Publications by authors named "Luoping Zhang"

159 Publications

Using the Key Characteristics of Carcinogens to Develop Research on Chemical Mixtures and Cancer.

Environ Health Perspect 2021 Mar 30;129(3):35003. Epub 2021 Mar 30.

Division of Environmental Health Sciences, University of California Berkeley, School of Public Health, Berkeley, California, USA.

Background: People are exposed to numerous chemicals throughout their lifetimes. Many of these chemicals display one or more of the key characteristics of carcinogens or interact with processes described in the hallmarks of cancer. Therefore, evaluating the effects of chemical mixtures on cancer development is an important pursuit. Challenges involved in designing research studies to evaluate the joint action of chemicals on cancer risk include the time taken to perform the experiments because of the long latency and choosing an appropriate experimental design.

Objectives: The objectives of this work are to present the case for developing a research program on mixtures of environmental chemicals and cancer risk and describe recommended approaches.

Methods: A working group comprising the coauthors focused attention on the design of mixtures studies to inform cancer risk assessment as part of a larger effort to refine the key characteristics of carcinogens and explore their application. Working group members reviewed the key characteristics of carcinogens, hallmarks of cancer, and mixtures research for other disease end points. The group discussed options for developing tractable projects to evaluate the joint effects of environmental chemicals on cancer development.

Results And Discussion: Three approaches for developing a research program to evaluate the effects of mixtures on cancer development were proposed: a chemical screening approach, a transgenic model-based approach, and a disease-centered approach. Advantages and disadvantages of each are discussed. https://doi.org/10.1289/EHP8525.
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http://dx.doi.org/10.1289/EHP8525DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8009606PMC
March 2021

Biomarkers of COVID-19 and technologies to combat SARS-CoV-2.

Adv Biomark Sci Technol 2020 19;2:1-23. Epub 2020 Aug 19.

Division of Infectious Diseases and Vaccinology, School of Public Health, University of California, Berkeley, CA, 94720, USA.

Due to the unprecedented public health crisis caused by COVID-19, our first contribution to the newly launching journal, , has abruptly diverted to focus on the current pandemic. As the number of new COVID-19 cases and deaths continue to rise steadily around the world, the common goal of healthcare providers, scientists, and government officials worldwide has been to identify the best way to detect the novel coronavirus, named SARS-CoV-2, and to treat the viral infection - COVID-19. Accurate detection, timely diagnosis, effective treatment, and future prevention are the vital keys to management of COVID-19, and can help curb the viral spread. Traditionally, biomarkers play a pivotal role in the early detection of disease etiology, diagnosis, treatment and prognosis. To assist myriad ongoing investigations and innovations, we developed this current article to overview known and emerging biomarkers for SARS-CoV-2 detection, COVID-19 diagnostics, treatment and prognosis, and ongoing work to identify and develop more biomarkers for new drugs and vaccines. Moreover, biomarkers of socio-psychological stress, the high-technology quest for new virtual drug screening, and digital applications are described.
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http://dx.doi.org/10.1016/j.abst.2020.08.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7435336PMC
August 2020

Formaldehyde and Brain Disorders: A Meta-Analysis and Bioinformatics Approach.

Neurotox Res 2021 Jan 5. Epub 2021 Jan 5.

Division of Environmental Health Sciences, School of Public Health, University of California, Berkeley, CA, USA.

While there is significant investigation and investment in brain and neurodegenerative disease research, current understanding of the etiologies of illnesses like Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), and brain cancer remains limited. Environmental exposure to the pollutant formaldehyde, an emerging neurotoxin widely used in industry, is suspected to play a critical role in mediating these disorders, although findings are limited and inconsistent. Focusing on highly exposed groups, we performed a meta-analysis of human epidemiological studies of formaldehyde and neurodegenerative disease (N =  19) or brain tumors (N = 12). To assess the biological plausibility of observed associations, we then conducted a bioinformatics analysis using WikiPathways and the Comparative Toxicogenomics Database and identified candidate genes and pathways that may be related to these interactions. We reported the meta-relative risk (meta-RR) of ALS following high exposures to formaldehyde was increased by 78% (meta-RR = 1.78, 95% confidence interval, CI 1.20-2.65). Similarly, the meta-RR for brain cancer was increased by 71% (meta-RR = 1.71; 95% CI 1.07-2.73) among highly exposed individuals. Multiple sensitivity analyses did not reveal sources of heterogeneity or bias. Our bioinformatics analysis revealed that the oxidative stress genes superoxide dismutase (SOD1, SOD2) and the pro-inflammatory marker tumor necrosis factor (TNF) were identified as the top relevant genes, and the folate metabolism, vitamin B metabolism, and the ALS pathways were highly affected by formaldehyde and related to the most brain diseases of interest. Further inquiry revealed the two metabolic pathways are also intimately tied with the formaldehyde cycle. Overall, our bioinformatics analysis supports the link of formaldehyde exposure to ALS or brain tumor reported from our meta-analysis. This new multifactorial approach enabled us to both interrogate the robustness of the epidemiological data and identify genes and pathways that may be involved in these interactions, ultimately lending strong evidence and potential biological plausibility for the association between formaldehyde exposure and brain disease.
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http://dx.doi.org/10.1007/s12640-020-00320-yDOI Listing
January 2021

