Advancing immunotoxicology with single-cell sequencing: Challenges and progress defining mechanisms of arsenic toxicity

Defining mechanisms of immunotoxicity is complicated by the many cell types that comprise the immune system, their phenotypic heterogeneity, distribution in tissues throughout the body, and complexity of in vivo interactions. Single-cell RNA-sequencing (scRNA-seq) methods hold promise for determining how chemical exposures alter gene expression and phenotype of individual immune cell phenotypes, leading to adverse effects on immune function. Using arsenic as a case study, this review will examine challenges in defining mechanisms of immunotoxicity and highlight findings from recent studies that have addressed immunotoxicological questions with scRNA-seq. Advancements in immunotherapeutic development driven by single-cell sequencing technologies will be discussed, along with how these state-of-the art methods may be applied to accelerate immunotoxicity testing in future studies. We will finally consider how cell-type-specific gene expression data can be leveraged to glean immune profiles from existing gene expression data, improving our understanding of immunotoxicity and ability to assess the health impacts of immunotoxic chemicals.