Altered bcl-2 family expression during non-genotoxic hepatocarcinogenesis in mice. (1/44)

Dysregulation of apoptosis is an important component of multistage hepatocarcinogenesis. Members of the bcl-2 protein family are important in the regulation of apoptosis and their expression is altered in several cancers. The objectives of the present study were to determine whether the expression of members of the bcl-2 protein family are altered in mouse liver during acute treatment with non-genotoxic carcinogens and throughout non-genotoxic hepatocarcinogenesis. Acute treatment of B6C3F1 mice with phenobarbital resulted in increased levels of bcl-2 and decreased levels of bax protein, while acute treatment with WY-14,643 resulted in increased bcl-2 and BAG-1 protein in the liver. Following chronic treatment, altered hepatic foci and adenomas were classified as: small-cell, heterogeneous basophilic lesions (spontaneous or tetrachlorodibenzo-p-dioxin-induced); large-cell, homogeneous basophilic lesions (WY-14,643-induced); acidophilic lesions (phenobarbital- or chlordane-induced). Of the small-cell heterogeneous basophilic lesions, 86% of foci (31/36) and 85% of adenomas (35/41) exhibited increased bcl-2 protein levels compared with surrounding normal hepatocytes, whereas only 12.5% of foci (4/36) and 12% of adenomas (5/41) exhibited increased bcl-X(L) levels. Of the large-cell, homogenous, basophilic lesions, 100% of foci (3/3) and 90% of adenomas (9/10) expressed bcl-2 protein, whereas 100% of foci (3/3) and 80% of adenomas (8/10) exhibited increased bcl-X(L) protein levels compared with surrounding normal hepatocytes. Of the acidophilic lesions, the majority of foci (28/32, 88%) and adenomas (47/50, 94%) expressed increased bcl-X(L), whereas increased bcl-2 was observed in only 12.5% of acidophilic preneoplastic foci (4/32) and 14% of acidophilic adenomas (7/50). Of the carcinomas analyzed, 81% expressed increased bcl-2 (54/67), 78% expressed increased bcl-X(L) (52/67) and 69% expressed increased levels of both bcl-2 and bcl-X(L) (46/67). Collectively, only 8% of preneoplastic foci, 3% of adenomas and 1.5% of carcinomas did not express either bcl-2 or bcl-X(L). These results suggest that regulation of apoptotic proteins is altered during non-genotoxic carcinogenesis in mouse liver. Furthermore, there were both chemical- and lesion-specific aspects of expression of apoptotic proteins during hepatocarcinogenesis in mice.  (+info)

Two organochlorine pesticides, toxaphene and chlordane, are antagonists for estrogen-related receptor alpha-1 orphan receptor. (2/44)

Estrogen-related receptor (ERR) alpha-1 shares a high amino acid sequence homology with estrogen receptor alpha. Although estrogens are not ligands of ERR alpha-1, our recent results suggest that toxaphene and chlordane, two organochlorine pesticides with estrogen-like activity, behave as antagonists for this orphan nuclear receptor. The two compounds increased ERR alpha-1-mediated expression of the reporter enzyme beta-galactosidase in a yeast-based assay. The screen was developed by expressing the hERR alpha-1-yeast Gal 4 activation domain fusion protein in yeast cells carrying the beta-galactosidase reporter plasmid, which contains an ERR alpha-1-binding element. In transfection experiments using mammalian cell lines, such as the SK-BR-3 breast cancer cell line, the compounds were found to have an antagonist activity against ERR alpha-1-mediated expression of the reporter chloramphenicol acetyltransferase. In contrast to the findings with ERR alpha-1, the two compounds were found to slightly induce the estrogen receptor a-mediated expression of chloramphenicol acetyltransferase in SK-BR-3 cells. In a ligand-independent manner, the ERR alpha-1 activity in SK-BR-3 cells was induced 3-fold by cotransfection with the GRIP1 coactivator expression plasmid. Toxaphene was found to be capable of suppressing the GRIP1 coactivator-induced ERR alpha-1 activity in SK-BR-3 cells. In addition, a stable ERR alpha-1 expressing HepG2 hepatoma cell line was generated, and the aromatase activity in the transfected cell line was found to be twice that in the untransfected cell line. The enzyme aromatase converts androgens to estrogens, and aromatase expression in HepG2 cells is regulated in part by an ERR alpha-1-modulating promoter. A 24-h incubation of an ERR alpha-1-transfected HepG2 cell line with 10 microM toxaphene reduced its aromatase activity to the level in the untransfected cell line. Because toxaphene is not an inhibitor of aromatase, it is thought that the decrease of the aromatase activity in ERR alpha-1 transfected HepG2 cells following toxaphene treatment resulted from a suppression of the aromatase expression by toxaphene acting as the antagonist of ERR alpha-1. Toxaphene and chlordane are among the 12 persistent organic pollutants identified by the United Nations Environment Programme as requiring urgent attention. Their antagonistic effects on ERR alpha-1 should not be overlooked.  (+info)

