Liu J, Liu Y, Habeebu S S, Klaassen C D
Department of Pharmacology, Toxicology, and Therapeutics, University of Kansas Medical Center, Kansas City 66160-7417, USA.
Toxicol Appl Pharmacol. 1999 Sep 1;159(2):98-108. doi: 10.1006/taap.1999.8718.
Cadmium (Cd) is an environmental pollutant. Chronic exposure of humans to Cd results in various maladies, including anemia and altered immune function. Metallothionein (MT) has been proposed to play an important role in Cd detoxication. Thus, we hypothesized that intracellular MT protects against Cd-induced hematotoxicity and immunotoxicity. Control and MT-I/II knock-out (MT-null) mice were given s.c. injections of CdCl2 over a wide range of doses, 6 times/week for up to 10 weeks. Cd-induced anemia was evident after 5 weeks of exposure and progressed with time. MT-null mice were about 10 times more susceptible to Cd-induced anemia, as evidenced by decreased erythrocytes (25%), hemoglobin concentration (30%), and hematocrit (35%) after 10 weeks of Cd injections. Cd produced dose- and time-dependent increases in neutrophils (7x), along with a marked elevation of serum IL-1 beta (6x) and TNF-alpha (20x) levels. MT-null mice were more susceptible than controls to Cd-induced alterations in peripheral leukocytes and cytokine levels. Chronic exposure to Cd also produced dose- and time-dependent splenomegaly (5x), with loss of lymphoid structure, inflammation, hyperplasia, appearance of giant cells, and fibrosis. Thymus weights were decreased by Cd in a dose-dependent manner (60%). MT-null mice were also approximately 10 times more susceptible than controls to these lesions. In conclusion, the present study demonstrates that repeated injections of Cd produces hematotoxic and immunotoxic effects, and intracellular MT protects against these chronic Cd-induced effects.
镉（Cd）是一种环境污染物。人类长期接触镉会导致多种疾病，包括贫血和免疫功能改变。金属硫蛋白（MT）被认为在镉解毒过程中起重要作用。因此，我们假设细胞内的MT可保护机体免受镉诱导的血液毒性和免疫毒性。对野生型和MT-I/II基因敲除（MT基因缺失）小鼠皮下注射不同剂量的CdCl₂，每周6次，持续10周。接触镉5周后，镉诱导的贫血明显，并随时间进展。MT基因缺失小鼠对镉诱导的贫血的易感性约为野生型小鼠的10倍，在注射镉10周后，红细胞数量减少25%，血红蛋白浓度降低30%，血细胞比容下降35%，均可证明这一点。镉使中性粒细胞数量呈剂量和时间依赖性增加（7倍），同时血清白细胞介素-1β（IL-1β）水平显著升高（6倍），肿瘤坏死因子-α（TNF-α）水平升高20倍。MT基因缺失小鼠比野生型小鼠更易受到镉诱导的外周白细胞和细胞因子水平变化的影响。长期接触镉还会导致脾脏肿大呈剂量和时间依赖性（5倍），伴有淋巴结构丧失、炎症、增生、巨细胞出现和纤维化。镉使胸腺重量呈剂量依赖性下降（60%）。MT基因缺失小鼠对这些损伤的易感性也比野生型小鼠高约10倍。总之，本研究表明，反复注射镉会产生血液毒性和免疫毒性作用，而细胞内的MT可保护机体免受这些慢性镉诱导的影响。