Occupational exposure to antimony trioxide: a risk assessment.

Occup Environ Med 2020 Nov 26. Epub 2020 Nov 26.

Division of Environmental Health Sciences, University of California Berkeley School of Public Health, Berkeley, California, USA

Objectives: The US National Toxicology Program (NTP) recently recommended in its Report on Carcinogens Monograph for Antimony Trioxide that antimony trioxide be listed as '' based on sufficient evidence of carcinogenicity in experimental animals and supporting evidence from mechanistic studies. Our goal was to estimate the possible human cancer risk from occupational exposure to antimony trioxide.

Methods: We selected data from 2-year inhalation studies in male and female mice conducted by the NTP and performed cancer dose-response analyses using cancer models and benchmark dose methods developed by the US Environmental Protection Agency. In these analyses, we generated benchmark doses and cancer slope factors for antimony trioxide, and then estimated human cancer risk under various exposure scenarios. Typical and worst-case inhalation scenarios in multiple occupational settings were used in risk estimation.

Results: In typical case scenarios, the occupational cancer risk from antimony trioxide was estimated to be 0.025 (25 in 1000) for persons working with flame retardants in plastics and textiles for 40 years. Under worst-case scenarios, the occupational cancer risk was estimated to be 0.11 (110 in 1000) for persons working with flame retardants in plastics and textiles. At the current Occupational Safety and Health Administration Permissible Exposure Limit, the cancer risk for occupational inhalation exposure of antimony trioxide was estimated to be 0.096 (96 in 1000).

Conclusion: The risk estimates calculated in this study suggest that exposure to antimony trioxide at levels present in certain occupational settings results in a large increase in the risk of developing cancer.
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http://dx.doi.org/10.1136/oemed-2020-106980DOI Listing
November 2020

Applying genome-wide CRISPR to identify known and novel genes and pathways that modulate formaldehyde toxicity.

Chemosphere 2021 Apr 22;269:128701. Epub 2020 Oct 22.

School of Public Health, University of California, Berkeley, CA, United States. Electronic address:

Formaldehyde (FA), a ubiquitous environmental pollutant, is classified as a Group I human carcinogen by the International Agency for Research on Cancer. Previously, we reported that FA induced hematotoxicity and chromosomal aneuploidy in exposed workers and toxicity in bone marrow and hematopoietic stem cells of experimental animals. Using functional toxicogenomic profiling in yeast, we identified genes and cellular processes modulating eukaryotic FA cytotoxicity. Although we validated some of these findings in yeast, many specific genes, pathways and mechanisms of action of FA in human cells are not known. In the current study, we applied genome-wide, loss-of-function CRISPR screening to identify modulators of FA toxicity in the human hematopoietic K562 cell line. We assessed the cellular genetic determinants of susceptibility and resistance to FA at 40, 100 and 150 μM (IC10, IC20 and IC60, respectively) at two time points, day 8 and day 20. We identified multiple candidate genes that increase sensitivity (e.g. ADH5, ESD and FANC family) or resistance (e.g. FASN and KDM6A) to FA when disrupted. Pathway analysis revealed a major role for the FA metabolism and Fanconi anemia pathway in FA tolerance, consistent with findings from previous studies. Additional network analyses revealed potential new roles for one-carbon metabolism, fatty acid synthesis and mTOR signaling in modulating FA toxicity. Validation of these novel findings will further enhance our understanding of FA toxicity in human cells. Our findings support the utility of CRISPR-based functional genomics screening of environmental chemicals.
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http://dx.doi.org/10.1016/j.chemosphere.2020.128701DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7904579PMC
April 2021

Formaldehyde-induced hematopoietic stem and progenitor cell toxicity in mouse lung and nose.

