Occupational exposure to formaldehyde and biological monitoring of Research Institute workers

Aim: The aim of this study was to verify the presence of a relationship between formaldehyde exposure in the work environment with biological markers of exposure and of effect. Methods: Exposure to formaldehyde (FA) of 36 workers in different laboratories of a Cancer Research Institute and biomarkers of exposure, such as formaldehyde human serum albumin conjugate (FA-HSA) and biomarkers of effect, such as chromosome aberration (CA), micronuclei (MN) and sister chromatid exchanges (SCEs) were measured in peripheral blood lymphocytes of the same workers. Results: Individual FA levels of exposure ranged from 4.9 μg/m³ to 268.7 μg/m³. Subjects with high FA exposure showed a significant increase of the biomarker of exposure FA-HSA, but biomarkers of effect did not show any significant differences. Conclusions: A significant relationship was observed between occupational exposure to FA and a biological marker of exposure (FA-HSA). The markers of effect used (CA, MN and SCE) failed to indicate the presence of genetic damage.     

A Current Global View of Environmental and Occupational Cancers

This review is focused on current information of avoidable environmental pollution and occupational exposure as causes of cancer. Approximately 2% to 8% of all cancers are thought to be due to occupation. In addition, occupational and environmental cancers have their own characteristics, e.g., specific chemicals and cancers, multiple factors, multiple causation and interaction, or latency period. Concerning carcinogens, asbestos/silica/wood dust, soot/polycyclic aromatic hydrocarbons [benzo(a) pyrene], heavy metals (arsenic, chromium, nickel), aromatic amines (4-aminobiphenyl, benzidine), organic solvents (benzene or vinyl chloride), radiation/radon, or indoor pollutants (formaldehyde, tobacco smoking) are mentioned with their specific cancers, e.g., lung, skin, and bladder cancers, mesothelioma or leukemia, and exposure routes, rubber or pigment manufacturing, textile, painting, insulation, mining, and so on. In addition, nanoparticles, electromagnetic waves, and climate changes are suspected as future carcinogenic sources. Moreover, the aspects of environmental and occupational cancers are quite different between developing and developed countries. The recent follow-up of occupational cancers in Nordic countries shows a good example for developed countries. On the other hand, newly industrializing countries face an increased burden of occupational and environmental cancers. Developing countries are particularly suffering from preventable cancers in mining, agriculture, or industries without proper implication of safety regulations. Therefore, industrialized countries are expected to educate and provide support for developing countries. In addition, citizens can encounter new environmental and occupational carcinogen nominators such as nanomaterials, electromagnetic wave, and climate exchanges. As their carcinogenicity or involvement in carcinogenesis is not clearly unknown, proper consideration for them should be taken into account. For these purposes, new technologies with a balance of environment and gene are required. Currently, various approaches with advanced technologies—genomics, exposomics, etc.—have accelerated development of new biomarkers for biological monitoring of occupational and environmental carcinogens. These advanced approaches are promising to improve quality of life and to prevent occupational and environmental cancers.     

Past and Future Applications of CYP450-Genetic Polymorphisms for Biomonitoring of Environmental Toxicants

Cytochrome P450s (CYPs) are a huge gene superfamily of heme enzymes involved in xenobioitc as well as endobiotic metabolism. They play a critical role in adaptation to environmental changes for survival of living organisms. In addition, the huge environmental loads of human-made chemicals are biotransformed into bioactive or detoxified forms by CYPs. Thus, CYPs have been used for biomonitoring of environmental pollutants, screening of their metabolisms and exploring remedy. In particular, the induction or inhibition of CYPs has been applied to exposure monitoring of environmental toxicants, which are biotransformed by CYPs. This review considers past and future applications of CYP-genetic polymorphisms as susceptibility biomarkers for biomonitoring. Furthermore, we suggest the needs for further understanding of the characteristics of each CYP isozyme, consideration of real-life exposures such as mixed contamination with various chemicals, and incorporation of the presence of other phase I and phase II enzymes, for proper applications of CYP polymorphisms on biomonitoring.     

