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1.  Gene expression profiles in peripheral blood mononuclear cells of Chinese nickel refinery workers with high exposures to nickel and control subjects 
Background
Occupational exposure to nickel (Ni) is associated with an increased risk of lung and nasal cancers. Ni compounds exhibit weak mutagenic activity, alter the cell’s epigenetic homeostasis, and activate signaling pathways. However, changes in gene expression associated with Ni exposure have only been investigated in vitro. This study was conducted in a Chinese population to determine whether occupational exposure to Ni was associated with differential gene expression profiles in the peripheral blood mononuclear cells (PBMCs) of Ni-refinery workers when compared to referents.
Methods
Eight Ni-refinery workers and ten referents were selected. PBMC RNA was extracted and gene expression profiling was performed using Affymetrix exon arrays. Differentially expressed genes between both groups were identified in a global analysis.
Results
There were a total of 2756 differentially expressed genes (DEG) in the Ni-refinery workers relative to the control subjects (FDR adjusted p<0.05) with 770 up-regulated genes and 1986 down-regulated genes. DNA repair and epigenetic genes were significantly overrepresented (p< 0.0002) among the DEG. Of 31 DNA repair genes, 29 were repressed in the high exposure group and two were overexpressed. Of the 16 epigenetic genes 12 were repressed in the high exposure group and 4 were overexpressed.
Conclusions
The results of this study indicate that occupational exposure to Ni is associated with alterations in gene expression profiles in PBMCs of subjects.
Impact
Gene expression may be useful in identifying patterns of deregulation that precede clinical identification of Ni-induced cancers.
doi:10.1158/1055-9965.EPI-12-1011
PMCID: PMC3565097  PMID: 23195993
nickel; nickel refinery workers; gene expression; metals; carcinogenesis
2.  Association Between Arsenic Exposure and Global Post-translational Histone Modifications Among Adults in Bangladesh 
Background
Exposure to arsenic (As) is associated with an increased risk of several cancers, as well as, cardiovascular disease, and childhood neuro-developmental deficits. Arsenic compounds are weakly mutagenic, alter gene expression and post-translational histone modifications (PTHMs) in vitro.
Methods
Water and urinary As concentrations, as well as, global levels of histone 3 lysine 9 di-methylation and acetylation (H3K9me2 and H3K9ac), histone 3 lysine 27 trimethylation and acetylation (H3K27me3 and H3K27ac), histone 3 lysine 18 acetylation (H3K18ac) and histone 3 lysine 4 trimethylation (H3K4me3) were measured in peripheral blood mononuclear cells (PBMCs) from a subset of participants (N=40) of a folate clinical trial in Bangladesh (FACT study).
Results
Total urinary As (uAs) was positively correlated with H3K9me2 (r=0.36, p=0.02) and inversely with H3K9ac (r= -0.47, p=0.002). The associations between As and other PTHMs differed in a gender-dependent manner. Water As (wAs) was positively correlated with H3K4me3 (r=0.45, p=0.05) and H3K27me3 (r=0.50, p=0.03) among females and negatively correlated among males (H3K4me3: r= -0.44, p=0.05; H3K27me3: r= -0.34, p=0.14). Conversely, wAs was inversely associated with H3K27ac among females (r= -0.44, p=0.05) and positively associated among males (r=0.29, p=0.21). A similar pattern was observed for H3K18ac (females: r= -0.22, p=0.36; males: r=0.27, p=0.24).
Conclusion
Exposure to As is associated with alterations of global PTHMs; gender-specific patterns of association were observed between As exposure and several histone marks.
Impact
These findings contribute to the growing body of evidence linking As exposure to epigenetic dysregulation, which may play a role in the pathogenesis of As toxicity.
doi:10.1158/1055-9965.EPI-12-0833
PMCID: PMC3518638  PMID: 23064002
Arsenic; epigenetics; histone modifications; Bangladesh; gender difference
3.  The control of histone methylation and gene expression by oxidative stress, hypoxia and metals 
Free radical biology & medicine  2012;53(5):1041-1047.
