Environmental and occupational toxicant exposures may drive the emergence and expansion of clonal hematopoiesis of indeterminate potential, positioning the condition as an intermediate biological endpoint linking toxic insults to long-term health outcomes, according to a review published in Biology Direct.
Clonal hematopoiesis of indeterminate potential, or CHIP, is an age-associated condition marked by the clonal expansion of hematopoietic stem cells harboring somatic driver mutations. While researchers have long established its association with hematologic malignancies, growing evidence links CHIP to broader systemic consequences, including cardiovascular disease, chronic inflammation, and elevated overall mortality.
Specific environmental hazards highlighted in the evaluation include benzene, pesticides, ambient air pollution, heavy metals, and per- and polyfluoroalkyl substances, known collectively as PFAS. The authors report that these widespread contaminants alter hematopoietic stem-cell dynamics through multiple distinct pathways, including direct DNA damage, oxidative stress, sustained inflammation, epigenetic dysregulation, and the structural remodeling of the bone marrow niche.
The review distinguishes between two primary mechanisms through which environmental contaminants operate: acting directly as mutagenic agents that induce novel mutations, or fostering selective pressures that accelerate the clonal expansion of pre-existing mutant stem cells.
Evaluating CHIP as a potential toxicological biomarker, the researchers highlight its strong analytical measurability, biological plausibility, and capacity to predict disease risk, while cautioning that its utility faces ongoing limitations related to exposure specificity and temporal responsiveness.
Although critical knowledge gaps persist regarding definitive causality and exposure-specific mutational signatures, emerging tools such as error-corrected sequencing, single-cell genomics, multi-omics platforms, and longitudinal biomonitoring offer a promising framework to integrate environmental exposure, biological susceptibility, aging, and disease risk assessment.
By serving as an intermediate biological endpoint, clonal hematopoiesis offers a measurable connection between initial toxicological insults and later adverse systemic outcomes, including cardiovascular disease, hematologic malignancies, and increased mortality linked to sustained chronic inflammation.
A central focus of the review involves distinguishing how different classes of contaminants influence hematopoietic stem-cell dynamics. Certain toxic agents operate primarily as mutagens that directly damage cellular DNA and induce new driver mutations, whereas other non-mutagenic compounds act by altering the microenvironment to favor the selective survival and expansion of pre-existing mutant clones. The authors examine how diverse environmental pollutants, including benzene, pesticides, ambient air pollution, heavy metals, and per- and polyfluoroalkyl substances, contribute to these dynamics through oxidative stress, epigenetic dysregulation, and structural remodeling within the bone marrow niche.
In evaluating clonal hematopoiesis as a candidate toxicological biomarker, the review balances its analytical measurability and biological plausibility against critical methodological limitations. Although tracking mutant clones provides predictive insight into long-term disease risks, researchers face unresolved challenges regarding exposure specificity and temporal responsiveness.
To overcome these limitations, the authors highlight emerging genomic and analytical technologies that are transforming the study of clonal dynamics in exposed human populations. High-resolution tools such as error-corrected sequencing, single-cell genomics, and multi-omics approaches, coupled with longitudinal biomonitoring strategies, enable researchers to monitor clonal behavior over extended periods. Despite ongoing knowledge gaps regarding definitive causal links, the review concludes that clonal hematopoiesis establishes a valuable framework integrating environmental exposure, individual biological susceptibility, aging, and disease risk within modern environmental toxicology and risk assessment.
Subject of Research: Clonal hematopoiesis in environmental toxicology
Article Title: Clonal hematopoiesis as an intermediate endpoint in environmental toxicology: evidence, mechanisms and future applications
Article References: Barbieri, M., Mollari, M., Ubaldi, A., Galli, F. S., & Marcoccia, D. (2026). Clonal hematopoiesis as an intermediate endpoint in environmental toxicology: evidence, mechanisms and future applications. Biology Direct. https://doi.org/10.1186/s13062-026-01060-3
Image Credits: AI Generated
DOI: 10.1186/s13062-026-01060-3
Keywords: clonal hematopoiesis, environmental toxicology, somatic mutations, biomarkers, hematopoietic stem cells, benzene, air pollution, PFAS, Clonal, hematopoiesis, intermediate, endpoint
