Metabolomics reveals that hepatic stearoyl-CoA desaturase 1 downregulation exacerbates inflammation and acute colitis.

To investigate the pathogenic mechanism of ulcerative colitis, a dextran sulfate sodium (DSS)-induced acute colitis model was examined by serum metabolomic analysis. Higher levels of stearoyl lysophosphatidylcholine and lower levels of oleoyl lysophosphatidylcholine in DSS-treated mice compared to controls led to the identification of DSS-elicited inhibition of stearoyl-CoA desaturase 1 (SCD1) expression in liver. This decrease occurred prior to the symptoms of acute colitis and was well correlated with elevated expression of proinflammatory cytokines. Furthermore, Citrobacter rodentium-induced colitis and lipopolysaccharide treatment also suppressed SCD1 expression in liver. Scd1 null mice were more susceptible to DSS treatment than wild-type mice, while oleic acid feeding and in vivo SCD1 rescue with SCD1 adenovirus alleviated the DSS-induced phenotype. This study reveals that inhibition of SCD1-mediated oleic acid biogenesis exacerbates proinflammatory responses to exogenous challenges, suggesting that SCD1 and its related lipid species may serve as potential targets for intervention or treatment of inflammatory diseases.

The enhancing effect of ethanol on the mutagenic activation of N-nitrosomethylbenzylamine by cytochrome P450 2A in the rat oesophagus.

Alcohol consumption is frequently associated with various cancers and the enhancement of the metabolic activation of carcinogens has been proposed as a mechanism underlying this relationship. The ethanol-induced enhancement of N-nitrosodiethylamine (DEN)-mediated carcinogenesis can be attributed to an increase in hepatic activity. However, the mechanism of elevation of N-nitrosomethylbenzylamine (NMBA)-induced tumorigenesis remains unclear. To elucidate the mechanism underlying the role of ethanol in the enhancement of NMBA-induced oesophageal carcinogenesis, we evaluated the hepatic and extrahepatic levels of the cytochrome P450 (CYP) and mutagenic activation of environmental carcinogens by immunoblot analyses and Ames preincubation test, respectively, in F344 rats treated with ethanol. Five weeks of treatment with 10% ethanol added to the drinking water or two intragastric treatments with 50% ethanol, both resulted in elevated levels of CYP2E1 (1.5- to 2.3-fold) and mutagenic activities of DEN, N-nitrosodimethylamine and N-nitrosopyrrolidine in the presence of rat liver S9 (1.5- to 2.4-fold). This was not the case with CYP1A1/2, CYP2A1/2, CYP2B1/2 or CYP3A2, nor with the activities of 2-amino-3-methylimidazo[4,5-f]quinoline, 3-amino-1-methyl-5H-pyrido[4,3-b]indole, aflatoxin B(1) or other N-nitroso compounds (NOCs), including NMBA. Ethanol-induced elevations of CYP2A and CYP2E1 were observed in the oesophagus (up to 1.7- and 2.3-fold) and kidney (up to 1.5- and 1.8-fold), but not in the lung or colon. In oesophagus and kidney, the mutagenic activities of NMBA and four NOCs were markedly increased (1.3- to 2.4-fold) in treated rats. The application of several CYP inhibitors revealed that CYP2A were likely to contribute to the enhancing effect of ethanol on NMBA activation in the rat oesophagus and kidney, but that CYP2E1 failed to do so. These results showed that the enhancing effect of ethanol on NMBA-induced oesophageal carcinogenesis could be attributed to an increase in the metabolic activation of NMBA by oesophageal CYP2A during the initiation phase, and that this occurred independently of CYP2E1.

Peroxisome proliferator-activated receptor alpha regulates a microRNA-mediated signaling cascade responsible for hepatocellular proliferation.

