1995 STP YOUNG-INVESTIGATOR-AWARD RECIPIENT - INCREASED RATE OF APOPTOSIS CORRELATES WITH HEPATOCELLULAR PROLIFERATION IN FISCHER-344 RATS FOLLOWING LONG-TERM EXPOSURE TO A MIXTURE OF GROUNDWATER CONTAMINANTS

Apoptosis was evaluated in the livers of Fischer-344 rats following ob servations of increased hepatocellular proliferation from exposures, a t low parts per million (ppm) levels, to a drinking water mixture of 7 groundwater contaminants during a 6-mo timecourse study. The 7 chemic als used are among the most frequently detected contaminants associate d with hazardous waste sites: arsenic, benzene, chloroform, chromium, lead, phenol, and trichloroethylene. Significant increases in 5-bromo- 2'-deoxyuridine hepatocellular labeling were present in a unique patte rn surrounding large hepatic veins (0.5-2.0 mm). This did not appear t o be a regenerative response due to cytotoxicity, as assessed by the a bsence of increased plasma enzyme activity and the absence of hepatoce llular lesions. Immunohistochemical staining for apoptosis, using the terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end la beling (TUNEL) method showed patterns of labeling in treated animals t hat directly correlated to areas of increased hepatocyte proliferation . Apoptotic activity was maximum at the 1-mo exposure time point, wher eas proliferating hepatocytes reached a maximum rare at the 10-day tim e point. This may have been triggered as a compensatory response to th e increased cell proliferation or as a protective response to remove c ells with altered DNA due to chemical mixture exposure. The principal findings of this paper are that (a) apoptosis directly correlated with changes in cell proliferation; (b) observed effects were produced by repeated exposures to a relatively low-level chemical mixture; and (c) the TUNEL method detected apoptotic cells at very early and late stag es, potentially increasing the observable time period for apoptosis.