In the first part of a series of studies to account for perfluoroocatane sulfonate (PFOS)-induced sheep red blood cell (SRBC)-specific IgM antibody suppression in mice, a survey of clinical and immunotoxicological endpoints were examined. Adult female B6C3F1 mice were exposed orally for 28 days to a total administered dose of 0, 0.1, 0.5, 1, or 5 mg PFOS/kg. Uterus wet weight was significantly decreased compared to control at the 5 mg/kg dose. No indication of wasting syndrome, malnutrition, alteration of thyroid homeostasis, or signs of overt toxicity were observed. Numbers of splenic CD19+/CD21−, CD19+/CD21+, B220+/CD40+, CD4+/CD154−, CD4+/CD154+, and MHC-II+ cells were not altered. Additionally, ex vivo IL-4, IL-5, and IL-6 production by in vitro anti-CD3- or phorbol myristate acetate-stimulated CD4+ T-cells were not affected. Ex vivo IL-6 production by B-cells was significantly increased by in vitro stimulation with either anti-CD40 or lipopolysaccharide. Increased IL-6 production by B-cells was the most sensitive endpoint assessed resulting in alterations at the lowest dose tested (0.1 mg/kg TAD) following anti-CD40 stimulation. Further studies are required to characterize effects on inflammatory markers such as IL-6 at environmentally relevant concentrations of PFOS and to determine the key events associated with PFOS-induced IgM suppression to address potential human health risks.

Polybrominated diphenyl ethers (PBDEs) are an important class of flame-retardants that are environmentally persistent and bioaccumulative. Toxicity of these compounds has become a concern because detectable levels of PBDEs are present in humans and wildlife and they are structurally similar to polychlorinated biphenyls (PCBs). This study examined the effects of the commercial penta-BDE mixture, DE-71, in adult female B(6)C(3)F(1) mice on hematology, serum clinical chemistry, thyroid hormones, tissue histology, and several immunotoxicity end-points (lymphocyte proliferation, NK cell activity, splenic immunophenotypes, and SRBC-specific-IgM production). Mice were exposed via oral gavage for 28 days to achieve total administered doses (TAD) of 0, 0.5, 5, 50, or 100 mg/kg. No changes in histology, clinical chemistry, body or organ weights were observed. Serum total T3 and T4 levels were not altered by any of the DE-71 treatments. Peripheral blood monocyte numbers were decreased by the 0.5, 5, and 50 mg/kg treatments, but not by the 100 mg/kg TAD concentration. Compared to controls, mitogen-stimulated T- and B-cell proliferation was increased by the 100 mg/kg TAD concentration (ED(50) = 60 mg/kg TAD [2.14 mg/kg/day] and 58 mg/kg TAD [2.57 mg/kg/day], respectively). NK cell activity was decreased compared to controls by the 100 mg/kg TAD concentration (ED(50) = 20 mg/kg TAD [0.7 mg/kg/day]). No alterations were noted in thymic T-cell populations or in SRBC-specific-IgM production. Numbers of CD19(+)CD21(-), CD19(+)CD21(+), CD4(+)CD8(-), CD4(-)CD8(+), CD4(-)CD8(-), and MHC-II(+) cells in the spleen were not affected. However, the numbers of splenic CD4(+)CD8(+) cells were decreased compared to the controls by 0.5, 5, and 100 mg/kg TAD. This study provides an assessment of the systemic toxicity and immunotoxicity of DE-71, and indicates that immune parameters are modulated at exposure concentrations lower than previously reported.

Perfluorooctane sulfonate (PFOS; 1,1,2,2,3,3,4,4,5,5,6,6,7,7,8,8,8-heptadecafluoro-1-octanesulfonic acid) has been reported to alter humoral immune functions, but inflammatory processes following PFOS exposure have not been fully characterized. Therefore, the current study, assessed TNF-α and IL-6 concentrations in serum and peritoneal lavage fluid, numbers of splenoctyes expressing intracellular TNF-α, IL-6, IL-10 or IL-1, and ex vivo TNF-α and IL-6 production by peritoneal macrophages following either in vivo or in vitro LPS exposure. Adult female B6C3F1 mice were exposed orally for 28 days to 0, 1, 3, or 300 mg PFOS/kg total administered dose [TAD] (e.g., 0, 0.0331, 0.0993 or 9.93 mg/kg/day). Body and spleen masses were significantly reduced in the highest PFOS treatment group compared to the control group, whereas liver mass was significantly increased. Serum TNF-α levels were significantly decreased following exposure to 1 mg PFOS/kg TAD as compared to controls, while serum IL-6 levels were increased. IL-6 concentrations in peritoneal lavage fluid decreased with increasing dose. PFOS treatment did not alter numbers of splenocytes expressing intracellular levels of TNF-α, IL-10 or IL-1. Numbers of splenocytes expressing intracellular levels of IL-6 were significantly decreased in the 3 mg/kg treatment as compared to controls. Overall, these data suggest that PFOS exposure can alter some inflammatory processes, which could potentially lead to misdirected inflammatory responses.

Cetaceans are federally protected species that are prone to accumulate complex mixtures of persistent organic pollutants (POPs), which individually may exert estrogenic or antiestrogenic effects. In the present study it was assessed whether contaminant mixtures harbored by cetaceans are estrogenic or antiestrogenic using a comparative approach. Interactions of antiestrogenic and estrogenic compounds were first investigated with the E-Screen assay using a mixture of four POPs (dichlorodiphenyldichloroethylene [4,4'-DDE], trans-nonachlor, and polychlorinated biphenyls [PCBs] 138 180) prevalent in cetacean blubber. Estrogenic/antiestrogenic activity was determined for the individual compounds and their binary, tertiary, and quaternary combinations. Significantly different responses were observed for the various POP mixtures, including enhanced estrogenic and antiestrogenic effects and antagonistic interactions. These results were then compared to the concentrations and estrogenic/antiestrogenic activity of contaminant mixtures isolated directly from the blubber of 15 bottlenose dolphins (Tursiops truncatus) collected from five U.S. Atlantic and Gulf of Mexico locations. The lowest observed effect concentrations (LOECs) determined for 4,4'-DDE (20 µmol/L), PCB 138 (20 µmol/L), PCB 180 (21 µmol/L), and trans-nonachlor (3 µmol/L) in the E-Screen were greater than estimated dolphin blood concentrations. Although estimated blood concentrations were below the LOECs, significant estrogenic activity was detected in diluted dolphin blubber from Cape May, NJ and Bermuda. Positive correlations between blubber estrogenicity and select POP concentrations (ΣDDTs, ΣPBDEs, ΣHCB, Σestrogenic PCBs, Σestrogenic POPs) were also observed. Collectively, these results suggest that select bottlenose dolphin populations may be exposed to contaminants that act in concert to exert estrogenic effects at biologically relevant concentrations. These observations do not necessarily provide direct evidence of endocrine disruption; however, they may indicate an environmental source of xenoestrogenic exposure warranting future research.

No abstract