Smialowicz R J, Riddle M M, Luebke R W, Copeland C B, Andrews D, Rogers R R, Gray L E, Laskey J W
Health Effects Research Laboratory, U.S. Environmental Protection Agency, Research Triangle Park, North Carolina.
Toxicol Appl Pharmacol. 1991 Jul;109(3):494-506. doi: 10.1016/0041-008x(91)90012-4.
The immunotoxicity of the glycol ether 2-methoxyethanol (ME) was evaluated in adult Fischer 344 rats using a variety of in vitro and in vivo immune function assays. In the first phase of this study, male rats were dosed by oral gavage with ME in water, at dosages ranging from 50 to 200 mg/kg/day, for 10 consecutive days. Decreases in thymus weights were observed at dosages of 50-200 mg/kg/day in the absence of decreased body weights. Lymphoproliferative (LP) responses to concanavalin A and phytohemagglutinin were reduced at 50-200 mg/kg/day while pokeweed mitogen and Salmonella typhimurium mitogen responses were reduced at 200 mg/kg/day. No alterations were observed in natural killer cell activity, mixed lymphocyte reaction, or cytotoxic T lymphocyte responses. The frequency of W3/25-positive splenocytes was reduced in rats dosed at 200 mg/kg/day. Interleukin-2 production was reduced in splenocytes from rats exposed to all dosages of ME. The plaque-forming cell (PFC) response to sheep red blood cells was enhanced in rats dosed at 50 mg/kg/day. However, the PFC response to trinitrophenyl-lipopolysaccharide (TNP-LPS) was suppressed at all dosages. Similarly, the PFC response to TNP-LPS was suppressed in adult female rats dosed with ME. A reduction in the expulsion of adult worms was observed in rats dosed at 200 mg/kg/day that were infected with Trichinella spiralis. A number of male reproductive parameters were also evaluated in rats dosed with ME over 10 days. A significant reduction in testicular weight was observed in rats dosed at 200 mg/kg/day. In the second phase of this study, the PFC response to TNP-LPS was employed to assess the role that metabolism of ME to 2-methoxyacetic acid (MAA) plays in the immunotoxicity of this glycol ether. Ten-day oral dosing with MAA resulted in the inhibition of the PFC response to TNP-LPS at dosages of 50-200 mg/kg/day. Concomitant exposure of rats to ME and the alcohol dehydrogenase inhibitor 4-methylpyrazole blocked ME-induced suppression of this PFC response. Attempts to ameliorate ME-induced suppression of the PFC response with serine, which has been shown to reverse ME-induced developmental and reproductive toxicity, were unsuccessful. These results suggest that the immune system may be more sensitive than the reproductive system to the toxic effects of ME. Furthermore, it appears that MAA is the proximate toxicant for ME-induced alterations in the immune system, as has been demonstrated for ME-induced reproductive and developmental toxicity.
使用多种体外和体内免疫功能测定方法，在成年Fischer 344大鼠中评估了乙二醇醚2-甲氧基乙醇（ME）的免疫毒性。在本研究的第一阶段，雄性大鼠经口灌胃给予水中的ME，剂量范围为50至200 mg/kg/天，连续10天。在体重未降低的情况下，在50 - 200 mg/kg/天的剂量下观察到胸腺重量减轻。在50 - 200 mg/kg/天的剂量下，对刀豆球蛋白A和植物血凝素的淋巴细胞增殖（LP）反应降低，而在200 mg/kg/天的剂量下，对商陆有丝分裂原和鼠伤寒沙门氏菌有丝分裂原的反应降低。自然杀伤细胞活性、混合淋巴细胞反应或细胞毒性T淋巴细胞反应未观察到改变。在给予200 mg/kg/天剂量的大鼠中，W3/25阳性脾细胞的频率降低。暴露于所有剂量ME的大鼠脾细胞中白细胞介素-2的产生减少。在给予50 mg/kg/天剂量的大鼠中，对绵羊红细胞的空斑形成细胞（PFC）反应增强。然而，在所有剂量下，对三硝基苯基脂多糖（TNP-LPS）的PFC反应均受到抑制。同样，给予ME的成年雌性大鼠中，对TNP-LPS的PFC反应也受到抑制。在感染旋毛虫的大鼠中，给予200 mg/kg/天剂量时观察到成虫排出减少。还对给予ME 10天的大鼠评估了一些雄性生殖参数。在给予200 mg/kg/天剂量的大鼠中观察到睾丸重量显著降低。在本研究的第二阶段，采用对TNP-LPS的PFC反应来评估ME代谢为2-甲氧基乙酸（MAA）在这种乙二醇醚免疫毒性中所起的作用。用MAA进行10天口服给药，在50 - 200 mg/kg/天的剂量下导致对TNP-LPS的PFC反应受到抑制。大鼠同时暴露于ME和乙醇脱氢酶抑制剂4-甲基吡唑可阻断ME诱导的这种PFC反应的抑制。尝试用丝氨酸改善ME诱导的PFC反应抑制，丝氨酸已被证明可逆转ME诱导的发育和生殖毒性，但未成功。这些结果表明，免疫系统可能比生殖系统对ME的毒性作用更敏感。此外，似乎MAA是ME诱导免疫系统改变 的直接毒物，这已在ME诱导的生殖和发育毒性中得到证实。