Activation of peroxisome proliferator-activated receptor alpha (PPARalpha) leads to hepatocellular proliferation and liver carcinomas. The early events mediating these effects are unknown. A novel mechanism by which PPARalpha regulates gene expression and hepatocellular proliferation was uncovered. MicroRNA (miRNA) expression profiling demonstrated that activated PPARalpha was a major regulator of hepatic miRNA expression. Of particular interest, let-7C, an miRNA important in cell growth, was inhibited following 4-h treatment and 2-week and 11-month sustained treatment with the potent PPARalpha agonist Wy-14,643 in wild-type mice. let-7C was shown to target c-myc via direct interaction with the 3' untranslated region of c-myc. The PPARalpha-mediated induction of c-myc via let-7C subsequently increased expression of the oncogenic mir-17-92 cluster; these events did not occur in Pparalpha-null mice. Overexpression of let-7C decreased c-myc and mir-17 and suppressed the growth of Hepa-1 cells. Furthermore, using the human PPARalpha-expressing mouse model, which is responsive to Wy-14,643 effects on beta-oxidation and serum triglycerides but resistant to hepatocellular proliferation and tumorigenesis, we demonstrated a critical role for let-7C in liver oncogenesis. Wy-14,643 treatment did not inhibit let-7C or induce c-myc and mir-17 expression. These observations reveal a let-7C signaling cascade critical for PPARalpha agonist-induced liver proliferation and tumorigenesis.

[Four resected cases with basaloid carcinoma of esophagus--comparison of 5-FU-related enzymes (thymidylate synthase (TS), dihydropyrimidine dehydrogenase (DPD), orotate phosphoribosyl transferase (OPRT)) between basaloid carcinoma and squamous cell carcinoma].

We reported herein four resected cases with basaloid carcinoma of the esophagus and measured the activity of 5-FU related enzymes (TS, DPD, OPRT) in cancer tissue. These activities compared with those in squamous cell carcinoma. Only one case was diagnosed as basaloid carcinoma by preoperative biopsy specimen at endoscopic examination. The esophagectomy was performed thoracoscopically in all cases, and the abdominal procedure was done with the laparoscopic approach in two cases. Anastomotic leakage occurred in one case. No case had lymph node metastasis. On the other hand, a lymphatic invasion was detected in one case, and venous invasion in two, respectively. Two cases had mediastinal lymph node recurrence. DPD activity and OPRT activity showed no difference between squamous cell carcinoma and basaloid carcinoma. On the other hand, the TS activity was significantly higher in basaloid carcinoma. From the standpoint of 5-FU-related enzyme activities, basaloid carcinoma possibly has more resistance to 5-FU than squamous cell carcinoma.

[Selection of anticancer drug for poorly-differentiated adenocarcinoma of colorectum from the level of orotate phosphoribosyl transferase and dihydropyrimidine dehydrogenase activities in cancer tissue].

We investigated the relationship between DPD, OPRT activities and clinicopathological characteristics in 76 patients with colorectal cancer. There was no significant difference between cancer and normal tissue in DPD activity. OPRT activity was significantly higher in cancer tissue than in normal tissue. In poorly-differentiated adenocarcinoma, DPD activity was significantly higher, and OPRT activity was significantly lower than the other type of cancer. Furthermore, OPRT activity was significantly lower in patients with lymph node metastasis. These results suggested that poorly-differentiated adenocarcinoma of the colorectum shows lower efficacy with treatment by 5-fluorouracil than other types of colorectal cancer. Hence, DPD inhibitory fluorouracil, such as S-1, may have potent therapeutic efficacy for poorly-differentiated adenocarcinoma of the colorectum.

[Correlation between clinicopathological factors and enzymatic activity of orotate phosphoribosyl transferase (OPRT), dihydropyrimidine dehydrogenase (DPD) in esophageal cancer].

We investigated the relationship between orotate phosphoribosyl transferase (OPRT), dihydropyrimidine dehydrogenase (DPD) and clinicopathological characteristics in 48 patients with esophageal cancer. DPD activity resulted in no significant differences between cancer tissue and normal tissue, and no relationship with clinicopathological factors. OPRT activity was significantly increased in cancer tissue; its activity was significantly lower in patients with lymph node metastasis and lymph vessel invasion, and significantly higher in Stage I and II than in Stage III and IV. The OPRT/DPD ratio has a relation to cancer staging and survival rate. These results suggested that OPRT levels were related to the clinic pathological characteristics and survival of esophageal cancer.

