L-buthionine (S,R)-sulfoximine (BSO), an inhibitor of glutathione (GSH) synthesis, was administered to mice via drinking water for 14 days in order to establish an animal model with continuously depleted levels of GSH. No toxicity was observed at 20 mM BSO, even though a significant decrease in liver weight was observed at 30 mM BSO. GSH levels in the liver, kidney, brain, lung, heart, spleen, pancreas, small intestine, large intestine, skeletal muscle, plasma and blood cells from mice given 20 mM of BSO were all less than those from the control mice continuously throughout a 24-hr period. The ratios of the GSH levels to that of the control were 46.4% and 16.7% in the liver and kidney, respectively, suggesting a decrease in GSH conjugation activity in vivo by GSH depletion. Liver cytochrome P450 content and UDP-glucuronosyltransferase activity to p-nitrophenol were not influenced by the BSO dosing. To confirm the adequacy of this GSH-depletion model, 0.125 or 0.25% of acetaminophen (APAP) was administered via diet to this model for 14 days. Nine out of the ten mice given both 20 mM BSO and 0.25% APAP died on Day 2, and remarkable necrosis was observed in the hepatocytes and renal tubular epithelium. Moreover, focal necrosis of hepatocytes with proliferation of fibroblasts was observed on Day 15 in some mice coadministered 20 mM BSO and 0.125% APAP. However, no toxicity was observed in mice given APAP alone. Based on these results, a mouse given 20 mM of BSO via drinking water for 14 days was concluded to be an animal model with continuously depleted levels of GSH in various organs without toxicity. This model shows high susceptibility to toxicity induced by chemicals which are metabolized to electrophilic and reactive metabolite(s), such as APAP.
Gap junctional intercellular communication (GJIC), by which glutathione (GSH) and inorganic ions are transmitted to neighboring cells, is recognized as being largely involved in toxic processes of chemicals. We examined acetaminophen (APAP)-induced hepatotoxicity clinicopathologically using male wild-type mice and mice lacking the gene for connexin32, a major gap junction protein in the liver [knockout (Cx32KO) mice]. When APAP was intraperitoneally administered at doses of 100, 200, or 300mg/kg, hepatic centrilobular necrosis with elevated plasma aminotransferase activities was observed in wild-type mice receiving 300mg/kg, and in Cx32KO mice given 100mg/kg or more. At 200mg/kg or more, hepatic GSH and GSSG contents decreased significantly and the effect was more severe in wild-type mice than in Cx32KO mice. On the other hand, markedly decreased GSH staining was observed in the hepatic centrilobular zones of Cx32KO mice compared to that of wild-type mice. These results demonstrate that Cx32KO mice are more susceptible to APAP hepatotoxicity than wild-type mice, and indicate that the distribution of GSH of the centrilobular zones in the hepatic lobules, rather than GSH and GSSG contents in the liver, is important in APAP hepatotoxicity. In conclusion, Cx32 protects against APAP-induced hepatic centrilobular necrosis in mice, which may be through the GSH transmission to neighboring hepatocytes by GJIC.
Improving maternal health is a Millennium Development Goal adopted at the 2000 Millennium Summit of the United Nations. As part of the improving maternal health in Tanzania, it has been recommended that skilled birth attendants be present at all births to help reduce the high maternal mortality ratio. However, utilization of these attendants varies across socio-economic groups. The government of Tanzania has repeatedly attempted to carry out health sector reforms (HSRs) to alleviate disparities in health service utilization. In particular, around 1999, HSRs were incorporated into two approaches, including Decentralization by Devolution and Sector Wide Approach. This study aims to clarify the unresolved questions with little published evidence on the effect of HSRs on reducing disparities in utilization of skilled birth attendants across socio-economic groups over time. We used four cross-sectional datasets from the Tanzania Demographic and Health Survey: 1992Survey: , 1996Survey: , 1999Survey: , and 2004. Subjects included 14,752 women of reproductive age (15-49 years) and data on the most recent birth in the 5 years before each survey. Logistic regression analysis was performed with the dependent variable of whether respondents utilized skilled birth attendants or not, and with the main independent variables of time and socio-economic group. Results showed that the disparity in utilization of skilled birth attendants was significantly decreased from 1999 to 2004/05. These findings suggest that the two strategies, Decentralization by Devolution and Sector Wide Approach, in the process of HSRs are effective in reducing the disparities in utilization of skilled birth attendants among socio-economic groups.
ABSTRACT. Connexin 32 (Cx32) is a major gap junction protein in the liver. Neoplastic and non-neoplastic lesions were examined in Cx32-deficient (Cx32KO) mice maintained for 24-month, and compared with those in wild-type mice as a corresponding control. In neoplastic lesions, hepatocellular carcinoma increased significantly only in male Cx32KO mice, suggesting that Cx32 deficiency may be related to their pathogenesis. For females, the incidence of pituitary adenoma in the pars distalis of Cx32KO mice was lower than that of wild-type mice. No non-neoplastic lesions related to Cx32-deficiency were observed in the Cx32KO mice. In conclusion, these results demonstrate that the incidence of hepatocellular carcinoma increases only in male Cx32KO mice, presumably due to enhanced tumor promotion and progression signals associated with Cx32 deficiency. KEY WORDS: connexin 32, intercellular communication, knock-out mice, spontaneous mass.doi: 10.1292/jvms.12-0280; J. Vet. Med. Sci. 75(2): 207-210, 2013 Connexin 32 (Cx32) is one of the major gap junction proteins mainly existing in the liver as well as minimum expressions in other organs, and is thought to play an important role in maintaining tissue homeostasis through gap junction intercellular communication (GJIC). Cx32 is also recognized to be involved in cell growth, proliferation and differentiation [10,23]. Cx32 disruption was reported to induce dysfunction in several organs, namely, lower glucose mobilization in the liver, increased secretion of amylase from the exocrine pancreas and demyelinization in the peripheral nerves [1,2]. In addition, its disruption was known to enhance chemically-induced hepatic carcinogenesis [13]. Cx32 knockout (Cx32KO) mice showed a higher susceptibility to diethylnitrosamine (DEN)-induced carcinogenesis in the liver and lungs compared to wild-type mice [3,9]. Thus, Cx32 is considered to be a tumor suppressor [24], although the molecular mechanisms remain to be elucidated. Meanwhile, there has been no report dealing with background lesions in Cx32KO mice in comparison with wild-type mice, the background strain of Cx32KO mice, during 24 months after birth. In the present study, we examined the incidence of neoplastic and non-neoplastic lesions in Cx32KO mice as well as those in wild-type mice.Wild-type C57BL/6J mice were purchased from Charles River Laboratories (Yokohama, Japan). This strain is known to have a low susceptibility to spontaneous neoplastic lesions. Cx32KO mice were kindly provided by Willecke and colleagues [16], and then bred in our own facilities (Daiichi Sankyo Co., Ltd., Fukuroi, Japan). To confirm the genotype in Cx32KO mice, the excised tips of the tail were analyzed by a polymerase chain reaction (PCR). After identification, male and female Cx32KO and wild-type mice (50 mice/sex/ strain) were housed until 24 months of age in polycarbonated cages (5 mice/cage) in a barrier-sustained room controlled at a temperature of 23 ± 1°C, relative humidity of 55 ± 5%, illumination time of 12 hr/day at an intensity of about...
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