Health effects of inhaled radon progeny∗

Abstract

To clarify etiology of lung cancer in nonsmoker females, various studies have been done. Particularly, host factors and environmental tobacco smoking (ETS) of females have been emphasized. However, traditional epidemiological data showed controversial results of sex or gender differences in lung cancer susceptibility and suggest presence of some confounders. One of them is that most of epidemiology studies are based on self-reports for ETS. To prevent misestimate effects of ETS via the self-report, exposure monitoring of ETS is required. On the other hand, focusing on genetic polymorphisms in metabolic enzymes and DNA repair, molecular epidemiological studies have been done in nonsmoker females. Therefore, this review considered: 1. gender differences in lung cancer; 2. effects of passive smoking on lung cancer; 3. exposure monitoring of ETS including genetic risks of lung cancer to clarify etiology of lung cancer in the nonsmoker females with molecular epidemiological discussion.     

Immunotoxicity of mercury: Pathological and toxicological effects

Mercury (Hg) is toxic and hazardous metal that causes natural disasters in the earth's crust. Exposure to Hg occurs via various routes; like oral (fish), inhalation, dental amalgams, and skin from cosmetics. In this review, we have discussed the sources of Hg and its potential for causing toxicity in humans. In addition, we also review its bio-chemical cycling in the environment; its systemic, immunotoxic, genotoxic/carcinogenic, and teratogenic health effects; and the dietary influences; as well as the important considerations in risk assessment and management of Hg poisoning have been discussed in detail. Many harmful outcomes have been reported, which will provide more awareness.     

Incorporating molecular biomarkers into clinical practice for gastric cancer

ABSTRACT

Introduction: Gastric cancer is one of the most common causes of cancer-related mortality worldwide. To improve clinical outcomes, it is critical to develop appropriate approaches to diagnosis and treatment. Biomarkers have numerous potential clinical applications, including screening, assessing risk, determining prognosis, monitoring recurrence, and predicting response to treatment. Furthermore, biomarkers may contribute to the development of effective therapies.

Areas covered: Here we review recent progress in exploiting GC-specific biomarkers such as protein-coding genes, microRNAs, long noncoding RNAs, and methylated gene promoters.

Expert opinion: The development of biomarkers for diagnosing and monitoring gastric cancer and for individualizing therapeutic targets shows great promise for improving gastric cancer management.     

Occupational exposure to formaldehyde and biological monitoring of Research Institute workers

Aim: The aim of this study was to verify the presence of a relationship between formaldehyde exposure in the work environment with biological markers of exposure and of effect. Methods: Exposure to formaldehyde (FA) of 36 workers in different laboratories of a Cancer Research Institute and biomarkers of exposure, such as formaldehyde human serum albumin conjugate (FA-HSA) and biomarkers of effect, such as chromosome aberration (CA), micronuclei (MN) and sister chromatid exchanges (SCEs) were measured in peripheral blood lymphocytes of the same workers. Results: Individual FA levels of exposure ranged from 4.9 μg/m³ to 268.7 μg/m³. Subjects with high FA exposure showed a significant increase of the biomarker of exposure FA-HSA, but biomarkers of effect did not show any significant differences. Conclusions: A significant relationship was observed between occupational exposure to FA and a biological marker of exposure (FA-HSA). The markers of effect used (CA, MN and SCE) failed to indicate the presence of genetic damage.     

Is hyperthermic intraperitoneal chemotherapy (HIPEC) safe for healthcare workers?

Background

During hyperthermic intraperitoneal chemotherapy (HIPEC), caregivers are exposed by different routes to cytotoxic drugs. This review proposes an overview of the safety of HIPEC by assessing existing data on protection procedures, biological and non-biological samples. Based on these data, relevant good practices, eventual irrelevant overprotection procedures and missing data to implement adapted protections are highlighted.

