Polymorphisms in XPB and XPG subcomplexes of TFIIH is associated with lung cancer risk in a Chinese population: A case-control study

Objective:The transcription factor IIH (TFIIH) helicases XPB and XPD are responsible for opening the DNA strand around the lesion site and endonuclease XPG cleaves the damaged DNA strand on the 3’ side during nucleotide excision repair (NER). Polymorphisms in these three genes that affect DNA repair capacity may contribute to susceptibility of lung cancer. In this study, our objective is to conduct a case-control study of 100 Chinese patients with lung cancer and 100 cancer-free age and sex matched controls to analyse associations between these SNPs and lung cancer susceptibility.Methods:In this hospital-based case-control study, we genotyped 7 SNPs of XPB, XPD and XPG using matrix assisted laser desorption ionisation-time of flight mass spectrometry method (MALDI-TOF) to explore the association with lung cancer risk. To estimate the relative risk of lung cancer associated with SNP genotype, odds ratios (OR) and 95.0% confidence intervals (95.0% CI) were obtained from unconditional multinomial logistic regression models without and with adjustment for potential confounders including age, gender, cigarette smoking and alcohol consumption.Results:The results showed that individuals carrying XPB rs4150434 GA or AA genotype (OR per GA genotype, 1.997; 95.0% CI: 1.031-3.871; P=0.039; OR per AA genotype, 2.435; 95.0% CI: 1.037-5.718; P=0.037), and this association was also find in nondrinkers (OR per GA genotype, 2.477; 95.0% CI: 1.128-5.440; P=0.022). Individuals carrying XPG rs2094258 AA genotype had an increased risk of lung cancer (OR per AA genotype, 3.020; 95.0% CI: 1.015-8.980; P=0.040) compared with individuals with the GG genotype, especially in nondrinkers (OR per AA genotype, 4.020; 95.0% CI: 1.211-13.339; P=0.017). In addition, we found that XPG rs17655 CG or GG genotype associated with decreased lung cancer risk in drinkers (OR per XPG rs17655 CG genotype, 0.238; 95.0% CI: 0.061~0.925; P=0.034; OR per XPG rs17655 GG genotype, 0.l39; 95.0% CI: 0.021-0.938; P=0.032). Haplotype analysis of all 7 SNPs was also conducted. We found that the haplotype of XPB (rs4150441, G>A; rs4150434, G>A) GA and the haplotype of XPG (rs2094258, G>A; rs4771436, T>G; rs17655, C>G) ATC had an increased association with lung cancer.Conclusions:These findings suggest an important role of XPB rs4150434 and XPG rs17655 polymorphisms for a biomarker for lung cancer risk among the Chinese population.

Association of the PPAR-gamma Gene with Altered Glucose Levels and Psychosis Profile in Schizophrenia Patients Exposed to Antipsychotics

OBJECTIVE: Metabolic abnormalities, e.g., diabetes, are common among schizophrenia patients. Peroxisome proliferator activated receptor-gamma (PPAR-gamma) regulates glucose/lipid metabolisms, and schizophrenia like syndrome may be induced by actions involving retinoid X receptor-alpha/PPAR-gamma heterodimers. We examined a possible role of the PPAR-gamma gene in metabolic traits and psychosis profile in schizophrenia patients exposed to antipsychotics. METHODS: Single nucleotide polymorphisms (SNPs) of the PPAR-gamma gene and a serial of metabolic traits were determined in 394 schizophrenia patients, among which 372 were rated with Positive and Negative Syndrome Scale (PANSS). RESULTS: SNP-10, -12, -18, -19, -20 and -26 were associated with glycated hemoglobin (HbA1c) whereas SNP-18, -19, -20 and -26 were associated with fasting plasma glucose (FPG). While SNP-23 was associated with triglycerides, no associations were identified between the other SNPs and lipids. Further haplotype analysis demonstrated an association between the PPAR-gamma gene and psychosis profile. CONCLUSION: Our study suggests a role of the PPAR-gamma gene in altered glucose levels and psychosis profile in schizophrenia patients exposed to antipsychotics. Although the Pro12Ala at exon B has been concerned an essential variant in the development of obesity, the lack of association of the variant with metabolic traits in this study should not be treated as impossibility or a proof of error because other factors, e.g., genes regulated by PPAR-gamma, may have complicated the development of metabolic abnormalities. Whether the PPAR-gamma gene modifies the risk of metabolic abnormalities or psychosis, or causes metabolic abnormalities that lead to psychosis, remains to be examined.

