolipoprotein E knockout (ApoE^-/-) mice to elucidate transcriptomic and epigenetic changes in immune cells induced by arsenic exposure.

Methods: The ApoE^-/- mice were fed a high-fat diet and were exposed to either $200\text{\hspace{0.17em}ppb}$ arsenic in drinking water or a tap water control, and single-cell multi-omics profiling was performed on atherosclerotic plaque-resident immune cells. Transcriptomic and epigenetic changes in immune cells were analyzed within the same cell to understand the effects of arsenic exposure.

Results: Our data revealed that the transcriptional profile of macrophages from arsenic-exposed mice were significantly different from that of control mice and that differences were subtype specific and associated with cell-cell interaction and cell fates. Additionally, our data suggest that differences in arsenic-mediated changes in chromosome accessibility in arsenic-exposed mice were statistically more likely to be due to factors other than random variation compared to their effects on the transcriptome, revealing markers of arsenic exposure and potential targets for intervention.

Discussion: These findings in mice provide insights into how arsenic exposure impacts immune cell types in atherosclerosis, highlighting the importance of considering cellular heterogeneity in studying such effects. The identification of subtype-specific differences and potential intervention targets underscores the significance of understanding the molecular mechanisms underlying arsenic-induced atherosclerosis. Further research is warranted to validate these findings and explore therapeutic interventions targeting immune cell dysfunction in arsenic-exposed individuals. https://doi.org/10.1289/EHP14285.