Clinical significance of the mutational landscape and fragmentation of circulating tumor DNA in renal cell carcinoma

Reliable biomarkers for renal cell carcinoma (RCC) have yet to be determined. Circulating tumor DNA (ctDNA) is an emerging resource to detect and monitor molecular characteristics of various tumors. The present study aims to clarify the clinical utility of ctDNA for RCC. Fifty‐three patients histologically diagnosed with clear cell RCC were enrolled. Targeted sequencing was carried out using plasma cell‐free DNA (cfDNA) and tumor DNA. We applied droplet digital PCR (ddPCR) to validate detected mutations. cfDNA fragment size was also evaluated using a microfluidics‐based platform and sequencing. Proportion of cfDNA fragments was defined as the ratio of small (50‐166 bp) to large (167‐250 bp) cfDNA fragments. Association of mutant allele frequency of ctDNA with clinical course was analyzed. Prognostic potential was evaluated using log‐rank test. A total of 38 mutations across 16 (30%) patients were identified from cfDNA, including mutations in TP53 (n = 6) and VHL (n = 5), and median mutant allele frequency of ctDNA was 10%. We designed specific ddPCR probes for 11 mutations and detected the same mutations in both cfDNA and tumor DNA. Positive ctDNA was significantly associated with a higher proportion of cfDNA fragments (P = .033), indicating RCC patients with ctDNA had shorter fragment sizes of cfDNA. Interestingly, the changes of mutant allele frequency in ctDNA concurrently correlated with clinical course. Positive ctDNA and fragmentation of cfDNA were significantly associated with poor cancer‐specific survival (P < .001, P = .011). In conclusion, our study shows the clinical utility of ctDNA status and cfDNA fragment size as biomarkers for prognosis and disease monitoring in RCC.     

The contribution of molecular epidemiology to the identification of human carcinogens: current status and future perspectives

BackgroundThe use of biological-based markers of exposure, intermediate effect, outcome, and susceptibility has become standard practice in cancer epidemiology, which has contributed to identification of several carcinogenic agents. Nevertheless, with the exception of biological agents, this contribution, in terms of providing sufficiently strong evidence as required by the International Agency for Research on Cancer (IARC) monographs, has been modest.Materials and methodsWe discuss the overall contribution of molecular epidemiology to identification of carcinogens, with focus on IARC monographs.ResultsFor many carcinogens, valid biological markers of exposure and mechanisms of actions are not available. Molecular markers are usually assessed in single biological samples, which may not represent the actual exposure or biological events related to carcinogens. The contribution of molecular epidemiology to identification of carcinogens has mainly been limited to the carcinogens acting through a genotoxic mechanism, i.e. when carcinogens induce DNA damage. A number of factors, including certain hormones and overweight/obesity, may show carcinogenic effects through nongenotoxic pathways, for which mechanisms of carcinogenicity are not well identified and their biomarkers are sparse.ConclusionLongitudinal assessment of biomarkers may provide more informative data in molecular epidemiology studies. For many carcinogens and mechanistic pathways, in particular nongenotoxic carcinogenicity, valid biological markers still need to be identified.     

Integrating pharmacogenetics into gemcitabine dosing--time for a change?

Increasing the efficacy of anticancer agents and avoiding toxic effects is a critical issue in clinical oncology. Identifying biomarkers that predict clinical outcome would ensure improved patient care. Gemcitabine is widely used to treat various solid tumors as a single agent or in combination with other drugs. The therapeutic index of gemcitabine is narrow, and abnormal pharmacokinetics leading to changes in plasma exposure is a major cause of adverse effects. A number of biomarkers have been proposed to predict efficacy of gemcitabine, focusing on molecular determinants of response identified at the tumor level. Genetic and functional deregulations that affect the disposition of a drug could be the reason for life-threatening adverse effects or treatment failure. In particular, deregulation of cytidine deaminase, the enzyme responsible for detoxification of most nucleotide analogs, should be examined. Identifying and validating biomarkers for pharmacogenetic testing before administration of gemcitabine is a step towards personalized medicine.     

