title: Repeated high dose oral exposure or continuous subcutaneous infusion of 2-methoxyacetic acid does not suppress humoral immunity in the mouse.
abstract: 2-Methoxyethanol (ME) has been shown to be immunosuppressive in rats but not mice, with oxidation of ME to 2-methoxyacetic acid (MAA) being a prerequisite for immunosuppression. MAA is more rapidly cleared by mice than rats, consequently this study was designed to determine if increasing the bioavailability of MAA in mice might play a role in this species difference. Female B6C3F1 mice were given MAA by oral multiple daily high doses or by continuous subcutaneous infusion via mini-osmotic pumps. Humoral immunity was evaluated in MAA-exposed mice using the plaque-forming cell (PFC) response to either sheep red blood cells (SRBC) or trinitrophenyl-lipopolysaccharide (TNP-LPS). Female F344 rats were also used to compare the effects of multiple daily MAA exposure on these humoral immune responses. Rats and mice were dosed orally twice a day for 4 days by gavage with MAA at dosages ranging from 40-320 mg/kg/day and 240-1920 mg/kg/day, respectively. All animals were immunized on the first day of dosing and body and lymphoid organ weights and PFC responses to SRBC or TNP-LPS were evaluated 4 days later. While body weights in rats were unaffected, thymus weights were reduced at all dosages of MAA and spleen weights were reduced at 160 or 320 mg/kg/day. PFC responses to SRBC and TNP-LPS were suppressed in rats at dosages of 160 and 320 mg/kg/day. In contrast, thymus weights of mice were reduced only at 960 mg/kg/day or greater, with no effect on spleen or body weights. Furthermore, neither the PFC response to SRBC nor the response to TNP-LPS was suppressed in mice exposed to any oral dosage of MAA. In the continuous infusion study, mice were subcutaneously implanted with mini-osmotic pumps containing MAA which was delivered at 840 mg/kg/day over a 7-day period. Continuous exposure to MAA via mini-osmotic pumps did not suppress the PFC response to either SRBC or TNP-LPS, but rather significantly enhanced the response to TNP-LPS. These results indicate that mice are insensitive to MAA even at the high dosages given as a bolus or continuously over 1 week. The data further support earlier work, which suggested that the observed difference between rats and mice for MAA-induced immunosuppression appears to be unrelated to the availability of MAA to target lymphoid tissue in these rodent species.
authors.affiliation: National Health and Environmental Effects Research Laboratory, U.S. Enviromental Protection Agency, Research Triangle Park, NC 27711, USA.
authors.forename: M M
authors.initials: MM
authors.lastname: Riddle
authors.forename: W C
authors.initials: WC
authors.lastname: Williams
authors.forename: R J
authors.initials: RJ
authors.lastname: Smialowicz
mesh_terms: D000085:Acetates / Q000008:administration & dosage / Q000633:toxicity*; D000284:Administration, Oral; D000818:Animals; D000917:Antibody Formation / Q000187:drug effects* / Q000276:immunology; D000955:Antigens, T-Independent / Q000008:administration & dosage / Q000633:toxicity; D001682:Biological Availability; D004305:Dose-Response Relationship, Drug; D004912:Erythrocytes / Q000166:cytology; D005260:Female; D006462:Hemolytic Plaque Technique; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000633:toxicity*; D015918:Infusion Pumps, Implantable; D007279:Injections, Subcutaneous; D008070:Lipopolysaccharides / Q000008:administration & dosage / Q000633:toxicity; D051379:Mice; D009929:Organ Size / Q000187:drug effects; D009994:Osmolar Concentration; D051381:Rats; D011916:Rats, Inbred F344; D012756:Sheep; D013045:Species Specificity; D013154:Spleen / Q000187:drug effects; D013950:Thymus Gland / Q000187:drug effects / Q000378:metabolism
chemical_list: D000085:Acetates; D000955:Antigens, T-Independent; D007166:Immunosuppressive Agents; D008070:Lipopolysaccharides; C048761:trinitrophenyl-lipopolysaccharide; C013598:methoxyacetic acid