Exposure to a Titanium Dioxide Product Alters DNA Methylation in Human Cells.

The safety of titanium dioxide (TiO), widely used in foods and personal care products, has been of ongoing concern. Significant toxicity of TiO has been reported, suggesting a risk to human health. To evaluate its potential epigenotoxicity, the effect of exposure to a TiO product to which humans could be exposed on DNA methylation, a primary epigenetic mechanism, was investigated using two human cell lines (Caco-2 (colorectal) and HepG2 (liver)) relevant to human exposure.

Effect of titanium dioxide nanoparticles on histone modifications and histone modifying enzymes expression in human cell lines.

Titanium dioxide (TiO) nanoparticles are widely manufactured, with a range of applications in consumer products. Significant toxicity of TiO nanoparticles has, however, been recognized, suggesting considerable risk to human health. To evaluate fully their toxicity, assessment of the epigenetic action of these nanoparticles is critical.

Epigenetic Effects of Nanomaterials and Nanoparticles.

The rise of nanotechnology and widespread use of engineered nanomaterials in everyday human life has led to concerns regarding their potential effect on human health. Adverse effects of nanomaterials and nanoparticles on various molecular and cellular alterations have been well-studied. In contrast, the role of epigenetic alterations in their toxicity remains relatively unexplored.

Effect of titanium dioxide nanoparticles on DNA methylation in multiple human cell lines.

Nanoscale titanium dioxide (TiO) is manufactured in wide scale, with a range of applications in consumer products. Significant toxicity of TiO nanoparticles has, however, been recognized, suggesting considerable risk to human health. To evaluate fully their toxicity, assessment of the epigenetic action of these nanoparticles is critical.

In vitro analysis of factors influencing expression as potential determinants of interindividual variation.

Individual differences in drug metabolism contribute to interindividual variation that characterizes responses to drugs and risk in exposure to foreign chemicals. Large individual differences are found in expression levels of , a major drug-metabolizing enzyme. Underlying causes for this variation are not well understood.

Cigarette smoke condensate and individual constituents modulate DNA methyltransferase expression in human liver cells.

Objectives: Previous studies found higher expression levels of DNA methyltransferase 1 in liver samples from smokers compared to those from non-smokers. In contrast, expression levels of DNA methyltransferase 3a and DNA methyltransferase 3b were similar in smokers and non-smokers. This study extends these studies to establish a causal linkage to cigarette smoke exposure by examining whether DNA methyltransferase expression is modulated by cigarette smoke condensate.

Prolactin and Dehydroepiandrosterone Levels in Women with Systemic Lupus Erythematosus: The Role of the Extrapituitary Prolactin Promoter Polymorphism at -1149G/T.

Systemic lupus erythematosus (SLE) has shown an association with high levels of prolactin, low levels of dehydroepiandrosterone (DHEA), and induction of inflammatory cytokines in the serum of patients with the disease. This preliminary study examined the relevance of a -1149G/T functional single-nucleotide polymorphism (SNP) (rs1341239) in the promoter of the extrapituitary prolactin gene in a cohort of African American and European American women with lupus. Examination of this SNP revealed that the -1149TT genotype was correlated with higher levels of prolactin in serum and prolactin gene expression (p = 0.

Cytotoxicity of chronic exposure to 4 cigarette smoke condensates in 2 cell lines.

Tobacco use is the leading preventable cause of death. The cytotoxicity of cigarette smoke condensate (CSC), the particulate fraction of cigarette smoke without the vapor phase, has mostly been tested in short-term in vitro studies lasting from a few hours to a few days. Here, we assessed the toxicity of CSCs from 2 reference cigarettes, 3R4F and CM6, using a primary human small airway epithelial (PSAE) cell line by quantifying adenosine 5'-triphosphate (ATP), 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxy-methoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium (MTS), total glutathione (reduced glutathione [GSH] + oxidized glutathione [GSSG]), and lactate dehydrogenase (LDH) release over the course of 28 days.