The harmful consequences of carcinogenic metals, such as nickel, arsenic and chromium, are thought to be in part due to their ability to induce oxidative stress. The ubiquity of oxidative stress in biological systems has made it a fairly obvious culprit in causing cellular damage and/or development of disease. However, the full extent of oxidative stress-induced damage is not limited to its direct effects on cellular components, such as lipids, proteins and DNA, but may extend to its ability to alter gene expression. Gene expression regulation is an important component of cellular and/or tissue homeostasis, and its alteration can have detrimental consequences. Therefore, a growing amount of interest is being paid to understanding how oxidative stress can influence gene expression. Oxidative stress-induced epigenetic dysregulation in the form of post-translational histone modifications, in particular, is a popular topic of research. This review will therefore primarily focus on discussing the role of oxidative stress and hypoxia on histone methylation and/or gene expression alterations. The sources of oxidative stress discussed here are carcinogenic metals, such as, nickel, arsenic and chromium.
doi:10.1016/j.freeradbiomed.2012.07.020
PMCID: PMC3432141  PMID: 22841757
Metals; histones; hypoxia; oxidative stress; gene expression
4.  Carcinogenic Metals and the Epigenome: Understanding the effect of Nickel, Arsenic, and Chromium 
Carcinogenic metals, such as nickel, arsenic, and chromium, are widespread environmental and occupational pollutants. Chronic exposure to these metals has been connected with increased risks of numerous cancers and as well as non-carcinogenic health outcomes, including cardiovascular disease, neurologic deficits, neuro-developmental deficits in childhood, and hypertension. However, currently the specific molecular targets for metal toxicity and carcinogenicity are not fully understood. Here, we propose that the iron- and 2-oxoglutaratedependent dioxygenase family enzymes, as well as, other histone modifying enzymes are important intracellular targets that mediate the toxicity and carcinogenicity of nickel, and maybe potential targets in chromium and arsenic induced carcinogenesis. Our data demonstrates that all three metals are capable of inducing post-translational histone modifications and affecting the enzymes that modulate them (i.e. the iron- and 2-oxoglutaratedependent dioxygenase family, including HIF-prolyl hydroxylase PHD2, histone demethylase JHDM2A/JMJD1A, and DNA repair enzymes ABH3 and ABH2, and histone methyltransferases, G9a). Given the effects these metals can exert on the epigenome, future studies of their involvement in histone modifying enzymes dynamics would deepen our understanding on their respective toxicities and carcinogenicities.
doi:10.1039/c2mt20033c
PMCID: PMC3687545  PMID: 22473328
5.  THE EFFECT OF EXPOSURE TO CARCINOGENIC METALS ON HISTONE TAIL MODIFICATIONS AND GENE EXPRESSION IN HUMAN SUBJECTS 
The precise mechanisms for the carcinogenesis of nickel and arsenic compounds are not completely understood. In recent years, alterations of epigenetic mechanisms have been implicated in the carcinogenesis of these two metal compounds. In vitro exposure to nickel or arsenic induces changes in both DNA methylation patterns, as well as, in the levels of posttranslational modifications of histone tails. Changes in DNA methylation patterns have been reported in human subjects exposed to arsenic. Here we review our recent reports on the alterations in global levels of posttranslational histone modifications in peripheral blood mononuclear cells (PBMCs) of subjects with occupational exposure to nickel and subjects exposed to arsenic in their drinking water. Occupational exposure to nickel was associated with an increase in H3K4me3 and decrease in H3K9me2. A global increase in H3K9me2 and decrease in H3K9ac was found in subjects exposed to arsenic. Additionally, exposure to arsenic resulted in opposite changes in a number of histone modifications in males compared to females. The results of these two studies suggest that exposure to nickel or arsenic compounds, and possibly other carcinogenic metal compounds, can induce changes in global levels of posttranslational histone modifications in peripheral blood mononuclear cells.
doi:10.1016/j.jtemb.2012.03.012
PMCID: PMC3620044  PMID: 22633395
nickel; arsenic; epigenetics; histone tail modifications
6.  Histone modifications and cancer: biomarkers of prognosis? 
Epigenetic dysregulation is being increasingly recognized as a hallmark of cancer. Post-translational modifications of histones, in particular, are known to play important roles gene expression alterations in cancer development and progression. Given their key involvement in the various stages of carcinogenesis, histone modifications are also being explored as potential biomarkers of disease progression and prognosis. This review will therefore discuss the role of histone modifications in cancer biology and will explore their prognostic potential.