Embryonic treatment with xenobiotics disrupts steroid hormone profiles in hatchling red-eared slider turtles (Trachemys scripta elegans). (3/44)

Many compounds in the environment capable of acting as endocrine disruptors have been assayed for their developmental effects on morphogenesis; however, few studies have addressed how such xenobiotics affect physiology. In the current study we examine the effects of three endocrine-disrupting compounds, chlordane, trans-nonachlor, and the polychlorinated biphenyl (PCB) mixture Aroclor 1242, on the steroid hormone concentrations of red-eared slider turtle (Trachemys scripta elegans) hatchlings treated in ovo. Basal steroid concentrations and steroid concentrations in response to follicle-stimulating hormone were examined in both male and female turtles treated with each of the three compounds. Treated male turtles exposed to Aroclor 1242 or chlordane exhibited significantly lower testosterone concentrations than controls, whereas chlordane-treated females had significantly lower progesterone, testosterone, and 5[alpha]-dihydrotestosterone concentrations relative to controls. The effects of these endocrine disruptors extend beyond embryonic development, altering sex-steroid physiology in exposed animals.  (+info)

trans-Nonachlor and cis-nonachlor toxicity in Sprague-Dawley rats: comparison with technical chlordane. (4/44)

cis-Nonachlor and trans-nonachlor are bioaccumulating components of the pesticide chlordane, which can be detected in various environmental biota and in humans. Existing studies have focused on the potential adverse health effects of the parent chlordane mixture. Comparable toxicity data are nonexistent for individual chlordane constituents such as trans-nonachlor, cis-nonachlor, or oxychlordane, which are among the most common chlordane-related environmental contaminants and tissue residues. In this study, rats were administered cis-nonachlor, trans-nonachlor, or technical chlordane by gavage for 28 days at doses of 0.25 to 25 mg/kg body weight. Residue analyses indicated that trans-nonachlor accumulation in adipose was greater than cis-nonachlor when rats were administered each chemical under identical conditions of dose and exposure. For all test chemicals, the major metabolite oxychlordane accumulated in adipose tissue. Adipose tissue residue levels of all test chemicals and the major metabolite were higher in female rats. The liver was a target organ in male and female rats, indicated by increased liver weight and histopathological changes consistent with microsomal enzyme induction. Hepatic changes were most pronounced in rats treated with trans-nonachlor. Elevated kidney weights and depressed organic ion transport were observed in males treated with trans-nonachlor and chlordane. Although in general, changes in target organs and clinical chemistry endpoints were similar for all 3 test chemicals, the approximate toxicity ranking from most to least toxic was trans-nonachlor > technical chlordane > cis-nonachlor.  (+info)

Role of PKC and MAP kinase in EGF- and TPA-induced connexin43 phosphorylation and inhibition of gap junction intercellular communication in rat liver epithelial cells. (5/44)