Urinary bladder carcinogenesis induced by chronic exposure to persistent low-dose ionizing radiation after Chernobyl accident.

Urinary bladder urothelium as well as cells in the microenvironment of lamina propria (endothelial elements, fibroblasts and lymphocytes) demonstrate a number of responses to chronic persistent long-term, low-dose ionizing radiation (IR). Thus, oxidative stress occurs, accompanied by up-regulation of at least two signaling pathways (p38 mitogen-activated protein kinase and nuclear factor-kappaB cascades) and activation of growth factor receptors, in the bladder urothelium of people living in Cesium 137-contaminated areas of Ukraine, resulting in chronic inflammation and the development of proliferative atypical cystitis, so-called Chernobyl cystitis, which is considered a possible pre-neoplastic condition in humans. Furthermore, significant alterations in regulation of cell cycle transitions are associated with increased cell proliferation, along with up-regulated ubiquitination and sumoylation processes as well as inefficient DNA repair (base and nucleotide excision repair pathways) in the affected urothelium. The microenvironmental changes induced by chronic long-term, low-dose IR also appear to promote angiogenesis and remodeling of the extracellular matrix that could facilitate invasion as well as progression of pre-existing initiated cells to malignancy. Based on the available findings, new strategies have been developed for predicting and treatment of Chernobyl cystitis-a first step in urinary bladder carcinogenesis in humans.

Hypoxia-inducible factor augments experimental colitis through an MIF-dependent inflammatory signaling cascade.

BACKGROUND & AIMS: Colon epithelial cells are critical for barrier function and contain a highly developed immune response. A previous study has shown hypoxia-inducible factor (HIF) as a critical regulator of barrier protection during colon epithelial injury. However, the role of HIF signaling in colon mucosal immunity is not known. METHODS: With the use of cre/loxP technology, intestinal-specific disruption of von Hippel-Lindau tumor suppressor protein (Vhl), hypoxia-inducible factor (Hif)-1alpha, and aryl hydrocarbon nuclear translocator (Arnt) was generated. Colon inflammation was induced using a dextran sulfate sodium (DSS)-induced colitis model, and the mice were analyzed by histologic analysis, Western blot analysis, and quantitative polymerase chain reaction. RESULTS: In mice, colonic epithelium disruption of Vhl resulted in constitutive expression of HIF, which initiated an increase in inflammatory infiltrates and edema in the colon. These effects were ameliorated in mice by disruption of both Vhl and Arnt/Hif1beta (which inactivates HIF). In a DSS-induced colitis model, increased HIF expression correlated with more severe clinical symptoms and an increase in histologic damage, while disruption of both Vhl and Arnt in the colon epithelium inhibited these effects. Furthermore, colons with constitutive activation of HIF displayed increased expression of proinflammatory mediators that were synergistically potentiated following DSS administration and reduced by inhibition of the proinflammatory and direct HIF target gene macrophage migration inhibitory factor. CONCLUSIONS: The present study shows that a chronic increase in HIF signaling in the colon epithelial cells initiates a hyperinflammatory reaction that may have important implications in developing therapeutic strategies for inflammatory bowel disease.

Potassium bromate enhances N-ethyl-N-hydroxyethylnitrosamine-induced kidney carcinogenesis only at high doses in Wistar rats: indication of the existence of an enhancement threshold.

