The effects of lead and cadmium on GATA-1 regulated erythroid gene expression.

Lead (Pb) and cadmium (Cd) are heavy metal toxins that cause many pathophysiologic effects, including anemia. Previous in vitro studies have shown that these metals are able to replace coordinated Zinc (Zn) atoms in the Zn fingers of transcription factors and that this can alter the structure and DNA-binding characteristics of these proteins. This has lead to the hypothesis that one mechanism underlying the toxic effects of Pb and Cd is their ability to alter Zn finger transcription factor function resulting in aberrant target gene expression. A recent report that Pb is able to replace Zn in the Zn fingers of the hematopoietic transcription factor GATA-1 prompted us to address this hypothesis in the setting of MEL cell differentiation. If Pb or Cd is able to inhibit GATA-1 function, this should be detectable through alterations in chemically induced erythroid differentiation and GATA-1-dependent gene expression. Despite a strong rationale for this hypothesis, we have found no significant change in MEL differentiation, the expression of several GATA-1 target genes, or of in vitro and in vivo GATA-1 binding to DNA at concentrations well above those associated with toxic effects in humans. These results argue against the hypothesis that Pb or Cd significantly alters GATA-1 function in vivo.