Arch Toxicol 2021 02 21;95(2):693-701. Epub 2020 Oct 21.

Division of Environmental Health Sciences, School of Public Health, University of California, Berkeley, CA, USA.

Formaldehyde (FA), an economically important and ubiquitous chemical, has been classified as a human carcinogen and myeloid leukemogen. However, the underlying mechanisms of leukemogenesis remain unclear. Unlike many classical leukemogens that damage hematopoietic stem/progenitor cells (HSC/HPC) directly in the bone marrow, FA-as the smallest, most reactive aldehyde-is thought to be incapable of reaching the bone marrow through inhalation exposure. A recent breakthrough study discovered that mouse lung contains functional HSC/HPC that can produce blood cells and travel bi-directionally between the lung and bone marrow, while another early study reported the presence of HSC/HPC in rat nose. Based on these findings, we hypothesized that FA inhalation could induce toxicity in HSC/HPC present in mouse lung and/or nose rather than in the bone marrow. To test this hypothesis, we adapted a commercially available protocol for culturing burst-forming unit-erythroid (BFU-E) and colony-forming unit-granulocyte, macrophage (CFU-GM) colonies from bone marrow and spleen to also enable culture of these colonies from mouse lung and nose, a novel application of this assay. We reported that in vivo exposure to FA at 3 mg/m or ex vivo exposure up to 400 µM FA decreased the formation of both colony types from mouse lung and nose as well as from bone marrow and spleen. These findings, to the best of our knowledge, are the first empirically to show that FA exposure can damage mouse pulmonary and olfactory HSC/HPC and provide potential biological plausibility for the induction of leukemia at the sites of entry rather than the bone marrow.
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http://dx.doi.org/10.1007/s00204-020-02932-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7878325PMC
February 2021

Benzene-associated immunosuppression and chronic inflammation in humans: a systematic review.

Occup Environ Med 2020 Sep 16. Epub 2020 Sep 16.

Division of Environmental Health Sciences, School of Public Health, University of California Berkeley, Berkeley, California, USA

Objective: Recent evidence has accumulated that the immune system is intimately intertwined with cancer development. Two key characteristics of carcinogens in which the immune system plays a central role are chronic inflammation and immunosuppression. In this systematic review, we investigated the association of chronic inflammatory and immunosuppressive outcomes with benzene, a widely used industrial chemical. Benzene has been confirmed to cause acute myeloid leukaemia and suspected to cause non-Hodgkin lymphoma, two cancers of the blood-forming system that affect immune cells.

Methods: We systematically searched PubMed and Embase for all relevant studies using a combination of Medical Subject Headings (MeSH) and selected key words. The detailed review protocol, including search strategy, was registered with PROSPERO, the international prospective register of systematic reviews (#CRD42019138611).

Results: Based on all human studies selected in the final review, we report new evidence of a benzene-induced immunosuppressive effect on the immune system and activation of the immune system to cause inflammation. In particular, benzene significantly lowers the number of white blood cells, particularly lymphocytes such as CD4 T-cells, B-cells and natural killer cells, and increases proinflammatory biomarkers at low levels of exposure.

Conclusion: To the best of our knowledge, this is the first comprehensive review of benzene's immunotoxicity in humans. Based on results obtained from this review, we propose two potential immunotoxic mechanisms of how benzene induces leukaemia/lymphoma: (1) cancer invasion caused by proinflammatory cytokine production, and (2) cancer promotion via impaired immunosurveillance. Further studies will be required to confirm the connection between benzene exposure and its effects on the immune system.
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http://dx.doi.org/10.1136/oemed-2020-106517DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7960562PMC
September 2020

Weeding out inaccurate information on glyphosate-based herbicides and risk of non-Hodgkin lymphoma.

Environ Res 2020 12 29;191:110140. Epub 2020 Aug 29.

Division of Environmental Health Sciences, School of Public Health, University of California Berkeley, Berkeley, USA. Electronic address:

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http://dx.doi.org/10.1016/j.envres.2020.110140DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7889289PMC
December 2020

Combined exposure to formaldehyde and PM: Hematopoietic toxicity and molecular mechanism in mice.

Environ Int 2020 11 26;144:106050. Epub 2020 Aug 26.

