COVALENT MODIFICATION OF HEMOGLOBIN BY CARBON-DISULFIDE - III - A POTENTIAL BIOMARKER OF EFFECT

Although the neurotoxicity of CS2 has been recognized for over a centu ry, presently there is no accepted biomarker of effect for CS2 exposur e. Previous investigations ha ve supported covalent crosslinking of er ythrocyte spectrin as a potential preneurotoxic marker reflective of t he biochemical changes occurring within the axon. In the present inves tigation, the potential of using CS2 promoted modification of hemoglob in as a dosimeter for quantifying exposure to CS2 was evaluated. Liqui d chromatography was used to isolate and measure alpha and beta chains of globin in blood obtained from rats exposed to CS2 by inhalation as a function of exposure level and duration. The degree of globin modif ication was compared to light microscopic and ultrastructural changes in the central and peripheral nervous systems to determine the tempora l relationship of globin modification to the structural changes in the axon. Samples obtained from rats exposed to CS2 contained a globin ch ain not present in control samples. Analysis of the peak corresponding to the new chain using electrospray mass spectrometry was consistent with the generation of a single dithiocarbamate ester or thiourea intr amolecular cross-link in the alpha(1) major chain. This altered globin chain was detectable both at the subneurotoxic level of exposure and prior to axonal structural changes at the neurotoxic levels of exposur e used. The extent of modification was positively correlated to the ex posure level and duration for all conditions examined. These findings support hemoglobin as a potential preneurotoxic biomarker of effect fo r CS2 possessing several practical advantages relative to the use of C S2 mediated spectrin cross-linking. (C) 1998 Intox Press, Inc.