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Evaluation of the Immunomodulatory Effects of 2,3,3,3-Tetrafluoro-2-(Heptafluoropropoxy)-Propanoate in C57BL/6 Mice
Citation:
Rushing, B., Q. Hu, J. Franklin, R. McMahen, S. Dagnino, C. Higgins, M. Strynar, AND J. DeWitt. Evaluation of the Immunomodulatory Effects of 2,3,3,3-Tetrafluoro-2-(Heptafluoropropoxy)-Propanoate in C57BL/6 Mice. TOXICOLOGICAL SCIENCES. Society of Toxicology, RESTON, VA, 156(1):179-189, (2017). https://doi.org/10.1093/toxsci/kfw251
Impact/Purpose:
Per- and polyfluoroalkyl substances (PFASs) are anthropogenic organic compounds comprised of strong carbon-fluorine bonds that make them extremely useful as polymerization aids and surfactants for the processing of myriad consumer and industrial products. However, the characteristics that make PFASs beneficial in industrial processes often make them problematic from an environmental health standpoint: perfluoroalkyl acids (PFAAs), a class of PFASs, are extremely persistent in the environment, and some bioaccumulate in wildlife and humans. As well as being multisystem toxicants, they also have been associated with immunotoxicity and similar effects on the immune system have been observed in both exposed experimental animal models and humans (Keil, 2015). Among the most well characterized PFASs are perfluorooctanoic acid (PFOA) and perfluorooctane sulfonate (PFOS), which have been reported to potently suppress T cell-dependent antibody responses (TDAR) in experimental rodent models (DeWitt et al., 2008, 2009a, 2016; Loveless et al., 2008; Peden-Adams et al., 2008; Yang et al., 2002) and responses to vaccinations in exposed humans (Grandjean et al., 2012; Granum et al., 2013; Looker et al., 2014). Largely due to environmental persistence and growing reports of toxicity, PFOS was phased out of production by its major manufacturer in 2002 and PFOA was phased out of production by its major U.S. manufacturers in 2015. However, their usefulness as processing aids has prompted research into alternative PFASs that will provide optimal industrial usefulness but with reduced toxicity.
Description:
2,3,3,3-tetrafluoro-2-(heptafluoropropoxy)-propanoate was designed to replace perfluorooctanoic acid (PFOA), which has been mostly phased out of U.S. production due to environmental persistence, detectable human and wildlife serum concentrations, and reports of systemic toxicity. In rodent models, PFOA exposure suppresses T cell-dependent antibody responses (TDAR) and vaccine responses in exposed humans. To determine replacement compound effects on TDAR and related parameters, male and female C57BL/6 mice were gavaged with 0, 1, 10, or 100 mg/kg/day for 28 days. Mice immunized with antigen on day 24 were evaluated for TDAR and splenic lymphocyte subpopulations five days later. Serum and urine were collected for test compound concentrations and liver peroxisome proliferation was measured. Relative liver weight at 10 and 100 mg/kg and peroxisome proliferation at 100 mg/kg were increased in both sexes. TDAR was suppressed in females at 100 mg/kg. T lymphocyte numbers were increased in males at 100 mg/kg; B lymphocyte numbers were unchanged in both sexes. Females had less serum accumulation and higher clearance than males, and males had higher urine concentrations than females at all times and doses. While this PFOA-replacement compound appears less potent at suppressing TDAR relative to PFOA, it produces detectable changes in parameters affected by PFOA; further studies are necessary to determine its full immunomodulatory profile and potential synergism with other per- and polyfluoroalkyl substances of environmental concern.
URLs/Downloads:
DOI: Evaluation of the Immunomodulatory Effects of 2,3,3,3-Tetrafluoro-2-(Heptafluoropropoxy)-Propanoate in C57BL/6 Mice
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