Hubei Key Laboratory of Genetic Regulation and Integrative Biology, School of Life Sciences, Central China Normal University, Wuhan 430079, China. Electronic address:

PM and formaldehyde (FA) are major outdoor and indoor air pollutants in China, respectively, and both are known to be harmful to human health and to be carcinogenic. Of all the known chronic health effects, leukaemia is one of the most serious health risks associated with these two pollutants. To explore the influence and underlying mechanisms of exposure to formaldehyde and PM on hematopoietic toxicity, we systematically studied the toxicity induced in hematopoietic organs: bone marrow (BM); spleen; and myeloid progenitor cells (MPCs). Male Balb/c mice were exposed to: PM (20, 160 μg/kg·d) at a dose of 40 μL per mouse or formaldehyde (0.5, 3.0 mg/m) for 8 h per day for 2 weeks or co-exposed to formaldehyde and PM (20 μg/kg·d PM + 0.5 mg/m FA, 20 μg/kg·d PM + 3 mg/m FA, 160 μg/kg·d PM + 0.5 mg/m FA, 160 μg/kg·d PM + 3 mg/m FA) for 2 weeks. Similar toxic effects were found in the formaldehyde-only and PM-only groups, including significant decrease of blood cells and MPCs, along with decreased expression of hematopoietic growth factors. In addition, individual exposure of formaldehyde or PM increased oxidative stress, DNA damage and immune system disorder by destroying the balance of Th1/Th2, and Treg/Th17. DNA repair was markedly inhibited by deregulating the mammalian target of rapamycin (mTOR) pathway. Combined exposure to PM and formaldehyde led to more severe effects. Administration of Vitamin E (VE) was shown to attenuate these effects. In conclusion, our findings suggested that PM and formaldehyde may induce hematopoietic toxicity by reducing the expression of hematopoietic growth factors, increasing oxidative stress and DNA damage, activating the 'immune imbalance' pathway and suppressing the DNA-repair related mTOR pathway. The hematopoietic toxicity induced by combined exposure of PM and formaldehyde might provide further insights into the increased incidence of hematological diseases, including human myeloid leukaemia.
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http://dx.doi.org/10.1016/j.envint.2020.106050DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7839661PMC
November 2020

The Key Characteristics of Carcinogens: Relationship to the Hallmarks of Cancer, Relevant Biomarkers, and Assays to Measure Them.

Cancer Epidemiol Biomarkers Prev 2020 10 9;29(10):1887-1903. Epub 2020 Mar 9.

Expansion Therapeutics Inc, San Diego, California.

The key characteristics (KC) of human carcinogens provide a uniform approach to evaluating mechanistic evidence in cancer hazard identification. Refinements to the approach were requested by organizations and individuals applying the KCs. We assembled an expert committee with knowledge of carcinogenesis and experience in applying the KCs in cancer hazard identification. We leveraged this expertise and examined the literature to more clearly describe each KC, identify current and emerging assays and biomarkers that can be used to measure them, and make recommendations for future assay development. We found that the KCs are clearly distinct from the Hallmarks of Cancer, that interrelationships among the KCs can be leveraged to strengthen the KC approach (and an understanding of environmental carcinogenesis), and that the KC approach is applicable to the systematic evaluation of a broad range of potential cancer hazards and We identified gaps in coverage of the KCs by current assays. Future efforts should expand the breadth, specificity, and sensitivity of validated assays and biomarkers that can measure the 10 KCs. Refinement of the KC approach will enhance and accelerate carcinogen identification, a first step in cancer prevention.
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http://dx.doi.org/10.1158/1055-9965.EPI-19-1346DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7483401PMC
October 2020

Exposure to glyphosate-based herbicides and risk for non-Hodgkin lymphoma: A meta-analysis and supporting evidence.

Mutat Res 2019 Jul - Sep;781:186-206. Epub 2019 Feb 10.

Department of Environmental and Occupational Health Sciences, University of Washington, Seattle, USA; Department of Biostatistics, University of Washington, Seattle, USA.