The study of susceptibility to carbon tetrachloride and benzene in offspring of expanded simple tandem repeats mutation mice exposed to formaldehyde / 中华劳动卫生职业病杂志

<p><b>OBJECTIVE</b>To investigate the susceptibility to carbon tetrachloride and benzene in offspring of expanded simple tandem repeats (ESTR) mutation mice exposed to formaldehyde (FA).</p><p><b>METHODS</b>F5 and F10 offspring (200 mg/m3 x 2 hours) served as H group and ICR mice were used as control group (group C). The F5 and F10 offspring were exposed to 10 ml/kg carbon tetrachloride at the doses of 0.05%, 0.50% or 5.00% for 24 hours, respectively or 500 or 1000 mg/kg benzene for 24 hours, respectively by intraperitoneal injection. Serum alanine transaminase (ALT), aspartate transaminase (AST) and the hepatic superoxide dismutase (SOD) or malondialdehyde (MDA) were detected; also the hepatic pathological changes were observed under light microscope; the micronucleus in sternum bone marrow cells as the biomarker of benzene blood toxicity were measured.</p><p><b>RESULTS</b>ALT and AST activities in group C of F5 mice exposed to 0.50% and 5.00% CCl4, ALT in groups C and H of F10 mice exposed to 0.05%, 0.50%, 5.00% CCl4, AST in groups C and H of F10 mice exposed to 0.50% and 5.00% CCl4 were significantly higher than those in controls, respectively (P<0.05); as compared to the control, hepatic SOD activities in group C of F5 and F10 mice exposed to 0.50% and 5.00% CCl4, in group H of F5 mice exposed to 0.50% and 5.00% CCl4 and F10 mice exposed to 5.00% CCl4 were significantly reduced, respectively (P<0.05); however, MDA contents in group C of F10 mice exposed to 0.50% and 5.00% CCl4, in group H of F5 mice exposed to 0.05% and 0.50%, 5.00% CCl4 and F10 mice exposed to 0.50% and 5.00% CCl4 were significantly increased than those in control group, respectively (P<0.05). The susceptibility to CCl4 in ESTR mutation F5 mice exposed to FA was significantly higher than that in control F5 mice, but the susceptibility to CCl4 in ESTR mutation F10 mice exposed to FA was significantly lower than that in control F10 mice. The histopathological examination showed that the injury of hepatocytes in C and H groups significantly increased CCl4 doses, and the injury of hepatocytes in H group was higher than that in C group. The micronuclear rates in C and H group mice exposed to benzene(500 mg/kg C group, F5 and F10 mice; 1000 mg/kg C group, F5 and F10 mice; 500 mg/kg H group, F5 and F10 mice; 1000 mg/kg C group, F5 and F10 mice) were 5.88 per thousand +/- 4.55 per thousand, 8.25 per thousand +/- 2.06 per thousand, 7.50 per thousand +/- 6.99 per thousand, 10.67 per thousand +/- 1.16 per thousand, 7.88 per thousand +/- 3.09 per thousand, 9.20 per thousand +/- 1.30 per thousand, 9.63 per thousand +/- 4.34 per thousand and 13.33 per thousand +/- 2.08 per thousand, respectively, which were significantly higher than those (1.13 per thousand +/- 0.35 per thousand, 1.20 per thousand +/- 0.82 per thousand, 1.25 per thousand +/- 0.46 per thousand, 1.33 per thousand +/- 1.03 per thousand) in the solvent control group (P<0.05 or P<0.01).</p><p><b>CONCLUSION</b>FA could result in the change of susceptibility to CCl4 and benzene in offspring of ESTR mutation mice. ESTR mutation may be a biomarker of the susceptibility to chemicals, but the molecular mechanisms should be investigated in the future.</p>

Induction of aryl hydrocarbon receptor and CYP1A1 mRNA by 2,3,7,8-tetrachlorodibenzo-p-dioxin in rat liver / 中华劳动卫生职业病杂志

<p><b>OBJECTIVE</b>To explore the toxic mechanism of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) by studying the induction of cytochrome P4501A1 (CYP1A1) and aryl hydrocarbon receptor (AHR) mRNA in liver of TCDD-treated SD rats.</p><p><b>METHODS</b>Thirty female SD rats were randomly divided into control group and 5 exposure groups, every group had 5 rats. The animals were treated i.p. with 0.01, 0.1, 1, 10, 50 microg TCDD/kg BW. AHR and CYP1A1 mRNA expression were analyzed by RT-PCR after 24 h.</p><p><b>RESULTS</b>The contents of AHR and CYP1A1 mRNA were increased in all exposure groups except the 0.01 microg TCDD/kg BW group. AHR mRNA content was significantly increased in 50 microg TCDD/kg BW group (P<0.05); CYP1A1 mRNA contents were significantly increased in all exposure groups (P<0.05) but not 0.01 microg TCDD/kg BW group. There were dose-response relationship between TCDD doses and AHR, CYP1A1 gene expression.</p><p><b>CONCLUSION</b>Both AHR and CYP1A1 gene in liver of TCDD-treated SD rats can be induced 24 h after exposure and CYP1A1 gene is more inducible than AHR gene.</p>