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Differences between rats and mice in the immunosuppressive activity of 2-methoxyethanol and 2-methoxyacetic acid
R J Smialowicz1, M M Riddle, W C Williams
1Health Effects Research Laboratory, U.S. Environmental Protection Agency, Research Triangle Park, NC 27711.
Abstract:
Previous studies from this laboratory have demonstrated that 2-methoxyethanol (ME) and its principal metabolite 2-methoxyacetic acid (MAA) are immunosuppressive in young adult male Fischer 344 rats. In the present study, the immunosuppressive potential of ME and MAA was evaluated in young adult female Fischer 344 rats and C57BL/6J mice. Rats and mice were dosed by gavage with either ME or MAA in water, at dosages ranging from 50-400 mg/kg/day, for 10 consecutive days. Rats and mice were examined for alterations in body, spleen and thymus weights and mitogen-induced proliferation of splenic lymphocytes in vitro; separate groups were employed for the antibody plaque-forming cell (PFC) response to trinitrophenyl-lipopolysaccharide (TNP-LPS). Rats dosed at 100-400 mg/kg/day ME and rats dosed at 50-400 mg/kg/day MAA had decreased thymus weights in the absence of decreased body or spleen weights. Lymphoproliferative (LP) responses to concanavalin A (Con A), phytohemagglutinin (PHA), pokeweed mitogen (PWM) and Salmonella typhimurium mitogen (STM) were all reduced in rats treated with all dosages of ME. Rats treated with MAA displayed similar reductions in these LP responses except that the responses to PWM and STM in rats dosed at 50 mg/kg/day were not reduced. In contrast to the effects of ME and MAA on these end points in the rat, no thymic involution or suppression of LP responses were observed in mice dosed at 50-400 mg/kg/day. The PFC response to TNP-LPS was suppressed in rats dosed with either ME or MAA at dosages of 100-400 mg/kg/day. ME and MAA, however, failed to suppress the PFC response in mice immunized with TNP-LPS. These results indicate that unlike Fischer 344 rats, C57BL/6J mice are insensitive to the immunosuppressive effects of ME and MAA at the dosages employed in this study. Whether the different sensitivities of these two rodent species to ME- and MAA-induced immunosuppression are due to immunologic, pharmacokinetic or metabolic differences within each species remains to be determined.
Insights
2-methoxyethanol (ME) and 2-methoxyacetic acid (MAA) suppressed immune responses in female rats but not in C57BL/6J mice. This study highlights species-specific differences in sensitivity to these immunosuppressive chemicals.
Area of Science:
- Toxicology
- Immunology
- Pharmacology
Background:
- Previous studies indicated 2-methoxyethanol (ME) and its metabolite 2-methoxyacetic acid (MAA) are immunosuppressive in male rats.
- The immunosuppressive potential in females and a different species remained unevaluated.
Purpose of the Study:
- To evaluate the immunosuppressive effects of ME and MAA in young adult female Fischer 344 rats and C57BL/6J mice.
- To compare species-specific sensitivities to ME and MAA toxicity.
Main Methods:
- Rats and mice were administered ME or MAA (50-400 mg/kg/day) via gavage for 10 days.
- Assessed body, spleen, and thymus weights, and in vitro lymphocyte proliferation.
- Measured antibody plaque-forming cell (PFC) response to trinitrophenyl-lipopolysaccharide (TNP-LPS).
Main Results:
- Female rats exhibited decreased thymus weights and suppressed lymphoproliferative (LP) responses to mitogens with ME and MAA exposure.
- PFC responses were suppressed in rats treated with ME or MAA at higher doses.
- Mice showed no significant changes in thymus weight, LP responses, or PFC response, indicating insensitivity.
Conclusions:
- Fischer 344 rats are sensitive to the immunosuppressive effects of ME and MAA, evidenced by thymus involution and suppressed immune cell functions.
- C57BL/6J mice are insensitive to ME and MAA immunosuppression at the tested dosages.
- Species-specific differences in immunologic, pharmacokinetic, or metabolic factors may explain the varying sensitivities.