Comparison of early onco/suppressor gene expressions in peripheral leukocytes and potential target organs of rats exposed to the carcinogen 1-nitropyrene.

An in-vivo model has been developed to study early expressions of c-myc, Ha-ras oncogenes and p53 suppressor gene as biomarkers of carcinogenic exposure and/or tumorigenesis. In order to validate the in-vivo expression changes as biomarkers, rats were treated with the outdoor air pollutant carcinogen 1-nitropyrene. The gene expression levels were measured after 24 and 48 h in potential target tissues (lung, liver, lymph nodes, kidneys, spleen) and in peripheral blood leukocytes. Another main objective was to prove the applicability of leukocytes as a surrogate tissue, having a similar expression pattern of the selected genes upon carcinogenic exposure. The c-myc oncogene was not suitable as an early biomarker because of the lack or low level of its expression. However, in the case of the other oncogene Ha-ras and the suppressor gene p53, remarkable and early changes were detected in the expression signals. Similar expression patterns could only be detected in leukocytes and the spleen; therefore we continue this validation study by using other types and routes of exposure.     

Ionizing radiation-induced metabolic oxidative stress and prolonged cell injury

Cellular exposure to ionizing radiation leads to oxidizing events that alter atomic structure through direct interactions of radiation with target macromolecules or via products of water radiolysis. Further, the oxidative damage may spread from the targeted to neighboring, non-targeted bystander cells through redox-modulated intercellular communication mechanisms. To cope with the induced stress and the changes in the redox environment, organisms elicit transient responses at the molecular, cellular and tissue levels to counteract toxic effects of radiation. Metabolic pathways are induced during and shortly after the exposure. Depending on radiation dose, dose-rate and quality, these protective mechanisms may or may not be sufficient to cope with the stress. When the harmful effects exceed those of homeostatic biochemical processes, induced biological changes persist and may be propagated to progeny cells. Physiological levels of reactive oxygen and nitrogen species play critical roles in many cellular functions. In irradiated cells, levels of these reactive species may be increased due to perturbations in oxidative metabolism and chronic inflammatory responses, thereby contributing to the long-term effects of exposure to ionizing radiation on genomic stability. Here, in addition to immediate biological effects of water radiolysis on DNA damage, we also discuss the role of mitochondria in the delayed outcomes of ionization radiation. Defects in mitochondrial functions lead to accelerated aging and numerous pathological conditions. Different types of radiation vary in their linear energy transfer (LET) properties, and we discuss their effects on various aspects of mitochondrial physiology. These include short and long-term in vitro and in vivo effects on mitochondrial DNA, mitochondrial protein import and metabolic and antioxidant enzymes.     

Advances in cancer epidemiology in Japan

Epidemiologists in Japan have been performing calculations to estimate nationwide cancer incidence rates as well as 5‐year survival rates using population‐based cancer registry data. There have been remarkable changes in cancer incidence and/or mortality in cancers of the lung, liver and stomach, which were thought to be attributed to the changing impact of exposure to cigarette smoking, chronic hepatitis C virus infection and Helicobacter pylori infection, respectively. In systematic reviews providing evidence in risk/protective factors for cancer sites using case–control and cohort studies of the Japanese population, there were associations between cancer sites (esophagus, stomach, colo‐rectum, liver, pancreas, lung and breast) and various lifestyle factors. In the past 10 years, a hospital‐based case–control study at Aichi Cancer Center provided valuable evidence of gene‐environment interaction on the development of cancer [i.e., the effects of aldehyde dehydrogenase‐2 (ALDH2) polymorphism and heavy alcohol drinking on esophageal cancer, ALDH2 polymorphism and smoking on lung cancer, methylenetetrahydrofolate reductase polymorphism and heavy alcohol drinking on pancreatic cancer]. The database with stored DNA was also used and identified seven loci containing significant but low‐penetrance polymorphisms associated with the development of breast cancer. These findings together with established risk factors are likely to be useful to predict personalized breast cancer risk in East Asian women. In 2005, the Japan Multi‐Institution Collaborative Cohort (J‐MICC) study was launched to elucidate gene‐environment interactions as well as to confirm preclinical diagnostic biomarkers of cancer. J‐MICC, which has recruited 92,000 healthy individuals by the end of 2012, will follow the individuals until 2025.     

