Clonal hematopoiesis as an intermediate endpoint in environmental toxicology: evidence, mechanisms and future applications

Clonal hematopoiesis of indeterminate potential (CHIP) is an age-associated condition characterized by the clonal expansion of hematopoietic stem cells (HSCs) carrying somatic driver mutations. Beyond its established link to hematologic malignancies, CHIP is increasingly recognized as a systemic condition associated with cardiovascular disease, chronic inflammation, and increased mortality. Growing evidence suggests that environmental and occupational exposures may contribute to the emergence and expansion of CHIP, positioning clonal hematopoiesis as a potential intermediate biological endpoint linking environmental insults to long-term adverse health outcomes. This review examines current evidence connecting environmental toxicants to CHIP and discusses the biological mechanisms underlying mutation acquisition and clonal selection. Environmental exposures, including benzene, pesticides, air pollution, heavy metals, and per- and polyfluoroalkyl substances (PFAS), may influence hematopoietic stem-cell dynamics through DNA damage, oxidative stress, chronic inflammation, epigenetic dysregulation, and bone marrow niche remodeling. We discuss the distinction between contaminants acting primarily as mutagenic agents and those promoting the selective expansion of pre-existing mutant clones. The potential utility of CHIP as a toxicological biomarker is critically evaluated, highlighting its analytical measurability, biological plausibility, and predictive value for disease risk, while also addressing limitations related to exposure specificity and temporal responsiveness. We further review emerging technologies, including error-corrected sequencing, single-cell genomics, multi-omics approaches, and longitudinal biomonitoring strategies, which are transforming the study of clonal dynamics in environmentally exposed populations. Although important knowledge gaps remain regarding causality and exposure-specific signatures, CHIP represents a promising framework for integrating environmental exposure, biological susceptibility, aging, and disease risk within modern environmental toxicology, human biomonitoring, and risk assessment.