| Summary |
Well over 10,000 individual synthetic chemicals have been identified as per- and polyfluoroalkyl substances (PFAS). Many are used in non-stick cooking ware, medical garments, and food packaging. Numerous PFAS are environmentally and biologically persistent and some have demonstrated toxicity, including cancer, liver damage, high cholesterol effects on reproduction and development, endocrine disruption and immune dysfunction. Suppression of vaccine responses in epidemiological studies of humans and suppression of the T-cell dependent antibody responses (TDAR) and T- cell independent antibody responses (TIAR) have been observed in experimental animal studies of legacy PFAS. Molecular mechanisms of this PFAS-induced immunosuppression remain elusive, leading our lab to focus on B cell subclasses, enumerating B cells as they transform from naive B cells to memory B cells and antibody-secreting plasma cells. Adult male and female C57BL/6 mice were given the legacy PFAS, perfluorooctanoic acid (PFOA; 0 or 7.5mg/kg) via gavage for 15 days, a time sufficient for suppression of the TDAR and TIAR. Separate groups of animals were injected with antigens and one day after dosing ended, spleens were prepared for determination of B cell populations via a flow cytometric panel to identify B cell subsets. Suppression of the TDAR and TIAR by this dose of PFOA was confirmed with enzyme-linked immunosorbent assays. Flow cytometric analysis revealed that follicular and plasmablast B cell subclasses were likely impacted by PFOA exposure. Our data indicate overall B cell numbers are impacted by PFOA exposure and changes in numbers of B cell subsets suggest that the ability of B cells to differentiate is impacted. Our next step led us to interrogate three other lesser known PFAS: perfluorohexanoic acid (PFHxA), perfluoror-2-methoxyaacetic acid (PFMOAA) and perfluro-3,5,7,9,11-pentaoxa dodecanoic acid (PFO5DoA) to investigate if the findings would be similar to PFOA. PFHxA is a drinking water contaminant that is used in the production of fluoroploymers and this compound was given to adult C57BL/6 mice (0, 0.5, 5 of 50 mg/kg) via gavage for 30 days. The TDAR was evaluated along with immunophenotyping of the thymus, spleen and liver peroxisomal enzyme activity. Females and males exposed to PFHxA had reductions in naive B cells and plasmablasts across all dose groups. Our data suggests that oral ingestion of PFHxA leads to disruption in the immune system and affects the liver similar to what was observed in PFOA. and PFO5DoA are short-chain compounds with an ether linkage that were detected in in the Cape Fear River (CFR) in North Carolina which is used for drinking water. PFO5DoA was also detected in human serum from residents living near CFR. PFMOAA was given to adult C57BL/6 mice (0, 0.5, 5 of 50 mg/kg) via gavage for 30 days and PFO5DoA was given to adult C57BL/6 mice (0, 0.005, 0.05 of 0.5 mg/kg) via gavage for 30 days. The TDAR was evaluated along with immunophenotyping of the thymus, spleen and liver peroxisomal enzyme activity. Our data proposes PFMOAA exposure did not suppress the TDAR or alter liver peroxisomal enzyme activity, however, its exposure impacted naive B cells and marginal zone B cell subsets.PFO5DoA exposure suppressed the TDAR at 0.5 mg/kg and altered production of plasmablasts, follicular cells and marginal zone B cell subsets, as well as liver peroxisomal enzyme activity. |