As susceptibility to carcinogens varies considerably among different strains of experimental animals, evaluation of dose-response relationships for genotoxic carcinogen in different strains is indispensable for risk assessment. Potassium bromate (KBrO(3)) is a genotoxic carcinogen inducing kidney cancers at high doses in male F344 rats, but little is known about its carcinogenic effects in other strains of rats. The purpose of the present study was to determine dose-response relationships for carcinogenic effects of KBrO(3) on N-ethyl-N-hydroxyethylnitrosamine (EHEN)-induced kidney carcinogenesis in male Wistar rats. We found that KBrO(3) showed significant enhancement effects on EHEN-induced kidney carcinogenesis at above 250 ppm but not at doses of 125 ppm and below when evaluated in terms of induction of either preneoplastic lesions or tumors in male Wistar rats. Furthermore, KBrO(3) significantly increased the formation of oxidative DNA damage at doses of 125 and above but not at doses of 30 ppm and below in kidneys. These results demonstrated that low doses of KBrO(3) exert no effects on development of EHEN-initiated kidney lesions and induction of oxidative DNA damage. Taking account of previous similar findings in male F344 rats, it is strongly suggested that a threshold dose exists for enhancement effects of KBrO(3) on kidney carcinogenesis in rats.

Remnant gastritis should be evaluated histologically rather than endoscopically.

BACKGROUND/AIMS: Many patients who undergo distal gastrectomy develop remnant gastritis. The diagnosis of remnant gastritis is commonly established endoscopically. This report describes the correlation between endoscopic and histological findings of inflammatory changes in the remnant gastric mucosa. METHODOLOGY: Ninety-seven patients who underwent curative distal gastrectomy for gastric cancer, with radical lymphadenectomy, were studied. Endoscopy was performed 12 weeks after surgery. Patients with marked redness, erosion, or edema of the gastric remnant, as seen by endoscopy, were judged to have remnant gastritis, and were divided into group P (positive) and group N (negative). Histological remnant gastritis was evaluated with the neutrophil infiltration score based on the updated Sydney System for endoscopically taken biopsies. Cyclooxygenase (COX)-2 expression was evaluated immunohistochemically. RESULTS: There was no difference in neutrophil infiltration or COX-2 expression scores between the patients in groups P and N. There was a significant correlation between neutrophil infiltration score and COX-2 expression score (p<0.001). CONCLUSIONS: Endoscopic diagnosis of remnant gastritis was not correlated with histological findings. Histological remnant gastritis had significant correlation with COX-2 expression score, which was induced by inflammation. Therefore, proper diagnosis of remnant gastritis should be based on histological examination.

Elevated oxidative stress and DNA damage and repair levels in urinary bladder carcinomas associated with schistosomiasis.

To cast light on mechanisms underlying development of urothelial carcinomas (UCs) of the urinary bladder associated with Schistosomiasis, we immunohistochemically analyzed the relationship between oxidative stress markers, DNA single strand breaks (ssDNA) which could also measure the levels of base damage and apoptosis in DNA, and expression of DNA repair genes with levels of nitric oxide synthases in bladder carcinomas of Egyptian patients with or without Schistosoma hematobium infection. Marked elevation of 8-hydroxy-2'-deoxyguanosine (8-OHdG) levels was found in squamous cell carcinomas and UCs associated with Schistosomiasis when compared with non-Schistosomal carcinomas. This was accompanied by strong over expression of the DNA-repair genes, 8-oxoguanine-DNA-glycosylase and apurinic/apyrimidinic endonuclease, as well as increased formation levels of ssDNA. Expression levels of inducible nitric oxide synthase (iNOS) which is known to be indirectly related to oxidative stress was higher in Schistosomal than in the non-Schistosomal carcinomas. However, expression of endothelial nitric oxide synthase was slightly stronger in non-Schistosomal than in the Schistosomal carcinomas. In conclusion, these findings suggest a strong correlation between Schistosoma haematobium infection and increased levels of oxidative stress accompanied by a continuous DNA damage and repair in UCs, all directly correlating with elevated iNOS.

Evidence of a threshold-effect for 2-amino-3,8-dimethylimidazo-[4,5-f]quinoxaline liver carcinogenicity in F344/DuCrj rats.