Glyphosate is the most widely used broad-spectrum systemic herbicide in the world. Recent evaluations of the carcinogenic potential of glyphosate-based herbicides (GBHs) by various regional, national, and international agencies have engendered controversy. We investigated whether there was an association between high cumulative exposures to GBHs and increased risk of non-Hodgkin lymphoma (NHL) in humans. We conducted a new meta-analysis that includes the most recent update of the Agricultural Health Study (AHS) cohort published in 2018 along with five case-control studies. Using the highest exposure groups when available in each study, we report the overall meta-relative risk (meta-RR) of NHL in GBH-exposed individuals was increased by 41% (meta-RR = 1.41, 95% confidence interval, CI: 1.13-1.75). For comparison, we also performed a secondary meta-analysis using high-exposure groups with the earlier AHS (2005), and we calculated a meta-RR for NHL of 1.45 (95% CI: 1.11-1.91), which was higher than the meta-RRs reported previously. Multiple sensitivity tests conducted to assess the validity of our findings did not reveal meaningful differences from our primary estimated meta-RR. To contextualize our findings of an increased NHL risk in individuals with high GBH exposure, we reviewed publicly available animal and mechanistic studies related to lymphoma. We documented further support from studies of malignant lymphoma incidence in mice treated with pure glyphosate, as well as potential links between glyphosate / GBH exposure and immunosuppression, endocrine disruption, and genetic alterations that are commonly associated with NHL or lymphomagenesis. Overall, in accordance with findings from experimental animal and mechanistic studies, our current meta-analysis of human epidemiological studies suggests a compelling link between exposures to GBHs and increased risk for NHL.
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http://dx.doi.org/10.1016/j.mrrev.2019.02.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6706269PMC
March 2020

Proposed Key Characteristics of Female Reproductive Toxicants as an Approach for Organizing and Evaluating Mechanistic Data in Hazard Assessment.

Environ Health Perspect 2019 07 19;127(7):75001. Epub 2019 Jul 19.

School of Public Health, University of California, Berkeley, Berkeley, California, USA.

Background: Identification of female reproductive toxicants is currently based largely on integrated epidemiological and toxicology data and, to a lesser degree, on mechanistic data. A uniform approach to systematically search, organize, integrate, and evaluate mechanistic evidence of female reproductive toxicity from various data types is lacking.

Objective: We sought to apply a key characteristics approach similar to that pioneered for carcinogen hazard identification to female reproductive toxicant hazard identification.

Methods: A working group of international experts was convened to discuss mechanisms associated with chemical-induced female reproductive toxicity and identified 10 key characteristics of chemicals that cause female reproductive toxicity: 1) alters hormone receptor signaling; alters reproductive hormone production, secretion, or metabolism; 2) chemical or metabolite is genotoxic; 3) induces epigenetic alterations; 4) causes mitochondrial dysfunction; 5) induces oxidative stress; 6) alters immune function; 7) alters cell signal transduction; 8) alters direct cell–cell interactions; 9) alters survival, proliferation, cell death, or metabolic pathways; and 10) alters microtubules and associated structures. As proof of principle, cyclophosphamide and diethylstilbestrol (DES), for which both human and animal studies have demonstrated female reproductive toxicity, display at least 5 and 3 key characteristics, respectively. 2,3,7,8-Tetrachlorodibenzo--dioxin (TCDD), for which the epidemiological evidence is mixed, exhibits 5 key characteristics.

Discussion: Future efforts should focus on evaluating the proposed key characteristics against additional known and suspected female reproductive toxicants. Chemicals that exhibit one or more of the key characteristics could be prioritized for additional evaluation and testing. A key characteristics approach has the potential to integrate with pathway-based toxicity testing to improve prediction of female reproductive toxicity in chemicals and potentially prevent some toxicants from entering common use. https://doi.org/10.1289/EHP4971.
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http://dx.doi.org/10.1289/EHP4971DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6791466PMC
July 2019

Human exposure to trichloroethylene is associated with increased variability of blood DNA methylation that is enriched in genes and pathways related to autoimmune disease and cancer.

Epigenetics 2019 11 26;14(11):1112-1124. Epub 2019 Jun 26.

Division of Cancer Epidemiology and Genetics, National Cancer Institute , Rockville , MD , USA.

Human exposure to trichloroethylene (TCE) is linked to kidney cancer, autoimmune diseases, and probably non-Hodgkin lymphoma. Additionally, TCE exposed mice and cell cultures show altered DNA methylation. To evaluate associations between TCE exposure and DNA methylation in humans, we conducted an epigenome-wide association study (EWAS) in TCE exposed workers using the HumanMethylation450 BeadChip. Across individual CpG probes, genomic regions, and globally (i.e., the 450K methylome), we investigated differences in mean DNA methylation and differences in variability of DNA methylation between 73 control (< 0.005 ppm TCE), 30 lower exposed (< 10 ppm TCE), and 37 higher exposed ( 10 ppm TCE) subjects' white blood cells. We found that TCE exposure increased methylation variation globally (Kruskal-Wallis -value = 3.75e-3) and in 25 CpG sites at a genome-wide significance level (Bonferroni -value < 0.05). We identified a 609 basepair region in the gene promoter that exhibited hypomethylation with increased exposure to TCE (FWER = 1.20e-2). Also, genes that matched to differentially variable CpGs were enriched in the 'focal adhesion' biological pathway (-value = 2.80e-2). All in all, human exposure to TCE was associated with epigenetic alterations in genes involved in cell-matrix adhesions and interferon subtype expression, which are important in the development of autoimmune diseases; and in genes related to cancer development. These results suggest that DNA methylation may play a role in the pathogenesis of TCE exposure-related diseases and that TCE exposure may contribute to epigenetic drift.
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http://dx.doi.org/10.1080/15592294.2019.1633866DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6773405PMC
November 2019