Expression of drug transporters in human kidney: impact of sex, age, and ethnicity.

Background: Differences in expression of drug transporters in human kidney contribute to changes in pharmacokinetics and toxicokinetics of a variety of drug compounds. The basal expression levels of genes involved in drug transport processes in the kidney introduces differences in bioavailability, distribution, and clearance of drugs, possibly influencing drug efficacy and adverse reactions. Sex differences in gene expression of transporters are a key cause of differences in sex-dependent pharmacokinetics, which may characterize many drugs and contribute to individual differences in drug efficacy and toxicity.

Effect of cigarette smoke condensate on gene promoter methylation in human lung cells.

Background: In lung cancer, an association between tobacco smoking and promoter DNA hypermethylation has been demonstrated for several genes. However, underlying mechanisms for promoter hypermethylation in tobacco-induced cancer are yet to be fully established.

Methods: Promoter methylation was evaluated in control and cigarette smoke condensate (CSC) exposed human lung cells using the Methyl-Profiler DNA Methylation PCR System.

ATP-Binding Cassette Genes Genotype and Expression: A Potential Association with Pancreatic Cancer Development and Chemoresistance?

Genetic polymorphisms in ABC (ATP-binding cassette) transporter genes are associated with differential responses to chemotherapy in various cancers including pancreatic cancer. In this study, four SNPs in the ABCB1, ABCC1, and ABCG2 genes were investigated in normal and pancreatic cancerous specimens. The expression of the three transporters was also analyzed.

Increased expression of Toll-like receptors (TLRs) 7 and 9 and other cytokines in systemic lupus erythematosus (SLE) patients: ethnic differences and potential new targets for therapeutic drugs.

Increased expression of pro-inflammatory cytokines such as interferon, tumor necrosis factors (TNFs) and specific interleukins (ILs) has been found in a number of autoimmune diseases, including systemic lupus erythematous (SLE). These cytokines are induced by toll-like receptors (TLRs). Toll-like receptors are activated in response to accumulation of apoptotic bodies.

Cigarette smoke condensate induces differential expression and promoter methylation profiles of critical genes involved in lung cancer in NL-20 lung cells in vitro: short-term and chronic exposure.

Establishing early diagnostic markers of harm is critical for effective prevention programs and regulation of tobacco products. This study examined effects of cigarette smoke condensate (CSC) on expression and promoter methylation profile of critical genes (DAPK, ECAD, MGMT, and RASSF1A) involved in lung cancer development in different human lung cell lines. NL-20 cells were treated with 0.

Transcriptional activity of DNMT3B in pancreatic cancer cells: effects of -149 (C→T) promoter polymorphism.

Polymorphic C-to-T change in the promoter region of DNA-methyltransferase-3B (DNMT3B) gene is associated with risk of several cancers. The aim of this study was to investigate the effect of DNMT3B promoter genetic variant on its transcriptional activity and to compare activity in several pancreatic cell lines. DNMT3B promoter constructs carrying either -149C allele or -149T allele were transiently transfected into pancreatic cancer cells.

Gender differences in gemcitabine (Gemzar) efficacy in cancer cells: effect of indole-3-carbinol.

Pancreatic cancer has a poor prognosis, mainly due to lack of effective therapies. This study demonstrated the ability of dietary agent, indole-3-carbinol (I3C), to lower the LD(50) of gemcitabine (Gemzar) in decreasing growth of both male (MiaPaca2) and female (SU86.86) pancreatic cancer cells.

Food contaminant acrylamide increases expression of Cox-2 and nitric oxide synthase in breast epithelial cells.

Acrylamide has been discovered in foods cooked at high temperature. A potentially harmful effect of this dietary component has been suggested by data indicating its association with increased breast cancer. This study investigated the potential effects of acrylamide in nontumorigenic breast cells by assessing expression levels of inducible nitric oxide synthase (iNOS) and cycloogenase-2 (Cox-2) and NOS activity, which are known to be early molecular changes in disease formation.