To estimate potential human risk of exposure to a food-derived, genotoxic hepatocarcinogen, 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx), a 2-year carcinogenicity test was conducted using male F344 rats administered MeIQx-containing diet at doses of 0 (control), 0.001, 1, and 100 ppm. The lowest dose 0.001 ppm was established as equivalent to the daily intake of this carcinogen in humans (0.2 to 2.6 microg/man/day). Significant decreases of survival rate and body weight gain were observed in rats treated with 100 ppm MeIQx. Histopathological examination revealed significant induction of hepatocellular carcinomas, adenomas, and development of glutathione S-transferase placental form-positive foci with MeIQx at 100 ppm. Moreover, the incidences of Zymbal's glands carcinoma, mammary fibroadenoma, and subcutaneous fibroma were found significantly increased in a 100 ppm MeIQx group. However, no significant induction of altered preneoplastic hepatocellular foci was observed in 0.001 and 1 ppm groups as compared to the controls. 8-Hydroxy-2'-deoxyguanosine levels in the rat liver DNA of the 100 ppm-treated group were not elevated, but MeIQx-DNA adduct formation increased as compared with the 1 ppm case, albeit without significance. No significant induction of any other neoplastic lesions related to the carcinogen administration was found in MeIQx-administered groups except for 100 ppm. These results imply that 1 ppm may be a no-effect level for MeIQx carcinogenesis.

Expression of 8-hydroxydeoxyguanosine in the gastric remnant after distal gastrectomy.

BACKGROUND/AIMS: The correlation between remnant gastritis after distal gastrectomy for gastric cancer and expression of 8-hydroxydeoxyguanosine (8-OHdG) and inducible oxide synthase (iNOS) as a marker of oxidative DNA damage was investigated. METHODOLOGY: Ninety-seven patients who had undergone curative distal gastrectomy for gastric cancer were studied. Reconstructive procedures included Billroth I, Billroth II, and Roux-Y reconstruction in 42, 27, and 28 patients, respectively. Histologic and immunohistochemical analyses were performed on biopsy specimens of the gastric mucosa obtained endoscopically within 2 weeks before and 12 weeks after surgery. The grades of remnant gastritis were evaluated according to the updated Sydney System. 8-OHdG and iNOS expression levels, detected immunohistochemically, were graded. RESULTS: Neutrophil infiltration correlated with expression of 8-OHdG (p = 0.02). Expression of iNOS also correlated with 8-OHdG (p = 0.02). The ratio of postoperative to preoperative infiltration of neutrophils was less in patients who underwent Roux-Y reconstruction than in others (p = 0.04). CONCLUSIONS: These results suggest that remnant gastritis possibly causes DNA damage. Excess production of reactive oxygen species correlates with carcinogenic DNA changes. Roux-Y reconstruction may reduce carcinogenesis in the gastric remnant.

High sensitivity of fatty liver Shionogi (FLS) mice to diethylnitrosamine hepatocarcinogenesis: comparison to C3H and C57 mice.

The fatty liver Shionogi (FLS) mouse is a new inbred strain that spontaneously develops fatty liver with infiltration of mononuclear cells. Moreover, this mouse is known to frequently develop spontaneous hepatic cancers. Recently, human non-alcholic steatohepatitis (NASH) has been focused of attention regarding hepatocellular carcinoma. Therefore, this mouse has potential as a model for human hepatic cancer due to steatosis. It is of interest therefore, whether it exhibits elevated susceptibility not only regarding spontaneous tumor development but also to chemical hepatocarcinogens. To examine this concern, we examined diethylnitrosamine (DEN) hepatocarcinogenesis in FLS mice with 30ppm in drinking water for 26 weeks in comparison to two other strains of mice, C3H and C57. The induction of spontaneous and DEN-induced hepatic tumors was clearly increased in the FLS case, along with levels of 8-hydroxy-2'-deoxyguanosine (8-OHdG), a marker of oxidative DNA damage, as compared to the other strains, with or without DEN treatment. These results indicate that the oxidative DNA stress is intimately involved in hepatocarcinogenesis in FLS mice and provide further support for use of this mouse as a useful model for investigating hepatocarcinogenesis due to human hepatic steatosis.

Analysis of gene expression in different stages of MeIQx-induced rat hepatocarcinogenesis.