Association between occupational exposure to trichloroethylene and serum levels of microRNAs: a cross-sectional molecular epidemiology study in China.

Int Arch Occup Environ Health 2019 11 3;92(8):1077-1085. Epub 2019 Jun 3.

Occupational and Environmental Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, Bethesda, MD, USA.

Objectives: The objective of our study was to evaluate the association between occupational exposure to trichloroethylene (TCE), a suspected lymphomagen, and serum levels of miRNAs in a cross-sectional molecular epidemiology study of TCE-exposed workers and comparable unexposed controls in China.

Methods: Serum levels of 40 miRNAs were compared in 74 workers exposed to TCE (median: 12 ppm) and 90 unexposed control workers. Linear regression models were used to test for differences in serum miRNA levels between exposed and unexposed workers and to evaluate exposure-response relationships across TCE exposure categories using a three-level ordinal variable [i.e., unexposed, < 12 ppm, the median value among workers exposed to TCE) and ≥ 12 ppm)]. Models were adjusted for sex, age, current smoking, current alcohol use, and recent infection.

Results: Seven miRNAs showed significant differences between exposed and unexposed workers at FDR (false discovery rate) < 0.20. miR-150-5p and let-7b-5p also showed significant inverse exposure-response associations with TCE exposure (P= 0.002 and 0.03, respectively). The % differences in serum levels of miR-150-5p relative to unexposed controls were - 13% and - 20% among workers exposed to < 12 ppm and ≥ 12 ppm TCE, respectively.

Conclusions: miR-150-5p is involved in B cell receptor pathways and let-7b-5p plays a role in the innate immune response processes that are potentially important in the etiology of non-Hodgkin lymphoma (NHL). Further studies are needed to replicate these findings and to directly test the association between serum levels of these miRNAs and risk of NHL in prospective studies.
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http://dx.doi.org/10.1007/s00420-019-01448-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6953905PMC
November 2019

Genome-Wide CRISPR Screening Identifies the Tumor Suppressor Candidate OVCA2 As a Determinant of Tolerance to Acetaldehyde.

Toxicol Sci 2019 05;169(1):235-245

Department of Physiological Sciences, College of Veterinary Medicine, University of Florida, Gainesville, Florida.

Acetaldehyde, a metabolite of ethanol, is a cellular toxicant and a human carcinogen. A genome-wide CRISPR-based loss-of-function screen in erythroleukemic K562 cells revealed candidate genetic contributors affecting acetaldehyde cytotoxicity. Secondary screening exposing cells to a lower acetaldehyde dose simultaneously validated multiple candidate genes whose loss results in increased sensitivity to acetaldehyde. Disruption of genes encoding components of various DNA repair pathways increased cellular sensitivity to acetaldehyde. Unexpectedly, the tumor suppressor gene OVCA2, whose function is unknown, was identified in our screen as a determinant of acetaldehyde tolerance. Disruption of the OVCA2 gene resulted in increased acetaldehyde sensitivity and higher accumulation of the acetaldehyde-derived DNA adduct N2-ethylidene-dG. Together these results are consistent with a role for OVCA2 in adduct removal and/or DNA repair.
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http://dx.doi.org/10.1093/toxsci/kfz037DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6484886PMC
May 2019

Vasodilatory effect of formaldehyde via the NO/cGMP pathway and the regulation of expression of K, BK and L-type Ca channels.

Toxicol Lett 2019 Sep 8;312:55-64. Epub 2019 Apr 8.

