Integration of Animal, Population, and Toxicogenomic Evidence on the Hematotoxic and Immunosuppressive Effects of Environmental Exposure to PFAS Mixtures in Adolescents

Perfluoroalkyl and polyfluoroalkyl substances (PFASs) are emerging contaminants widely found in drinking water and food, potentially entering the human body through these sources. To investigate these effects, we simulated PFAS exposure doses in animal models, ranging from general population to occupational levels, and analyzed blood and spleen samples. Epidemiological studies linked PFAS exposure to immunosuppression and hematotoxicity, while toxicogenomic analyses validated the underlying biological mechanisms. PFAS exposure caused immunotoxic effects, including altered blood parameters and lymphocyte edema. Cellular abnormalities such as decreased cytoplasmic density, incomplete rough endoplasmic reticulum, chromatin condensation, lymphocyte nuclear shrinkage, and reduced mitochondrial cristae were observed. Epidemiological evidence revealed a dose-response relationship between mixed PFAS exposure and hematologic indices such as hematocrit (HCT), hemoglobin (HGB), platelet count (PLT), platelet-to-lymphocyte ratio (PLR), white blood cell count (WBC), monocyte percentage, and platelet large cell ratio (PLCR), with perfluorooctanoic acid (PFOA) playing a dominant role. Toxicogenomic analysis identified genes associated with platelets, anemia, and leukocyte function, linked to inflammation, Th17 cell differentiation, apoptosis, lipid metabolism, atherosclerosis, and JAK-STAT signaling. This study provides novel insights into the hematotoxicity and immunosuppressive effects of mixed PFAS exposure, emphasizing the need for PFAS substitution, removal, and policies addressing mixed exposures to protect public health.