Tolerance for chronic heat exposure is greater in female than male mice

Purpose: Chronic heat exposure in mice has cellular and physiological effects that improve thermal tolerance [1], but also modifies innate immune responses with potential adverse consequences [2]. While male and female mice are known to respond differently to acute exposure to severe hyperthermia, sex-based differences in responses to chronic moderate heat exposure have not been reported. The major objective of this study was to compare the tolerance of male and female mice for chronic heat exposure.

Materials and methods: We used a mouse model of 5-day moderate heat exposure (ambient temperature ～37°C) to compare the physiological and cellular heat shock response in male and female mice. Core temperature, heart rate, and activity were monitored telemetrically and heat shock protein levels were measured in brain and lung by western blotting.

Results: Adult CD-1 female mice maintained a 1.2°C lower core temperature (38.31?±?0.64 versus 39.51?±?0.72°C; p?=?0.002), experienced less weight loss (1.54?±?0.45 versus 4.54?±?1.97?g; p?=?0.0007), and had improved survival (16/16 survived versus 13/21, p?<?0.006) than male mice of the same age. After 5 days of moderate heat exposure Hsp72 levels in brain and lung increased 2.1-fold (p?=?0.007) and 5-fold (p?=?0.048) in male mice compared with 1.3- (p?=?0.054) and 1.5-fold (p?=?0.134) in female mice.

Conclusions: This study reveals previously unknown and potentially important differences between male and female mice in physiological and cellular responses to chronic heat exposure, which had consequences for survival. Future studies may identify biomarkers of differential heat tolerance and treatments to improve heat tolerance in humans.     

Ginkgo Biloba Leave Extract: Biological,Medicinal, and Toxicological Effects

Ginkgo biloba leave extract is among the most widely sold herbal dietary supplements in the United States. Its purported biological effects include: scavenging free radical; lowering oxidative stress; reducing neural damages, reducing platelets aggregation; anti-inflammation; anti-tumor activities; and anti-aging. Clinically, it has been prescribed to treat CNS disorders such as Alzheimer's disease and cognitive deficits. It exerts allergy and changes in bleeding time. While its mutagenicity or carcinogenic activity has not been reported, its components, quercetin, kaempferol and rutin have been shown to be genotoxic. There are no standards or guidelines regulating the constituent components of Ginkgo biloba leave extract nor are exposure limits imposed. Safety evaluation of Ginkgo biloba leave extract is being conducted by the U.S. National Toxicology Program.     

Exploring a potential mechanistic role of DNA methylation in the relationship between in utero and post-natal environmental exposures and risk of childhood acute lymphoblastic leukaemia

The aetiology of childhood acute lymphoblastic leukaemia (ALL) is unclear. Genetic abnormalities have been identified in a number of ALL cases, although these alone are not sufficient for leukaemic transformation. Various in utero and post-natal environmental exposures have been suggested to alter risk of childhood ALL. DNA methylation patterns can be influenced by environmental exposures, and are reported to be altered in ALL, suggesting a potential mediating mechanism between environment and ALL disease risk. To investigate this, we used a ‘meet in the middle’ approach, investigating the overlap between exposure-associated and disease-associated methylation change. Genome-wide DNA methylation changes in response to possible ALL-risk exposures (i.e. breast feeding, infection history, day care attendance, maternal smoking, alcohol, caffeine, folic acid, iron and radiation exposure) were investigated in a sub-population of the Avon Longitudinal Study of Parents and Children (ALSPAC) cohort using an epigenome-wide association study (EWAS) approach (n = 861–927), and compared to a list of ALL disease-associated methylation changes compiled from published data. Hypergeometric probability tests suggested that the number of directionally concordant gene methylation changes observed in ALL disease and in response to the following exposures; maternal radiation exposure (p = 0.001), alcohol intake (p = 0.006); sugary caffeinated drink intake during pregnancy (p = 0.045); and infant day care attendance (p = 0.003), were not due to chance. Data presented suggests that DNA methylation may be one mediating mechanism in the multiple hit pathway needed for ALL disease manifestation.     

