Evaluation of the Immune System in Rats and Mice Administered Linear Ammonium Perfluorooctanoate

Abstract

Repeated high doses of ammonium perfluorooctanoate (APFO) have been reported to affect immune system function in mice. To examine dose-response characteristics in both rats and mice, male CD rats and CD-1 mice were dosed by oral gavage with 0.3-30 mg/kg/day of linear APFO for 29 days. Anti-sheep red blood cell (SRBC) IgM levels, clinical signs, body weights, selected hematology, and lipid parameters, liver weights, spleen, and thymus weights and cell number, selected histopathology, and serum corticosterone concentrations were evaluated. In rats, linear APFO had no effect on production of anti-SRBC antibodies. Ten and 30 mg/kg/day resulted in systemic toxicity as evidenced by decreases in body weight gain to 74 and 37%, and increases in serum corticosterone levels to 135 and 196% of control, respectively. In mice dosed with 10 and 30 mg/kg/day, marked systemic toxicity and stress were observed, as evidenced by a loss in body weight of 3.8 and 6.6 g, respectively (despite a tripling of liver weight), approximately 230% increase in serum corticosterone, and increases in absolute numbers of peripheral blood neutrophils and monocytes with an accompanying decrease in absolute lymphocyte numbers. Immune-related findings at 10 and 30 mg/kg/day that likely represent secondary responses to the systemic toxicity and stress observed at these doses include: decreased IgM antibody production at 10 (20% suppression) and 30 mg/kg/day (28% suppression); decreased spleen and thymus weights and cell numbers; microscopic depletion/atrophy of lymphoid tissue at 10 (thymus) and 30 mg/kg/day (spleen). In summary, no immune-related changes occurred in rats, even at doses causing systemic toxicity. In mice, immune-related changes occurred only at doses causing significant and profound systemic toxicity and stress.

Suppression of antigen-specific antibody responses in mice exposed to perfluorooctanoic acid: Role of PPARαand T- and B-cell targeting

“…Relative spleen and thymus weights were reduced in our WT controls exposed to 30 mg PFOA/kg (spleen) or 7.5 mg PFOA/kg (thymus). The reduction in spleen weight (Figure 2a) was consistent with our previous study (DeWitt et al, 2008) and studies by others (Yang et al, 2002a;Loveless et al, 2008) that demonstrated reductions in spleen weights in C57BL/6 mice given 30 mg PFOA/kg. However, the reduction in the relative thymus weight (Figure 2b) associated Figure 2.…”

“…This focus was based on a set of papers by Yang et al (2000Yang et al ( , 2001Yang et al ( , 2002b) that indicated reductions in relative spleen and thymus weights and suppression of the T-cell-dependant antibody response (TDAR). Succeeding studies of PFOA and related PFAS (PFOA, PFOS, and ammonium perfluorooctanoate [APFO, a precursor compound to PFOA]) also demonstrated suppression of the TDAR (DeWitt et al, 2008;Loveless et al, 2008) and that exposure to PFOS also affected the T-cell-independent antibody response (TIAR; Peden-Adams et al, 2008). Suppression of both the TDAR and TIAR suggests that B-cells are targeted by PFAS.…”

Epidemiologic Evidence on the Health Effects of Perfluorooctanoic Acid (PFOA)

“…Total doses received in the Dewitt et al (2008) study appear to have been about an order of magnitude higher than the total lifetime dose received by people drinking water contaminated with 1 ng/mL PFOA. There appears to be strain as well as species sensitivity to the immunotoxic effects of PFOA, with rats being considerably less sensitive than mice (Loveless et al 2008), leading some to question the relevance of these data to humans. Immunotoxicity by PFOA in rodents appears to occur both through and independent of peroxisome proliferation (Yang et al 2000).…”

Immunomodulating effects and hypersensitivity reactions caused by Northeast Indian black fly salivary gland extract

“…Further, in a number of immunotoxicology studies, rats and other rodent species have been used as their immune responses have been shown to be quite comparable to the human response (Esquifino et al, 1996;Minor, 2011;Loveless et al, 2008). Through the use of this particular rat model, it was hoped that the present study might provide new insights into the mechanisms responsible for the coagulopathic effects of black fly saliva in vivo and data regarding its potential efficacy for use in specific future therapeutic interventions.…”