PMCID: PMC3433108  PMID: 22957310
Histone modifications; cancer; biomarkers; prognosis
7.  Chromium induces chromosomal instability, which is partly due to deregulation of BubR1 and Emi1, two APC/C inhibitors 
Cell Cycle  2011;10(14):2373-2379.
Disruption of cell cycle checkpoints and interference with the normal cell cycle progression frequently result in cell death or malignant transformation. Hexavalent chromium [Cr(VI)] is a well-known carcinogen that has been implicated in the occurrence of many types of human malignancies, including lung cancer. However, the exact mechanism by which Cr(VI) causes malignant transformation in the lung remains unknown. We have demonstrated that chronic exposure to a noncytotoxic concentration of Cr(VI) induced a variety of chromosomal abnormalities, including premature sister chromatid separation, chromosomal breakage and the presence of lagging/misaligned chromosomes. After treatment with nocodazole, both HeLa and normal lung bronchial epithelial cells were arrested at mitosis. However, Cr(VI) significantly compromised M-phase arrest induced by nocodazole. Cr(VI) suppressed BubR1 activation and reduced expression of Emi1, leading to an unscheduled activation of APC/C. Consistent with this observation, Cr(VI) treatment caused enhanced polyubiquitination of geminin during mitotic release, while it deregulated the activity of Cdt1, a DNA replication licensing factor. Combined, these results suggest that Cr(VI)-induced chromosomal instability is partly due to a perturbation of APC/C activities, leading to chromosomal instability.
doi:10.4161/cc.10.14.16310
PMCID: PMC3230526  PMID: 21670593
chromium; checkpoint; chromosome instability; APC/C; BubR1; Emi1
8.  Global Levels of Histone Modifications in Peripheral Blood Mononuclear Cells of Subjects with Exposure to Nickel 
Environmental Health Perspectives  2011;120(2):198-203.
Background: Occupational exposure to nickel (Ni) is associated with an increased risk for lung and nasal cancers. Ni compounds exhibit weak mutagenic activity, cause gene amplification, and disrupt cellular epigenetic homeostasis. However, the Ni-induced changes in global histone modification levels have only been tested in vitro.
Objective: This study was conducted in a Chinese population to determine whether occupational exposure to Ni is associated with alterations of global histone modification levels and to evaluate the inter- and intraindividual variance of global histone modification levels.
Method: Forty-five subjects with occupational exposure to Ni and 75 referents were recruited. Urinary Ni and global H3K4 trimethylation, H3K9 acetylation, and H3K9 dimethylation levels were measured in peripheral blood mononuclear cells (PBMCs) of subjects.
Results: H3K4me3 was elevated in Ni-exposed subjects (0.25% ± 0.11%) compared with referents (0.15% ± 0.04%; p = 0.0004), and H3K9me2 was decreased (Ni-exposed subjects, 0.11% ± 0.05%; referents, 0.15% ± 0.04%; p = 0.003). H3K4me3 was positively (r = 0.4, p = 0.0008) and H3K9ac was negatively (r = 0.1, p = 0.01) associated with urinary Ni. Interindividual variances of H3K4me3, H3K9ac, and H3K9me2 were larger compared with intraindividual variance in both exposure test groups, resulting in reliability coefficients (an estimate of consistency of a set of measurements) of 0.60, 0.67, and 0.79 for H3K4me3, H3K9ac, and H3K9me2, respectively, for Ni-exposed subjects and of 0.75, 0.74, and 0.97, respectively, for referent subjects.
Conclusion: The results of this study indicate that occupational exposure to Ni is associated with alterations of global histone modification levels and that measurements of global levels of histone modifications are relatively stable over time in human PBMCs.
doi:10.1289/ehp.1104140
PMCID: PMC3279455  PMID: 22024396
epigenetics; H3K4 trimethylation; H3K9 acetylation; H3K9 dimethylation; histone modifications; interindividual variation; intraindividual variation; nickel; nickel refinery workers

Results 1-8 (8)