Evaluation of the immunotoxicity of orally administered 2-methoxyacetic acid in Fischer 344 rats.
We previously demonstrated that the glycol ether 2-methoxyethanol (ME) is immunotoxic in the rat. In this study, the immunotoxicity of 2-methoxyacetic acid (MAA), the principal metabolite of ME, was evaluated in adult male Fischer 344 rats. Rats were dosed by gavage with MAA on 10 consecutive days at dosages ranging from 50 to 200 mg/kg/day. Thymic involution, in the absence of body weight loss, was observed at 100 and 200 mg/kg/day MAA. Lymphoproliferative responses to the mitogens concanavalin A, phytohemagglutinin, and pokeweed mitogen were also reduced at these dosages. The in vitro generated cytotoxic T lymphocyte response was reduced at 200 mg/kg/day MAA. The mixed lymphocyte reaction and natural killer cell activity were unaffected by exposure to MAA. Enumeration of splenic lymphocyte populations revealed a reduction in the percentage of W3/25-positive cells at 100 and 150 mg/kg/day and an increase in the percentage of OX39-positive cells at 200 mg/kg/day; however, no changes in the absolute number of either of these subsets were observed. The plaque forming cell (PFC) response to trinitrophenyl-lipopolysaccharide (TNP-LPS) was suppressed at 50-200 mg/kg/day MAA, while the PFC response to sheep red blood cells (SRBC) was elevated at 50 mg/kg/day. Immunization of rats with TNP-LPS or SRBC followed by oral exposure to MAA at 4 and 28 hr postimmunization resulted in the suppression of the PFC response to TNP-LPS and SRBC at dosages of 100 and 200 mg/kg and 200 and 400 mg/kg, respectively. Equal suppression of the PFC response to TNP-LPS was achieved at equimolar concentrations of ME and MAA. The effects of MAA on the immune system of the rat presented here are very similar to results reported from this lab for ME-induced immune alterations. These results, along with results of experiments in which ME-induced suppression of the PFC response to TNP-LPS was reversed by 4-methylpyrazole, an inhibitor of the oxidation of ME to MAA by alcohol dehydrogenase, indicate that MAA is the proximate immunotoxicant following exposure to the glycol ether 2-methoxyethanol.
Smialowicz
R J
RJ
Health Effects Research Laboratory, U.S. Environmental Protection Agency, Research Triangle Park, North Carolina 27711.
Riddle
M M
MM
Rogers
R R
RR
Copeland
C B
CB
Luebke
R W
RW
Andrews
D L
DL
D000085:Acetates / Q000633:toxicity*; D000818:Animals; D001835:Body Weight / Q000187:drug effects; D004912:Erythrocytes / Q000276:immunology; D005026:Ethylene Glycols / Q000633:toxicity; D006462:Hemolytic Plaque Technique; D007109:Immunity / Q000187:drug effects*; D007694:Killer Cells, Natural / Q000187:drug effects; D008214:Lymphocytes / Q000187:drug effects / Q000276:immunology; D008297:Male; D008934:Mitogens / Q000494:pharmacology; D009929:Organ Size / Q000187:drug effects; D051381:Rats; D011916:Rats, Inbred F344; D012756:Sheep; D013154:Spleen / Q000166:cytology / Q000187:drug effects; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology
D000085:Acetates; D005026:Ethylene Glycols; D008934:Mitogens; C005219:methyl cellosolve; C013598:methoxyacetic acid