Hepatic ploidy, nuclearity, and distribution of DNA synthesis: a comparison of nongenotoxic hepatocarcinogens with noncarcinogenic liver mitogens

Toxicology and Applied Pharmacology
Susan Hasmall, R A Roberts

Abstract

Most nongenotoxic hepatocarcinogens such as diethylhexyl phthalate (DEHP) and chlorendic acid (CEA) induce hepatocyte replicative DNA synthesis. However, not all mitogens are carcinogenic; in National Toxicology Program (NTP) studies 1,4-dichlorobenzene (DCB) was not hepatocarcinogenic in the rat despite the induction of substantial hepatic DNA synthesis. We have examined the hypothesis that the profile of hepatocyte labeling index (LI) may dictate hepatocarcinogenic potential. Using flow cytometry, we investigated the effects of DEHP, CEA, and DCB on hepatocyte ploidy, nuclearity, and LI distribution among the ploidy/nuclearity classes in male Fischer 344 rats. Dosing was for 7 days at the dose and route employed previously in the NTP cancer bioassays. Unlike DEHP and CEA, DCB reduced the proportion of tetraploid cells (4N plus 2 x 2N) and increased the proportion of mononucleated octoploid (8N) cells. DCB and DEHP increased the mean hepatic LI (17 +/- 2 and 23 +/- 3%, respectively, compared with 1.4 +/- 0.4% in controls), whereas, as expected for a chronic inducer of S-phase, CEA did not. LI was increased in all hepatocyte ploidy/nuclearity classes except the binucleated tetraploid cells (2 x 2N) and was elevated most in the ...Continue Reading

Citations

Oct 30, 2003·Journal of Cellular Physiology·Irma BuiraMaria Soley
Nov 15, 2012·International Journal of Hepatology·Géraldine GentricSéverine Celton-Morizur
Apr 10, 2012·Mutation Research·Jane C Caldwell
Jan 27, 2015·The Journal of Clinical Investigation·Géraldine GentricChantal Desdouets
Feb 21, 2003·Biochemical and Biophysical Research Communications·Elizabeth A ConnerSnorri S Thorgeirsson
Feb 18, 2003·The Journal of Histochemistry and Cytochemistry : Official Journal of the Histochemistry Society·Eugenia LamasPascale Debey
Aug 30, 2007·Mammalian Genome : Official Journal of the International Mammalian Genome Society·Pin LuDavid J Harrison
Jul 31, 2003·The Journal of Nutrition·Hélène MartinAlain Berthelot

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