To clarify hepatocarcinogenesis by the heterocyclic amine, 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx), we investigated the global expression of genes in rat liver. Rats were continuously fed MeIQx 100 ppm in their diet, and were sacrificed at weeks 4 and 16 for early time points, and week 104 for tumor sampling. Global expression analysis using oligonucleotide microarrays (Affimetrix Gene Chip, Rat Genome 230 2.0 Array) was carried out to detect altered genes in MeIQx-treated liver at 4 and 16 weeks (n=5, each), MeIQx-induced hepatocellular adenomas (HCA; n=3), and hepatocellular carcinomas (HCC; n=3), compared with age-matched normal livers (n=5). To investigate functional networks and gene ontology, two clusters were analyzed by Ingenuity Pathway Analysis. Clustering analysis of global genes demonstrated gene profiles of HCA and HCC to greatly differ from those of age-matched normal liver. However, after treatment with MeIQx for 4 or 16 weeks, no major differences were apparent. Ingenuity Pathway Analysis suggested pathways related to the cell cycle and glutathione metabolism may be involved in MeIQx-induced hepatocarcinogenesis. Real-time PCR analysis confirmed elevation of cyclin B1, cell division cycle 2, glutathione peroxidase 2 and glutathione S-transferase A2 in tumors, but not in early stage livers. In conclusion, molecular signatures of MeIQx-induced tumors clearly vary from that of age-matched normal liver, but no such shift is evident at early stages of hepatocarcinogenesis.

Correlation of N-myc downstream-regulated gene 1 expression with clinical outcomes of colorectal cancer patients of different race/ethnicity.

AIM: To evaluate the role of N-myc downstream-regulated gene 1 (NDRG1) expression in prognosis and survival of colorectal cancer patients with different ethnic backgrounds. METHODS: Because NDRG1 is a downstream target of p53 and hypoxia inducible factor-1 alpha (HIF-1 alpha), we examined NDRG1 expression together with p53 and HIF-1 alpha by immunohistochemistry. A total of 157 colorectal cancer specimens including 80 from Japanese patients and 77 from US patients were examined. The correlation between protein expression with clinicopathological features and survival after surgery was analyzed. RESULTS: NDRG1 protein was significantly increased in colorectal tumor compared with normal epithelium in both Japanese and US patient groups. Expression of NDRG1 protein was significantly correlated with lymphatic invasion, venous invasion, depth of invasion, histopathological type, and Dukes' stage in Japanese colorectal cancer patients. NDRG1 expression was correlated to histopathological type, Dukes' stage and HIF-1 alpha expression in US-Caucasian patients but not in US-African American patients. Interestingly, Kaplan-Meier survival analysis demonstrated that NDRG1 expression correlated significantly with poorer survival in US-African American patients but not in other patient groups. However, in p53-positive US cases, NDRG1 positivity correlated significantly with better survival. In addition, NDRG1 expression also correlated significantly with improved survival in US patients with stages III and IV tumors without chemotherapy. In Japanese patients with stages II and III tumors, strong NDRG1 staining in p53-positive tumors correlated significantly with improved survival but negatively in patients without chemotherapy. CONCLUSION: NDRG1 expression was correlated with various clinicopathological features and clinical outcomes in colorectal cancer depending on the race/ethnicity of the patients. NDRG1 may serve as a biological basis for the disparity of clinical outcomes of colorectal cancer patients with different ethnic backgrounds.

Existence of no-observed effect levels for 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline on hepatic preneoplastic lesion development in BN rats.

There is increasing evidence that dose-response curve of genotoxic carcinogen is nonlinear and a practical threshold dose exists. However, little is known about differences in the dose-response relationship of genotoxic carcinogen among different strain rats. Herein, we showed that low doses of genotoxic carcinogen 2-amino-3,8-dimethylimidazo[4,5-f] quinoxaline (MeIQx) had no effects on induction of liver glutathione S-transferase placental form (GST-P)-positive foci in both BN and F344 rats, and therefore demonstrated the existence of no-observed effect level for hepatocarcinogenicity of this genotoxic carcinogen irrespective of strains. These findings further support our notion that a practical threshold dose for MeIQx hepatocarcinogenicity exists in rats.

