Non-genotoxic carcinogens: early effects on gap junctions, cell proliferation and apoptosis in the rat.
Non-genotoxic carcinogens are thought to induce tumour formation by disturbing the balance between cell growth and cell death. Gap junctions (GJ) contribute to the maintenance of tissue homeostasis by allowing the intercellular exchange of growth regulatory signals and potential inhibition of GJ intercellular communication through loss of connexin (Cx) plaques has been shown to be involved in the cancer process. We have investigated the time- and dose-dependent effects of the non-genotoxic hepatocarcinogens Wy-14,643, 2,3,7,8-tetrachlorodibenzo-p-dioxin, methapyrilene and hexachlorobenzene and the male rat kidney carcinogens chloroform, p-dichlorobenzene and d-limonene on gap junction plaque expression in relation to proliferation and apoptosis. With the exception of limonene, all non-genotoxic carcinogens significantly reduced the expression of GJ plaques containing Cx32 in their respective target tissue. No dose-dependent, significant effects were seen in non-target organs. Although alteration of Cx32 expression did not appear to correlate with induction of cell proliferation, out data suggest that the interaction of both processes-interference of GJ coupled with a proliferative stimulus (at the carcinogenic dose)-may be important in non-genotoxic carcinogenesis and provide a potential alert for non-genotoxic carcinogens in short-term toxicity tests.
Mally
Angela
A
School of Biosciences, The University of Birmingham, Edgbaston, B15 2TT, Birmingham, UK.
Chipman
James Kevin
JK
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001835:Body Weight / Q000187:drug effects; D002273:Carcinogens / Q000633:toxicity*; D002455:Cell Division / Q000187:drug effects; D000072259:Connexin 26; D017630:Connexins / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation / Q000187:drug effects; D005260:Female; D017629:Gap Junctions / Q000187:drug effects* / Q000648:ultrastructure; D022781:Hepatocytes / Q000187:drug effects; D007150:Immunohistochemistry; D007668:Kidney / Q000473:pathology; D008099:Liver / Q000473:pathology; D008297:Male; D008701:Methapyrilene / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D051381:Rats; D011916:Rats, Inbred F344; D013997:Time Factors; D000097002:Gap Junction beta-1 Protein
D002273:Carcinogens; D000072259:Connexin 26; D017630:Connexins; D008701:Methapyrilene; D011743:Pyrimidines; D000097002:Gap Junction beta-1 Protein; C006253:pirinixic acid