CHEMICAL MODULATION OF METALLOTHIONEIN-I AND METALLOTHIONEIN-III MESSENGER-RNA IN MOUSE-BRAIN

Metallothioneins (MTs) are sulfhydryl-rich proteins. MT-I and MT-II ar e found in all tissues of the body, while MT-III exists only in brain. Regulation of MT-I and MT-III mRNA was studied in brain and liver of control C57BL/6J mice and mice given chemicals known to increase MT-I, namely, lipopolysaccharide (LPS), zinc chloride (Zn), cadmium chlorid e (Cd), dexamethasone (Dex), ethanol, and kainic acid (KA). Northern b lot analysis revealed that MT-I mRNA levels in liver were induced dram atically (12-27-fold over basal levels) by all of the chemicals, while in brain only LPS produced an increase in MTI mRNA (2-fold). Interest ingly, the MT-I inducers, Cd, Dex, ethanol, and KA, down-regulated bra in MT-III mRNA levels by approx. 30%. Because brain is such a heteroge nous tissue, in situ hybridization was used to localize MT-I and MT-II I mRNA in control and treated mice. MT-I mRNA signal, which was most a bundant in the glial cells of the Purkinje cell layer of the cerebellu m in control mice, appeared to be enhanced in mice given the MT-I indu cers (LPS, Zn, Cd, Dex, ethanol, and KA). MT-I mRNA hybridization sign al was also enhanced in the olfactory bulbs from LPS- and Cd-treated m ice, while this signal was present but weak in control brains. MT-III mRNA hybridization signals were localized in hippocampus and co-locali zed with MT-I message in the glial cells of the Purkinje cell layer of the cerebellum. In addition, diffuse MT-III mRNA signals were visible in areas of the cerebral cortex, and in the molecular layer of the ce rebellum. Signals for MT-III in hippocampus appeared to be reduced by KA, Dex and LPS treatment, while in the cortical region, MT-III mRNA s ignals appeared to be enhanced by KA, Cd, and ethanol treatment. In co nclusion, both MT-I and MT-III expression in brain appears to be modul ated by exogenous treatment, however, the changes are small in relatio n to those observed in liver. Chemical-induced alterations of MT mRNA are non-uniform throughout the brain, and thus best studied in a regio n-specific manner.