Age and gender affect DNMT3a and DNMT3b expression in human liver.

DNA methylation is catalyzed by a family of DNA methyltransferases (DNMTs) including the maintenance enzyme DNMT 1 and de novo methyltransferases DNMT 3a and DNMT 3b. Elevated levels of DNMTs have been found in cancer cells and in several types of human tumors. A polymorphism found in DNMT3b has been associated with increased risk for several cancers.

A biopsychosocial approach to examining tobacco-related health disparities among racially classified social groups.

Aims: To articulate a broader, multi-causal model that incorporates psychosocial and environmental factors that can differ systematically across racially classified social groups (RCSGs) and impact biological pathways related to the development of tobacco-related diseases.

Methods: This paper is built upon a review of the existing scientific literature on selected biopsychosocial factors (diet/nutrition, obesity, alcoholic intake, psychosocial stress, occupational/environmental exposures and exposure to other diseases and illnesses) and tobacco use in examining the biological contributions to differences in tobacco-related health outcomes among RCSGs.

Findings: Recent work has focused on RCSG genetic variations as a possible explanation for differences in tobacco-related health disparities.

Search for an association between the human CYP1A2 genotype and CYP1A2 metabolic phenotype.

The genotype responsible for more than 60-fold interindividual differences in human hepatic CYP1A2 constitutive expression is not understood. Resequencing the human CYP1A1_CYP1A2 locus (39.6 kb) in five major geographically isolated subgroups recently led to the identification of 85 single nucleotide polymorphisms (SNPs), 57 of which were double-hit SNPs.

Modulation of the constitutive activated STAT3 transcription factor in pancreatic cancer prevention: effects of indole-3-carbinol (I3C) and genistein.

Background: The signal transducer and activator of transcription 3 (STAT3) is a latent transcription factor required in proliferation and differentiation. STAT3 is activated constitutively in a number of cancers.

Materials And Methods: This study was conducted to assess the possible involvement of STAT3 activation in pancreatic cancer and the potential for this pathway as a target in chemopreventive strategy.

Carcinogenesis of the food mutagen PhIP in mice is independent of CYP1A2.

2-Amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) is the most abundant of the heterocyclic amines found in cooked meat. Based on in vitro studies with rats and humans, CYP1A2 is believed to be the primary enzyme responsible for N(2)-hydroxylation, the initial step in the metabolic activation of PhIP. To determine whether CYP1A2 is the primary P450 responsible for metabolic activation of PhIP in mice that leads to tumor formation, neonatal Cyp1a2-null and wild-type mice were treated with approximately 11 (low dose) and approximately 22 (high dose) mg/kg PhIP at days 8 and 15, corresponding cumulatively to 600 and 1200 nmol PhIP, and analyzed at 19-21 months of age.

Increased expression of heterogeneous nuclear ribonucleoprotein A2/B1 (hnRNP) in pancreatic tissue from smokers and pancreatic tumor cells.

Pancreatic cancer is a major cause of deaths in the United States, and has one of the lowest 5-year survival rates. Early diagnosis has not been possible due to the lack of reliable early tumor markers. The heterogeneous nuclear ribonucleoprotein A1/B2 (hnRNP) was recently shown to be up-regulated in the early stage of lung cancer.

CYP2A6 activity determined by caffeine phenotyping: association with colorectal cancer risk.

Cytochrome P450 2A6 (CYP2A6) catalyzes the metabolic activation of several procarcinogens including dietary and environmental nitrosamines, and the involvement of CYP2A6 in cancer development has been postulated. CYP2A6 phenotype was determined using caffeine as a probe drug in individuals participating in a case-control study of colorectal cancer (127 cases and 333 controls matched on age, gender, race, and geographic region). Conversion of the caffeine metabolite 1,7-dimethylxanthine (17X) to 1,7-dimethyl uric acid (17U) is catalyzed primarily by CYP2A6, and this activity can be assayed by comparison of urinary molar ratios of metabolites.