Alteration in expression of gap junction proteins in rat liver after treatment with the tumour promoter 3,4,5,3′,4′-pentachiorobiphenyl

Abstract

Polychlorinated biphenyls (PCBs) are industrial chemicals which are highly persistent and widely distributed in the environment. We have previously shown that 3,4,5,3',4'-pentachlorobiphenyl (PCB 126) is a potent tumour promoter in two separate 20 week initiation-promotion studies. In the present study, rat livers from these two studies were further investigated for connexin expression. The results demonstrated that treatment with PCB 126 caused a decrease in the amount of the two major liver connexins, cx 26 and cx 32, in livers of treated animals. This reduction was also prominent after treatment at low doses, although gamma-glutamyl transpeptidase-positive foci had not developed in these livers. The quantity of cx 26 and cx 32 in immunostained liver sections was determined using a computerized fluorescence image analyzer. Western blot analysis of liver extracts confirmed these results. No changes in the RNA levels in the treated rats were seen, suggesting that the down-regulation of cx 26 and cx 32 is post-transcriptional.

Interaction of 3,4,5,3′,4′‐Pentachlorobiphenyl and 2,4,5,2′,4′,5′‐Hexachlorobiphenyl in Promotion of Altered Hepatic Foci in Rats

“…The two PCBcongeners are potent enhancers of GGT-positive altered hepatic focus development as shown by Hemming et al (1993). However, inhibition of gap junction intercellular communication has been thought to play an important role (Hemming et al 1991;Bager et al 1994). In contrast to the non-planar PCB 153 the planar PCB 126 has a high dioxin-like activity and its toxic effects are probably mediated by binding to the Ah-receptor (arylhydrocarbon-receptor) which initiate induction of several different enzymes including induction of CYPlAl (Safe et al 1985).…”

“…Although it is generally accepted that the dioxin-like PCBs mediate their toxic effects via the Ahreceptor little is known about the mechanisms behind the focus formation caused by dioxin-like and no-dioxin-like PCBs. However, inhibition of gap junction intercellular communication has been thought to play an important role (Hemming et al 1991;Bager et al 1994).…”

The E3 ubiquitin ligase NEDD4 induces endocytosis and lysosomal sorting of connexin 43 to promote loss of gap junctions

“…There is increasing evidence that modulation of the connexin endocytosis and turnover rate represents an important mechanism by which cells regulate the level of gap junctions at the plasma membrane under basal conditions (Falk et al, 2014;Johnson et al, 2013;Laing and Beyer, 1995;Laing et al, 1997;Laird, 2006;Musil et al, 2000;Qin et al, 2003;Rivedal and Leithe, 2005;VanSlyke and Musil, 2005). Moreover, many growth factors, oncogenes and tumor-promoting agents are potent inducers of connexin endocytosis and degradation (Bager et al, 1994;Guan and Ruch, 1996;Krutovskikh et al, 1995;Mograbi et al, 2003;Oh et al, 1991). Endocytosis of gap junctions involves the formation of a double-membrane vacuole called an annular gap junction or connexosome.…”

Inhibition of gap junctional intercellular communication in normal human breast epithelial cells after treatment with pesticides, PCBs, and PBBs, alone or in mixtures.

“…This trend has been attributed to risk factors such as more women smoking and increased oral contraceptive use, as well as early menarche, late menopause, family history, "delayed" childbearing, and potential exposure to various environmental chemicals (1,47). There is growing concern that a large number of human-made chemicals that have been released into the environment and that have been found to persist and travel through the food chain, can cause cancers in laboratory rodents (8)(9)(10).…”

“…Among these chemicals, pesticides, herbicides, polychlorinated biphenyls (PCBs), and polybrominated biphenyls (PBB) have been found in both aqueous and soil matrices and in the food chain associated with these environments (8)(9)(10)(11). Many of these chemicals have accumulated in animals and humans through several routes of exposure.…”