Decreased gap junctional intercellular communication in hexachlorobenzene-induced gender-specific hepatic tumor formation in the rat

Abstract

Hexachlorobenzene (HCB), an epigenetic carcinogen, HCB induces the formation of liver tumors in female rats, whereas only a small percentage of males are responsive. Intercellular communication via gap junctions is decreased in carcinogenesis. Gap junctions are composed of proteins termed connexins (Cxs). The objectives of this study were (i) to determine if HCB-induced tumor development is associated with a loss of gap junctional communication; (ii) to assess if HCB causes a gender-specific decrease in the expression of Cx32 and Cx26; and (iii) to establish if these effects result from gender differences in the constitutive expression of these Cxs. Rats were given HCB by gavage for five consecutive days. In the first experiment, control and HCB-treated female rats were sampled on day 100. Intercellular communication was significantly decreased in HCB-treated females compared to controls. To investigate if changes in Cx levels occur prior to day 100, experiments done using male and female rats sampled on day 50. Hepatic mRNA levels for Cx26 and Cx32 were significantly lower only in HCB-treated females as compared to controls. Cx26 mRNA levels were 3-fold higher and Cx32 mRNA levels were 8-fold lower in females compared with males. In a third experiment, ovariectomy abolished any differences between male and female controls for both Cxs, while estradiol had a partial role in the regulation of Cx32. This suggests that the sexual dimorphism in hepatic Cx levels is determined by the ovarian hormones. However, the HCB-induced decrease in Cx32 and Cx26 mRNA levels was maintained in ovariectomized rats, suggesting that the HCB effects are not mediated via an ovary-dependent pathway. Overall results show that HCB exposure induces gender-specific long-term alterations in intercellular gap junctional communication in female rat liver. This effect appears to be a critical mechanism of HCB-induced liver carcinogenesis and tumor promotion.

Hexachlorobenzene, a dioxin-like compound, disrupts auditory function in rat

“…It could also affect cochlear neural elements. Indeed, it has been shown that, in the liver, HCB decreases gap junctional communication between cells by decreasing the production of connexin 32 and connexin 26 (Plante et al, 2002). However, all disturbances concerning connexins 26 and 30 in the cochlea induce deafness (DÕAndrea et al, 2002;Rabionet et al, 2002;Ahmad et al, 2003).…”

“…HCB has also been demonstrated to induce liver tumors (Plante et al, 2002), renal adenomas , and parathyroid adenoma (Arnold et al, 1986) in rodents.…”

Hormesis in Carcinogenicity of Non-genotoxic Carcinogens

“…Furthermore, in the low DDT dose group, mRNA expression and immunohistochemical staining of connexin 32 (Cx32) were found to be elevated 16 . Many previous studies indicated that high doses of DDT and other nongenotoxic carcinogens inhibit Cx32, resulting in the loss of the function of gap junction intracellular communication (GJIC) and release of potentially initiated cells from growth constraints imposed by normal neighboring cells, resulting in clonal expansion and ultimately tumor formation and progression [66][67][68][69][70] . In the present study, mRNA expression of one of the transcriptional factors, HNF-1α, which regulates Cx32 expression 71,72 , was in good correlation with that of Cx32 61 .…”

Inorganic arsenic trioxide induces gap junction loss in association with the downregulation of connexin43 and E‐cadherin in rat hepatic “stem‐like” cells

“…The ozonation products of benzo( a )pyrene inhibit cell communication [28] and are believed to be carcinogenic [29]. It has been reported that chemicals such as dioxins, polychlorinated aromatic hydrocarbons, and cadmium, which can promote tumorigenesis, have been linked to decreased gap junctional intercellular communication in cultured hepatocytes [29–31]. Several oncogenes have also been reported as inhibiting GJIC [32].…”