Department of Toxicology, School of Public Health, Peking University, Beijing Key Laboratory of Toxicological Research and Risk Assessment for Food Safety, 100191 Beijing, PR China.
Department of Toxicology, School of Public Health, Peking University, Beijing Key Laboratory of Toxicological Research and Risk Assessment for Food Safety, 100191 Beijing, PR China.
Toxicology. 2023 Aug 15;495:153601. doi: 10.1016/j.tox.2023.153601. Epub 2023 Jul 31.
2-Acetyl-4-tetrahydroxybutylimidazole (THI), a by-product of Class Ⅲ caramel color, is generally recognized to cause lymphopenia in mammals. However, it remains unknown whether THI exposure during gestation and lactation causes damage to the immune system of offspring. In this study, pregnant Balb/c mice were gavaged with 0, 0.5, 2.5 and 12.5 mg/kg THI from gestation day (GD) 6 to postanal day (PND) 21, after which we treated another batch of dams from GD6 to PND21 and the offspring for 3 weeks after weaning with 0, 2, 10, 50 mg/L THI in drinking water respectively, and investigated the immunological anomalies of dams and offspring. The results showed that lymphopenia was observed in dams but not in weaning pups on PND21, which were exposed to THI during gestation and lactation. 2 mg/L THI and 2.5 mg/kg THI began to cause a remarkable reduction of the numbers of white blood cells and lymphocytes in dams. Besides both the cellular and the humoral immune response was not affected in weaning pups, which were measured by plaque-forming cell (PFC) assay and delayed-type hypersensitivity (DTH) assay respectively. Furthermore, THI could be detected in the plasma of dams with a dose-dependent manner, but not in that of both female and male weaning pups. In both male and female offspring being treated with 10 and 50 mg/L THI for another 3 weeks after weaning, lymphocytopenia was observed and T lymphocytes including CD4 and CD8 cells were significantly reduced in their spleens except lymph nodes. 10 and 50 mg/L THI treatment increased CD4 and CD8 single positive cells in thymus of female and male weaning mice. Mitogen-induced proliferation ability of T cells in the spleen and lymph nodes was impaired in female weaning mice exposed 50 mg/L THI, while male weaning mice treated with 10 and 50 mg/L THI showed impairment in the spleen but not lymph nodes. Based on the results in this study, no observed adverse effect level (NOAEL) for 3-week THI treatment in weaning mice was considered to be 2 mg/L (0.30 mg/kg bw for female mice and 0.34 mg/kg bw for male mice). And NOAEL for THI treatment in dams might be set to 0.5 mg/kg bw/day. Collectively from the perspective of NOAEL, offspring are not more sensitive than dams or adult mice.
2-乙酰基-4-四氢基丁酸咪唑（THI）是 III 类焦糖色素的副产物，通常被认为会导致哺乳动物的淋巴细胞减少。然而，目前尚不清楚妊娠期和哺乳期暴露于 THI 是否会对后代的免疫系统造成损害。在这项研究中，从妊娠第 6 天（GD）到产后第 21 天（PND），给怀孕的 Balb/c 小鼠灌胃 0、0.5、2.5 和 12.5mg/kg 的 THI，之后我们又从 GD6 到 PND21 给另一批母鼠和断奶后的幼鼠喂食 0、2、10、50mg/L 的 THI 水，持续 3 周，并研究了母鼠和幼鼠的免疫异常情况。结果显示，在妊娠期和哺乳期暴露于 THI 的母鼠在 PND21 时出现淋巴细胞减少，但断奶幼鼠并未出现这种情况。2mg/L 的 THI 和 2.5mg/kg 的 THI 开始显著减少母鼠的白细胞和淋巴细胞数量。此外，通过溶血空斑形成细胞（PFC）试验和迟发型超敏反应（DTH）试验分别测量，断奶幼鼠的细胞和体液免疫反应均未受到影响。此外，THI 可以在母鼠的血浆中以剂量依赖的方式检测到，但在雌性和雄性断奶幼鼠的血浆中均未检测到。在断奶后再用 10 和 50mg/L THI 处理 3 周的雄性和雌性子代中，观察到淋巴细胞减少，除淋巴结外，脾脏中的 T 淋巴细胞（包括 CD4 和 CD8 细胞）显著减少。10 和 50mg/L THI 处理增加了雌性和雄性断奶幼鼠胸腺中 CD4 和 CD8 单阳性细胞的数量。在暴露于 50mg/L THI 的雌性断奶幼鼠的脾脏和淋巴结 T 细胞有丝分裂原诱导增殖能力受损，而雄性断奶幼鼠的脾脏和淋巴结 T 细胞增殖能力受损，仅在脾脏中，而不在淋巴结中。基于本研究的结果，认为断奶幼鼠 3 周 THI 处理的未观察到不良效应水平（NOAEL）为 2mg/L（雌性小鼠为 0.30mg/kg bw，雄性小鼠为 0.34mg/kg bw）。THI 处理的母鼠的 NOAEL 可能设定为 0.5mg/kg bw/天。从 NOAEL 的角度来看，子代并不比母代或成年小鼠更敏感。