Hubei Key Laboratory of Genetic Regulation and Integrative Biology, School of Life Sciences, Central China Normal University, 152 Luoyu Road, Wuhan 430079, PR China. Electronic address:

Formaldehyde (FA), a well-known toxic gas molecule similar to nitric oxide (NO), carbon monoxide (CO), and hydrogen sulfide (HS), is widely produced endogenously via numerous biochemical pathways, and has a number of physiological roles in the biosystem. We attempted to investigate the vasorelaxant effects of FA and their underlying mechanisms. We found that FA induced vasorelaxant effects on rat aortic rings in a concentration-dependent manner. The NO/cyclic guanosine 5' monophosphate (cGMP) pathway was up-regulated when the rat aortas were treated with FA. The expression of large-conductance Ca-activated K (BK) channel subunits α and β of the rat aortas was increased by FA. Similarly, the levels of ATP-sensitive K (K) channel subunits K6.1 and K6.2 were also up-regulated when the rat aortas were incubated with FA. In contrast, levels of the L-type Ca channel (LTCC) subunits, Ca1.2 and Ca1.3, decreased dramatically with increasing concentrations of FA. We demonstrated that the regulation of FA on vascular contractility may be via the up-regulation of the NO/cGMP pathway and the modulation of ion channels, including the upregulated expression of the K and BK channels and the inhibited expression of LTCCs. Further study is needed to explore the in-depth mechanisms of FA induced vasorelaxation.
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http://dx.doi.org/10.1016/j.toxlet.2019.04.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7790163PMC
September 2019

Alterations in immune and renal biomarkers among workers occupationally exposed to low levels of trichloroethylene below current regulatory standards.

Occup Environ Med 2019 06 10;76(6):376-381. Epub 2019 Apr 10.

Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, Rockville, Maryland, USA.

Objectives: The occupational exposure limit for trichloroethylene (TCE) in different countries varies from 1 to 100 ppm as an 8-hour time-weighted average (TWA). Many countries currently use 10 ppm as the regulatory standard for occupational exposures, but the biological effects in humans at this level of exposure remain unclear. The objective of our study was to evaluate alterations in immune and renal biomarkers among workers occupationally exposed to low levels of TCE below current regulatory standards.

Methods: We conducted a cross-sectional molecular epidemiology study of 80 healthy workers exposed to a wide range of TCE (ie, 0.4-229 ppm) and 96 comparable unexposed controls in China, and previously reported that TCE exposure was associated with multiple candidate biological markers related to immune function and kidney toxicity. Here, we conducted further analyses of all of the 31 biomarkers that we have measured to determine the magnitude and statistical significance of changes in the subgroup of workers (n=35) exposed to <10 ppm TCE compared with controls.

Results: Six immune biomarkers (ie, CD4+ effector memory T cells, sCD27, sCD30, interleukin-10, IgG and IgM) were significantly decreased (% difference ranged from -16.0% to -72.1%) and one kidney toxicity marker (kidney injury molecule-1, KIM-1) was significantly increased (% difference: +52.5%) among workers exposed to <10 ppm compared with the control group. These associations remained noteworthy after taking into account multiple comparisons using the false discovery rate (ie, <0.20).

Conclusion: Our results suggest that occupational exposure to TCE below 10 ppm as an 8-hour TWA may alter levels of key markers of immune function and kidney toxicity.
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http://dx.doi.org/10.1136/oemed-2018-105583DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6953904PMC
June 2019

Functional Profiling Identifies Determinants of Arsenic Trioxide Cellular Toxicity.

Toxicol Sci 2019 05;169(1):108-121

Department of Physiological Sciences, College of Veterinary Medicine, University of Florida, Gainesville, Florida.

Arsenic exposure is a worldwide health concern associated with an increased risk of skin, lung, and bladder cancer but arsenic trioxide (AsIII) is also an effective chemotherapeutic agent. The current use of AsIII in chemotherapy is limited to acute promyelocytic leukemia (APL). However, AsIII was suggested as a potential therapy for other cancer types including chronic myeloid leukemia (CML), especially when combined with other drugs. Here, we carried out a genome-wide CRISPR-based approach to identify modulators of AsIII toxicity in K562, a human CML cell line. We found that disruption of KEAP1, the inhibitory partner of the key antioxidant transcription factor Nrf2, or TXNDC17, a thioredoxin-like protein, markedly increased AsIII tolerance. Loss of the water channel AQP3, the zinc transporter ZNT1 and its regulator MTF1 also enhanced tolerance to AsIII whereas loss of the multidrug resistance protein ABCC1 increased sensitivity to AsIII. Remarkably, disruption of any of multiple genes, EEFSEC, SECISBP2, SEPHS2, SEPSECS, and PSTK, encoding proteins involved in selenocysteine metabolism increased resistance to AsIII. Our data suggest a model in which an intracellular interaction between selenium and AsIII may impact intracellular AsIII levels and toxicity. Together this work revealed a suite of cellular components/processes which modulate the toxicity of AsIII in CML cells. Targeting such processes simultaneously with AsIII treatment could potentiate AsIII in CML therapy.
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http://dx.doi.org/10.1093/toxsci/kfz024DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6484884PMC
May 2019

The evidence of human exposure to glyphosate: a review.