Alpha-benzene hexachloride exerts hormesis in preneoplastic lesion formation of rat hepatocarcinogenesis with the possible role for hepatic detoxifying enzymes.

Recently there has been a shift in the prevailing paradigm regarding the dose dependence of carcinogen action with increasing acceptance of hormesis phenomenon, although underlying mechanisms remain to be established. To ascertain whether alpha-benzene hexachloride (alpha-BHC) might act by hormesis, rats were initiated with diethylnitrosamine and then alpha-BHC ranging from 0.01 to 500 ppm was administered in the diet for 10 weeks. The highest concentration of alpha-BHC significantly increased the number and area of glutathione S-transferase placental form (GST-P) positive foci, preneoplastic lesions in the liver, but its low dose, 0.05 ppm, caused significant reduction, showing a J-shape dose-response curve. The proliferating cell nuclear antigen positive index for GST-P positive foci in the low dose-treated group was significantly reduced. The dose response curves of CYP450 content, NADPH-P450 reductase activity and 8-hydroxydeoxyguanosine formation revealed the same pattern as GST-P positive foci data. The response curves of CYP2B1 and 3A2 in their activities, protein and mRNA expression showed a threshold but CYP2C11 activity exhibited an inverted J-shape. These results might suggest the possibility of hormesis of alpha-BHC at early stages of rat hepatocarcinogenesis. The possible mechanism involves induction of detoxifying enzymes at low dose, influencing free radical production and oxidative stress, and consequently pathological change in the liver.

Testicular toxicity of DEHP, but not DEHA, is elevated under conditions of thioacetamide-induced liver damage.

As part of an investigation of possible enhancement by liver disease of testicular toxicity caused by phthalates, we tested the effects of di(2-ethylhexyl)phthalate (DEHP) and di(2-ethylhexyl)adipate (DEHA) in a thioacetamide (TAA)-induced rat liver damage model. Male, 6-week-old, F344 rats (n=60) were divided into ten groups. Animals of groups 1-5 received TAA (200 mg/kg, intraperitoneal, three times per week) for 4 weeks, and groups 6-10 served as controls without TAA. After a 1 week interval, at week 5, powder diet containing DEHP or DEHA was provided to the animals of groups 1 and 6 (DEHP 25000 ppm), groups 2 and 7 (DEHP 6000 ppm), groups 3 and 8 (DEHA 25000 ppm) and groups 4 and 9 (DEHA 6000 ppm), while groups 5 and 10 received basal diet. All animals were sacrificed at week 9. Significant decrease in sperm numbers and motility and increase in morphology abnormalities were evident in group 1 as compared to groups 5 and 6 (p<0.01). However, DEHA treatment was not associated with any apparent testicular toxicity in either TAA- or vehicle-treated animals. Histopathological examination of the testes revealed severe atrophy and degeneration of testicular tubules in all animals given TAA and DEHP at high dose, only mild to moderate lesions being found with DEHP alone. We conclude that liver toxicity induced by TAA is associated with the enhancement of testicular toxicity of DEHP, but not DEHA, in rats.

Inhibition of rat urinary bladder carcinogenesis by the antiangiogenic drug TNP-470.

Potential inhibitory effects of the antiangiogenic drug TNP-470 on rat urinary bladder carcinogenesis were investigated in F344 male rats initiated with 0.05% BBN in the drinking water for 8 weeks. Group 1 was then continuously treated with TNP-470 by subcutaneous injection using osmotic minipump until the end of the experiment; group 2 served as the control with only initiation. The incidences and multiplicities of papillomas and carcinomas in the TNP-470-treated group were significantly decreased compared to the control group values along with the tumor vascular density. In conclusion, TNP-470 can inhibit rat urinary bladder carcinogenesis, presumably through its effects on angiogenesis.