Gap junction intercellular communication (GJIC) is involved in the regulation of many cellular processes. The gap junction channels are made up of connexins and the flow of polar low molecular weight molecules through these channels is inhibited by several groups of substances, such as tumour promoters and growth factors. The phorbol ester 12-O-tetradecanoylphorbol 13-acetate (TPA), chlordane and the growth factor epidermal growth factor (EGF) are potent inhibitors of GJIC in several cell types, including the rat liver epithelial cell line IAR6.1. The induced inhibition of communication by TPA and EGF in IAR6.1 cells is associated with hyperphosphorylation of connexin43, the connexin responsible for GJIC. Two enzyme inhibitors, PD98059, a specific inhibitor of MEK kinase, and GF109203X, a selective inhibitor of protein kinase C (PKC), were used to study the signalling pathways involved in the effect of EGF and TPA on GJIC, with the following conclusions. The inhibition of cell communication in IAR6.1 cells by EGF is likely to be mediated by direct phosphorylation of connexin43 by MAP kinase. TPA blocks GJIC mainly by the direct action of PKC, but also partly through cross-talk with the MAP kinase pathway. Connexin43 hyperphosphorylation induced by TPA is, as for EGF, mediated through MAP kinase, while PKC seems to block GJIC either through other substrates or induces a type of connexin43 phosphorylation that causes no significant electrophoresis mobility shift.  (+info)

Increased concentrations of polychlorinated biphenyls, hexachlorobenzene, and chlordanes in mothers of men with testicular cancer. (6/44)

An increasing incidence of testicular cancer has been reported from several countries in the Western world during the last decades. According to current hypothesis, testicular cancer is initiated during the fetal period, and exposure to endocrine disruptors, i.e., xenoestrogens, has been of concern. In this investigation we studied the concentrations of the sum of 38 polychlorinated biphenyls (PCBs), p,p'-dichlorodiphenyl-dichloroethylene, hexachlorobenzene (HCB), and chlordanes, in 61 cases with testicular cancer and 58 age-matched controls. Furthermore, case and control mothers were also asked to participate, and 44 case mothers and 45 control mothers agreed. They were of similar age. In cases only the concentration on lipid basis of cis-nonachlordane was significantly increased, whereas case mothers showed significantly increased concentrations of the sum of PCBs, HCB, trans- and cis-nonachlordane, and the sum of chlordanes. Among case mothers the sum of PCBs yielded an odds ratio (OR) of 3.8; 95% confidence interval (CI), 1.4-10 was calculated using the median concentration for the control mothers as cutoff value. For HCB, OR = 4.4 (95% CI, 1.7-12); for trans-nonachlordane, OR = 4.1 (95% CI, 1.5-11); for cis-nonachlordane, OR = 3.1 (95% CI, 1.2-7.8); and for sum of chlordanes, OR = 1.9 (95% CI, 0.7-5.0). No consistent different risk pattern was found for seminoma or nonseminoma testicular cancer.  (+info)

The significance of insecticide-resistant strains; with special reference to pests of medical importance. (7/44)

The author discusses the meaning of insecticide resistance and the manner in which it should be detected and measured. From some recent data he gives a number of examples of measurements of resistance in mosquitos of different species in various areas. He then proceeds to a speculative discussion on the way in which insecticide resistance arises, whether it can be prevented and overcome, its importance in the past and at present, and finally its future prospects.  (+info)

Resistance of anopheline larvae to chlordane and dieldrin; field and laboratory tests on Anopheles sacharovi. (8/44)

The authors present the results of field and laboratory tests carried out to determine the susceptibility to DDT, chlordane, and dieldrin of Anopheles sacharovi larvae in the small coastal plain of Astros, Peloponnesus, where chlorinated-hydrocarbon insecticides have been extensively used for house spraying and for ground and air larviciding for over ten years. It was found that the larvae had recently developed a substantial degree of resistance to chlordane and dieldrin, but no appreciable larval resistance to DDT was observed, although the latter was by far the commonest of all the larvicides used in recent years.  (+info)

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