Evaluating Intracellular Signaling Pathways as Biomarkers for Environmental Contaminant Exposures

The number of biomarkers being evaluated as environmental indicatorscontinues to increase even as proposed assessments expand incomplexity. One key to a rational consolidation may lie in clearlyidentifying and characterizing those biochemical pathways sharedamong many biomarkers which are sensitive to environmental perturbation.Recent studies suggest that signal transduction pathways whichare common to many cell types and species may provide multipletargets for the toxic effects of heavy metals. Such intracellularcommunication pathways might provide a useful framework forunderstanding hormetic effects and for predicting responsesto complex contaminant mixtures. Preliminary in vitro experimentstested the effects of mercuric chloride (HgCl₂) and cadmiumchloride (CdCl₂) on signal transduction in cells of the teleostimmune system. Concentrations of inorganic mercury µMsuppressed DNA synthesis and induced rapid influx of radiolabelledcalcium within ten minutes as well as tyrosine phosphorylationof numerous cellular proteins within one minute. Lower concentrations(0.1 – 1 µM) of HgCl₂ which activated cell growthalso induced a slow rise over two minutes in intracellular calciumin cells loaded with the calcium indicator dye, fura-2, butdid not produce detectable tyrosine phosphorylation of leukocyteproteins. Although CdCl₂ >10 µM also suppressed DNAsynthesis, this environmental metal failed to activate cellgrowth or to induce tyrosine kinase activity at any concentrationtested. Future experiments will assess how cells which are exposedto both metals integrate these mixed signals. This approachmay provide a means of predicting cellular responses to multiplecontaminants over broad dose ranges