Pathological characteristics, survival, and risk of breast cancer associated with estrogen and xenobiotic metabolism polymorphisms in Mexican women with breast cancer.

Prolonged exposure to estrogens is the main factor associated with the risk and prognosis of breast cancer (BC). The genes involved in the biotransformation of estrogens and xenobiotics have allelic variants with modified enzymatic activities. We investigated the association of nine polymorphisms of some genes from the classical estrogen pathway with the risk of breast cancer and their role in the clinicopathological characteristics of poor clinical prognosis in a sample of Mexican women with BC. METHODS: We included 150 controls and 150 cases matched by age. To analyze the selected polymorphisms, TaqMan assays and high-resolution melting (HRM) analysis were used. RESULTS: The polymorphisms of the genes ERα, CYP1A1, CYP1B1, COMT, MGMT, and XRCC1 were positively associated with the BC risk. We found negative associations between CYP1B1G/G genotype and tumor size, and status of lymph node, estrogen receptor, triple negative, and survival. CONCLUSIONS: The polymorphisms included in this study are associated not only with the risk of BC, but also with some clinicopathological characteristics for poor prognosis of patients with breast cancer, highlighting the important role of CYP1B1 Leu432Val polymorphism.

Subacute intoxication with sodium nitrate induces hematological and biochemical alterations and liver injury in male Wistar rats.

Nitrate pollution has emerged as a problem of great importance because in recent years, the levels of nitrate in soil and groundwater have increased, mainly through anthropogenic activities, such as the use of fertilizers in agriculture, domestic wastewater and septic tanks, industrial waste and deforestation. In animals, nitrate reduction to nitrite (NO2) and nitric oxide (NO) promote the formation of methemoglobin in the blood and the generation of highly reactive intermediates that induce oxidative stress in target organs. Exposition to nitrates has been associated with methemoglobinemia, reproductive toxicity, metabolic and endocrine alterations and cancer. This study analyzed acute intoxication with sodium nitrate (NaNO3) in male Wistar rats, aged 12-16 weeks. Four groups with n = 10 rats each were formed: group 1 was the control, and group 2, group 3 and group 4 were treated for 10 days with intragastric doses of 19, 66 and 150 mg/kg/d NaNO3, respectively. Hematological, metabolic and histological biomarkers in the liver were analyzed. The results showed high percentages of methemoglobin, an increase in NO2 in the plasma and an accumulation in the liver. Moreover, there were high counts of white blood cells and platelets in all treated groups. Additionally, there was an increase in the spleen weight in group 4. High levels of glucose, triglycerides, lactate dehydrogenase (LDH), alanine aminotransferase (ALT), and aspartate aminotransferase (AST) were observed and were significantly increased in groups 3 and 4. For oxidative stress biomarkers, there were increases in Thiobarbituric Acid Reactive Substances (TBARS), total GSH and SOD activity, mainly in group 4. Changes in mitochondrial activity were not significant. Histopathological analyses of the liver showed inflammation, infiltration of mononuclear cells, steatosis, ischemia and necrosis, and these findings were more evident at high doses of NaNO3 in which high of S-nitrosylation were found. In conclusion, NaNO3 was reduced to NO2, thereby inducing methemoglobinemia, whereas other reactive species generated oxidative stress, causing hematological and metabolic alterations and injury to the liver.

Polymorphisms FTO rs9939609, PPARG rs1801282 and ADIPOQ rs4632532 and rs182052 but not lifestyle are associated with obesity related-traits in Mexican children.

Concerning the genetic factors of obesity, no consistent association between populations has been reported, which may be due to the frequency of polymorphisms, the lifestyle of studied populations and its interaction with other factors. We studied a possible association of polymorphisms FTO rs9939609, PPARG rs1801282, and ADIPOQ rs4632532 and rs182052 with obesity phenotypes in 215 Mexican children. Glucose, triglycerides, cholesterol, HDL and LDL were measured. In addition, weight, height, waist circumference and triceps skin thickness were recorded. High-energy diets and sedentary behavior were evaluated with a validated questionnaire. In contrast with other reports, only FTO rs9939609 was associated with obesity related-traits, including BMI (p = 0.03), waist circumference (p = 0.02), triceps skinfold (p = 0.03) and waist/height ratio (p = 0.01), and also with cholesterol levels (p = 0.02) and LDL (p = 0.009). Lower levels of triglycerides (p=0.04) were related with presence of PPARG rs1801282, while ADIPOQ rs4632532 showed an effect on HDL (p = 0.03) levels. On the other hand, diet, physical activity and screen time were not related with obesity. In summary, only FTO rs9939609 was associated with obesity related-traits, while PPARG2 rs1801282 and ADIPOQ rs4632532 were involved in lipid metabolism.

