METALLOTHIONEIN TRANSGENIC AND KNOCK-OUT MOUSE MODELS IN THE STUDY OF CADMIUM TOXICITY

Abstract

The role of MT in Cd toxicology has become clearer by the use of MT-I transgenic and MT-I and -II knock-out animals. We have shown that:(1)MT-transgenic and -null mice have altered tissue MT protein levels;(2)MT-transgenic and-null mice appear to be normal in other detoxifyng systems examined, except for slight alterations in tissue Zn concentration;(3)MT does not appear to inhibit Cd absorption from the gestrointestinal tract, nor affect Cd tissue distribution;(4)MT reduces the elimination of Cd from liver;(5)MT protects against acute inorganlc Cd-induced lethality and hepatotoxicity, and the mechanism of the protection appears to be due to its ability to sequester Cd in the cytosol, thus reducing the amunt of Cd in critical organelles;(6)MT modulates Cd-induced expression of protooncogene(c-jin) and tumor suppress genes(p53) in mouse liver;(7)MT does not protect against CdMT-induced acute renal injury, and Zn-induced protection against CdMT-induced acute nephrotoxicity does not appcear to be mediated through MT;(8)Chronic Cd administration produces renal injury inb MT-null mice, indicating that Cd-induced nephrotoxicity is not necessarily mediated through the CdMT complex;(9)MT protects against chronic CdC12 nephropathy, suggesting that intracellular MT is an important adaptive mechanism decreasing CdC12 nephrotoxicity, and that a single injection of CdMT may not be a good model to study chronic Cd nephropathy;(10)genetic background of mouse strains, rather than constitutive MT levels, is a more important determinant for Cd-induced acute testicular injury. In addition to Cd detoxication, MT-transgenic and MT-null mice are also good models to determine other functions of MT. MT plays important roles in maintaining Zn homeostasis and protection against Zn toxicity. Knock-out of the MT gene also renders animals/cells more vulnerable to oxidative stress and DNA alkylating agent-induced toxicity. Therefore, the MT-transgenic and knock-out mouse models provide complementary approaches to those used previously, and have greatly increased our understanding of the role of MT in Cd toxicology, as well as other biological functions of MT.