Suppression of Humoral Immunity by Perfluorooctanoic Acid is Independent of Elevated Serum Corticosterone Concentration in Mice

Abstract

The T-cell-dependent antibody response is suppressed in mice exposed to 3.75, 7.5, 15, and 30 mg PFOA (perfluorooctanoic acid)/kg body weight (bw). Reduced bw accompanied immunosuppression at 15 and 30 mg/kg. We investigated the hypothesis that the observed immunosuppression is secondary to elevated serum corticosterone levels by assessing immune function in adrenalectomized (adx) or sham-operated C57BL/6N female mice exposed to 0, 7.5, or 15 mg PFOA/kg bw in drinking water for 10 days. Bw, primary antibody responses to a T-dependent antigen, clinical serum chemistries related to liver health, and serum corticosterone levels were evaluated. Exposure to 15 mg/kg decreased bw by approximately 10% after 8 days of dosing and until 2 days postdosing in both adx and sham animals; bw of adx animals were still reduced 5 days postdosing. IgM antibody titers were statistically reduced by 15% in sham animals and 18% in adx animals exposed to 15 mg/kg and by 11.8% in adx animals exposed to 7.5 mg/kg. Corticosterone concentrations were elevated by 157% in dosed sham animals relative to control animals and were reduced by 27% in dosed adx animals relative to control animals (neither changes were statistically significant). Clinical serum chemistries related to liver health were not statistically altered by either dose or adrenalectomy. The failure of adrenalectomy to protect mice from the immunosuppressive effects of PFOA indicates that suppression of antibody synthesis is not the result of liver toxicity or stress-related corticosterone production.

Dermal Penetration Potential of Perfluorooctanoic Acid (PFOA) in Human and Mouse Skin

“…In addition, certain inflammatory cytokines produced by keratinocytes, such as IL-18 and IL-33, have the potential to engage the adaptive immune response and can regulate the development of humoral versus cellular immune responses (Moussion et al 2008;Wittmann et al 2009). Since dermal exposure to PFOA was shown to suppress T-cell-dependent IgM and IgG antibodies response and enhance IgE-mediated responses to protein and chemical allergens, evaluation of these cytokines was included in these studies (Anderson et al 2009;Dewitt et al 2008;2009a;2009b;Fairley et al 2007;Yang et al 2001;2002).…”

“…Although it was long believed that PFOA was biologically inactive, more recent experiments, using controlled animal studies, showed an association between PFOA exposure and hepatic toxicity, carcinogenicity, reproductive toxicity, hormone disruption, and immunotoxicity (DeWitt et al 2009b). While the majority of animal studies investigated the health effects associated with oral and inhalation routes of PFOA exposure, little is known about the significance of dermal exposure in the human population.…”

“…PFOA is also immunosuppressive following oral exposure in murine models. A reduction in thymocyte and splenocyte populations, altered T lymphocyte populations, and an inhibition in T-cell-dependent immunoglobulin (Ig) M and IgG antibody responses have been documented (Dewitt et al 2008;2009a;2009b;Yang et al 2001;2002). Our laboratory previously showed these same immunotoxic effects following dermal exposure to PFOA (Anderson et al 2009).…”

Perfluorinated compounds: Emerging POPs with potential immunotoxicity

“…However, DeWitt et al (2008) demonstrated that suppression of the antigen-specific IgM antibody response occurs at doses that produce no signs of acute toxicity or effects on spleen weight. Furthermore, this group (DeWitt et al (2009a) determined that adrenalectomy did not protect mice from the immunosuppressive effects of PFOA at doses that reduced body weight gain. Although the HPA axis may contribute to immunotoxicity at high doses in intact animals, suppression of humoral immunity at lower doses (e.g., 3.75 and 7.5 mg PFOA/kg PFOA) is independent of elevated corticosterone and therefore represents a true immunotoxic effect (DeWitt et al, 2009a).…”

Dietary exposure to perfluorooctanoate or perfluorooctane sulfonate induces hypertrophy in centrilobular hepatocytes and alters the hepatic immune status in mice

“…In addition to these hepatic effects, a number of studies have shown that short-term or sub-chronic exposure to relatively high doses of PFOA or PFOS can suppress various aspects of adaptive immunity [28][29][30][31][32][33][34], while at the same time activating the innate branch of the immune system [35].…”