Colorectal cancer and RASSF family—A special emphasis on RASSF1A

The RAS‐association domain family, commonly referred to as RASSF, is a family of 10 members (RASSF1‐10) implicated in a variety of key biological processes, including cell cycle regulation, apoptosis and microtubule stability. Furthermore, RASSFs have been implicated in tumorigenesis and several family members are now thought to be tumor suppressors. As opposed to the KRAS oncogene, for which mutational activation is frequent in colorectal cancer (CRC), RASSFs are found to be silenced mainly by aberrant promoter methylation. In particular, RASSF1A, RASSF2 and RASSF5 methylation has been associated with CRC development, though the mechanisms of action remain poorly understood. This review focus on the current knowledge of RASSF inactivation in CRC, particularly RASSF1A, and on the implications RASSFs may have as potential biomarkers and for the development of new targeted therapies for CRC.     

Identification of Clinically Relevant Molecular Subtypes in Colorectal Cancer: The Dawning of a New Era

In recent years, a number of protein and genomic‐based biomarkers have begun to refine the prognostic information available for colorectal cancer (CRC) and predict defined patient groups that are likely to benefit from systemic treatment or targeted therapies. Of these, KRAS represents the first biomarker integrated into clinical practice for CRC. Microarray‐based gene expression profiling has been used to identify prognostic signatures and, to a lesser extent, predictive signatures in CRC. Despite these advances, a number of major challenges remain. This article, which is based on a lecture delivered as part of the 2013 Bob Pinedo Cancer Care Prize, reviews the impact of molecular biomarkers on the management of CRC, emphasizing changes that have occurred in recent years, and focuses on potential mechanisms of patient stratification and opportunities for novel therapeutic development based on enhanced biological understanding of colorectal cancer.     

Overexpression of <i>lnc-ERP44-3:6</i> Causes Cell Death and Sensitivity to Cisplatin in Breast Cancer Cell Lines

Breast cancer (BC) is one of the leading causes of death in women worldwide. A major challenge in BC is chemoresistance, which is often modulated by epigenetic regulators such as long non-coding RNAs (lncRNAs). Because these regulator lncRNAs may play diverse roles, determining their specific pathways and/or functions is crucial to identify possible biomarkers and/or therapeutic targets for BC. In this study, we used gene expression microarrays in order to identify lncRNAs related to the BC biology. We found, among six differentially expressed (DE) lncRNAs, that the expression of lnc-ERP44-3:6 was consistently down-regulated in all breast tumor tissues compared to normal adjacent tissues of BC patients from northeastern Mexico. Since the role of lnc-ERP44-3:6 remains unknown in BC, we induced its transient overexpression in three different BC cell lines (i.e., MCF10A, MCF-7, and HCC1395) by transfection in order to elucidate its potential downstream effects. Remarkably, our results showed a significant increase in cell death and chemosensitivity to cisplatin at 48 h post-transfection (p < 0.01). In addition, we observed that GAPDH and FAS were up-regulated following the overexpression of lnc-ERP44-3:6. As GAPDH and FAS promote apoptosis in cancer, our findings suggest that the lnc-ERP44-3:6 overexpression induces cell death possibly via up-regulation of one or both genes in BC cell lines. To the best of our knowledge, this is the first study evaluating the overexpression of lnc-ERP44-3:6 and providing insights about its role in BC cells, which suggests that this lncRNA may be an interesting candidate as a potential therapeutic target for BC in our population. However, further studies would be needed to clarify the mechanisms by which an overexpression of lnc-ERP44-3:6 causes both cell death and chemosensitivity to cisplatin.