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Suppression of antigen-specific antibody responses in mice exposed to perfluorooctanoic acid: Role of PPARalpha and T- and B-cell targeting
Citation:
DeWitt, J., W. Williams, J. Creech, AND R. Luebke. Suppression of antigen-specific antibody responses in mice exposed to perfluorooctanoic acid: Role of PPARalpha and T- and B-cell targeting. JOURNAL OF IMMUNOTOXICOLOGY. Taylor & Francis, Inc., Philadelphia, PA, 13(1):38-45, (2016).
Impact/Purpose:
Perfluoroalkyl substances (PFASs) are stable, synthetic, fluorinated chemicals used in numerous industrial and consumer products, including protective coatings for packaging, textiles, paper, and carpeting, nonstick agents, and fluoropolymers for other product applications. In a review of the US EPA draft risk assessment, the US EPA Science Advisory Board highlighted immunotoxicity as an endpoint of concern. The role of PPARalpha ligation in rodent carcinogenesis is relatively well accepted, as are the differences between rodent and human PPARalpha biology and function, but PPARalpha ligation as a mode of action for suppression of antibody synthesis has yet to be established in experimental rodent models or humans. To better understand the rodent data in terms of potential immunotoxicological risk posed by human PFOA exposure, experiments were conducted to determine if suppression of the TDAR in rodents is dependent on PPARalpha ligation. Effects of PFOA exposure on antibody responses that do not require "help" from T lymphocytes. Effects on this class of antibody were investigated because the structurally-related compound perfluorooctane sulfonate (PFOS) was reported to inhibit antibody responses by directly targeting the cells that make antibody. These antibodies are critical to surviving bacterial and viral infections of the respiratory and digestive tracts.
Description:
T-cell-dependent antibody responses (TDAR) are suppressed in female C57BL/6N mice exposed to ≥3.75 mg/kg of perfluorooctanoic acid (PFOA) for 15 days. To determine if suppression of humoral immunity by PFOA is peroxisome proliferator activated receptor alpha (PPARa)-dependent and if suppression is associated with specific targeting of T- or B-cells, three separate experiments were conducted: (1) female PPARa constitutive knockout (PPARa KO; B6.129S4-Ppar(tm1Gonz)N12) and wild-type controls (WT; C57BL/6-Tac) exposed to 0, 7.5, or 30 mg PFOA/kg for 15 days were immunized on Day 11 with a T-cell-dependent antigen and sera then collected for measures of antigen-specific lgM titers (TDAR) 5 days later; (2) female C57BL/6N WT mice exposed to 0, 0.94, 1.88, 3.75, or 7.5mg PFOA/kg for 15 days were immunized with a T-cell-independent antigen on Day 11 and sera were then collected foranalyses of antigen-specific lgM titers (TIAR) 7 days later; and (3) splenic lymphocyte phenotypes were assessed in unimmunized female C57BL/6N WT mice exposed to 0, 3.75, or 7.5 mg PFOA/kg for 10 days to investigate effects of PFOA in the absence of specific immunization. Separate groups of mice were immunized with a T-cell-dependent antigen after 11 days of exposure and splenic lymphocyte sub-populations were assessed after 13 or 15 days of exposure to assess numbers of stimulated cells. The results indicated that exposure to ≥1.88mg PFOA/kg suppressed the TIAR; exposure to 30 mg PFOA/kg suppressed the TDAR in bothPPARa KO and WT mice. The percentage of splenic B-cells was unchanged. Results obtained in the PPARa KO mice indicated that PPARa suppression of TDAR was independent of PPARa involvement. Suppression of the TIAR and the TDAR with minimal lymphocyte sub-population effects suggested that effects on humoral immunity are likely mediated by disruption of B-cell/plasma cell function.
