The role of metabolism in 2-methoxyethanol-induced suppression of in vitro polyclonal antibody responses by rat and mouse lymphocytes

Abstract

Previous studies from this laboratory have shown that the glycol ether 2-methoxyethanol (ME) produces immunosuppression in the rat but not in the mouse. To investigate possible mechanisms for this species difference in ME-induced immunotoxicity, the effects of ME and its metabolites, 2-methoxyacetic acid (MAA) and 2-methoxyacetaldehyde (MAAD), on in vitro polyclonal antibody responses by Fisher 344 rat and B6C3F1 mouse lymphocytes, were studied. MAAD and MAA suppressed IgM and IgG production by both mouse and rat lymphocytes at non-cytotoxic doses. However, ME had no effect on antibody production by either mouse or rat lymphocytes. Lower concentrations of MAA suppressed rat lymphocyte IgM and IgG production (at 0.5 and 1.0 mM MAA, respectively) compared with mouse lymphocytes (2.0 mM MAA). IgM and IgG production by both rat and mouse lymphocytes was suppressed at comparable concentrations of MAAD (0.3 mM MAAD). The role that metabolism of ME to its immunosuppressive forms plays in this in vitro suppression was demonstrated using hepatocyte-lymphocyte co-cultures. IgM production by both mouse and rat lymphocytes was suppressed at a lower concentration of ME following co-culture with mouse (12.5 mM ME) versus rat (25 and 50 mM ME) hepatocytes. These in vitro results indicate that rat lymphocytes are more sensitive to MAA than are mouse lymphocytes and that mouse hepatocytes have a greater capacity to metabolize ME to its immunosuppressive metabolites than do rat hepatocytes. In addition, MAAD is more immunotoxic than MAA, suggesting that this metabolite may be the proximate immunotoxicant. These observation may partially explain the species differences in ME-induced immunosuppression in vivo.