Genetic susceptibility to lung cancer based on candidate genes in a sample from the Mexican Mestizo population: a case-control study.

BACKGROUND: Lung cancer (LC) is the leading cause of mortality caused by neoplasias worldwide. Although cigarette smoking is the primary cause, not all smokers develop LC. Polymorphic variations in genes associated with carcinogen metabolism, DNA repair, and cell-cycle dysregulation may alter an individual risk of developing LC. A polygenic cancer model was proposed, which considers genetic susceptibility to cancer is a global mechanism and suggests that it might be defined by the contributions of low-risk alleles in several candidate genes. This study focused on the analysis of 15 polymorphisms in 12 low-penetrance genes in a case-control study of a sample of Mexican Mestizo population. METHODS: A case-control study was performed with a total of 572 unrelated individuals, including 190 cases with a primary LC diagnosis and 382 healthy controls. The polymorphic status of the individuals was determined by TaqMan probe and RFLP techniques. The association between LC and genotype score (GS) was assessed by logistic regression. RESULTS: The results suggests a protective effect of the genotypes Arg/Lys of AhR rs2066853 (odds ratio [OR] 0.55, p = 0.03), Ile/Val of CYP1A1 rs1048943 (OR 0.49, p = 0.009), Tyr/His of EPHX1 rs1051740 (OR 0.53, p = 0.03), and A/A of CCND1 rs603965 (OR 0.44, p = 0.02). Analyses using the GS suggest that average cases have a larger number of risk alleles than controls (Student's t test -4.85, p = 0.001; OR 1.25, p < 0.001). CONCLUSIONS: Our results suggest significant differences between the GS for the cases and controls, which support the hypothesis underlying the additive and polygenic models for lung cancer risk depending on the polymorphisms in low-penetrance genes.

Differences in 4-hydroxyestradiol levels in leukocytes are related to CYP1A1(∗)2C, CYP1B1(∗)3 and COMT Val158Met allelic variants.

Exposure to estrogen and its metabolites, including catechol estrogens (CEs) and catechol estrogen quinones (CE-Qs) is closely related to breast cancer. Polymorphisms of the genes involved in the catechol estrogens metabolism pathway (CEMP) have been shown to affect the production of CEs and CE-Qs. In this study, we measured the induction of CYP1A1, CYP1B1, COMT, and GSTP1 by 17ß-estradiol (17ß-E2) in leukocytes with CYP1A1(∗)2C, CYP1B1(∗)3, COMT Val158Met and GSTP1 Ile105Val polymorphisms by semi quantitative RT-PCR and compared the values to those of leukocytes with wild type alleles; we also compared the differences in formation of 4- hydroxyestradiol (4-OHE2) and DNA-adducts. The data show that in the leukocytes with mutant alleles treatment with 17ß-E2 up-regulates CYP1A1 and CYP1B1 and down-regulates COMT mRNA levels, resulting in major increments in 4-OHE2 levels compared to leukocytes with wild-type alleles. Therefore, we propose induction levels of gene expression and intracellular 4-OHE2 concentrations associated with allelic variants in response to exposure of 17ß-E2 as a noninvasive biomarker that can help determine the risk of developing non-hereditary breast cancer in women.

Polymorphisms of catechol estrogens metabolism pathway genes and breast cancer risk in Mexican women.

Breast cancer is associated to estrogen exposure. Allelic variants involved in estrogen metabolism might change the risk of developing this neoplasia. We examined the potential association of breast cancer risk in Mexican women with the polymorphisms CYP1A1 rs1048943, CYP1B1 rs1056836, COMT rs4680, GSTP1 rs1695, GSTT1 null and GSTM1 null which are involved in estrogen metabolism pathway. This study included 150 cases and 150 controls. A significant association was observed between, CYP1A1 rs1048943 (OR = 1.95, C.I. 1.13-3.36) and GSTP1 rs1695 (OR = 2.39, C.I. 1.24-4.24) polymorphisms with the risk of breast cancer. This risk was increased when the women were stratified according to their menopausal status. The results show that breast cancer risk significantly increases in women with 3-6 risk polymorphisms (OR = 3.75, C.I. 1.44-9.74).