title: 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.
abstract: Apoptosis was evaluated in the livers of Fischer-344 rats following observations of increased hepatocellular proliferation from exposures, at low parts per million (ppm) levels, to a drinking water mixture of 7 groundwater contaminants during a 6-mo time-course study. The 7 chemicals used are among the most frequently detected contaminants associated 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 pattern surrounding large hepatic veins (0.5-2.0 mm). This did not appear to be a regenerative response due to cytotoxicity, as assessed by the absence of increased plasma enzyme activity and the absence of hepatocellular lesions. Immunohistochemical staining for apoptosis, using the terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling (TUNEL) method showed patterns of labeling in treated animals that directly correlated to areas of increased hepatocyte proliferation. Apoptotic activity was maximum at the 1-mo exposure time point, whereas proliferating hepatocytes reached a maximum rate at the 10-day time point. This may have been triggered as a compensatory response to the increased cell proliferation or as a protective response to remove cells 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 stages, potentially increasing the observable time period for apoptosis.
authors: Department of Environmental Health, Colorado State University, Fort Collins 80523, USA. constan@ciit.org
authors: A A
authors: AA
authors: Constan
authors: S A
authors: SA
authors: Benjamin
authors: J D
authors: JD
authors: Tessari
authors: D C
authors: DC
authors: Baker
authors: R S
authors: RS
authors: Yang
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D001973:Bromodeoxyuridine; D002455:Cell Division / Q000187:drug effects; D005821:Genetic Techniques; D006503:Hepatic Veins / Q000473:pathology; D006651:Histocytochemistry; D008099:Liver / Q000473:pathology*; D008297:Male; D051381:Rats; D011916:Rats, Inbred F344; D014874:Water Pollutants, Chemical / Q000633:toxicity*; D014881:Water Supply / Q000032:analysis*
chemical_list: D014874:Water Pollutants, Chemical; D001973:Bromodeoxyuridine