Environ Health 2019 01 7;18(1). Epub 2019 Jan 7.

Institute for Translational Epidemiology and Department of Population Health Science and Policy, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, Box 1133, New York, NY, 10029, USA.

Background: Despite the growing and widespread use of glyphosate, a broad-spectrum herbicide and desiccant, very few studies have evaluated the extent and amount of human exposure.

Objective: We review documented levels of human exposure among workers in occupational settings and the general population.

Methods: We conducted a review of scientific publications on glyphosate levels in humans; 19 studies were identified, of which five investigated occupational exposure to glyphosate, 11 documented the exposure in general populations, and three reported on both.

Results: Eight studies reported urinary levels in 423 occupationally and para-occupationally exposed subjects; 14 studies reported glyphosate levels in various biofluids on 3298 subjects from the general population. Average urinary levels in occupationally exposed subjects varied from 0.26 to 73.5 μg/L; environmental exposure urinary levels ranged from 0.16 to 7.6 μg/L. Only two studies measured temporal trends in exposure, both of which show increasing proportions of individuals with detectable levels of glyphosate in their urine over time.

Conclusions: The current review highlights the paucity of data on glyphosate levels among individuals exposed occupationally, para-occupationally, or environmentally to the herbicide. As such, it is challenging to fully understand the extent of exposure overall and in vulnerable populations such as children. We recommend further work to evaluate exposure across populations and geographic regions, apportion the exposure sources (e.g., occupational, household use, food residues), and understand temporal trends.
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http://dx.doi.org/10.1186/s12940-018-0435-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6322310PMC
January 2019

Identification of gene expression predictors of occupational benzene exposure.

PLoS One 2018 9;13(10):e0205427. Epub 2018 Oct 9.

Occupational and Environmental Epidemiology Branch, Division of Cancer Epidemiology and Genetics, NCI, NIH, DHHS, Bethesda, Maryland, United States of America.

Background: Previously, using microarrays and mRNA-Sequencing (mRNA-Seq) we found that occupational exposure to a range of benzene levels perturbed gene expression in peripheral blood mononuclear cells.

Objectives: In the current study, we sought to identify gene expression biomarkers predictive of benzene exposure below 1 part per million (ppm), the occupational standard in the U.S.

Methods: First, we used the nCounter platform to validate altered expression of 30 genes in 33 unexposed controls and 57 subjects exposed to benzene (<1 to ≥5 ppm). Second, we used SuperLearner (SL) to identify a minimal number of genes for which altered expression could predict <1 ppm benzene exposure, in 44 subjects with a mean air benzene level of 0.55±0.248 ppm (minimum 0.203ppm).

Results: nCounter and microarray expression levels were highly correlated (coefficients >0.7, p<0.05) for 26 microarray-selected genes. nCounter and mRNA-Seq levels were poorly correlated for 4 mRNA-Seq-selected genes. Using negative binomial regression with adjustment for covariates and multiple testing, we confirmed differential expression of 23 microarray-selected genes in the entire benzene-exposed group, and 27 genes in the <1 ppm-exposed subgroup, compared with the control group. Using SL, we identified 3 pairs of genes that could predict <1 ppm benzene exposure with cross-validated AUC estimates >0.9 (p<0.0001) and were not predictive of other exposures (nickel, arsenic, smoking, stress). The predictive gene pairs are PRG2/CLEC5A, NFKBI/CLEC5A, and ACSL1/CLEC5A. They play roles in innate immunity and inflammatory responses.

Conclusions: Using nCounter and SL, we validated the altered expression of multiple mRNAs by benzene and identified gene pairs predictive of exposure to benzene at levels below the US occupational standard of 1ppm.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0205427PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6177191PMC
March 2019

Elevated Levels of Organochlorine Pesticides in South Asian Immigrants Are Associated With an Increased Risk of Diabetes.

J Endocr Soc 2018 Aug 22;2(8):832-841. Epub 2018 May 22.

Department of Cardiology, Ealing Hospital, Middlesex, United Kingdom.

Objective: Rates of diabetes mellitus are higher in South Asians than in other populations and persist after migration. One unexplored cause may be higher exposure to persistent organic pollutants associated with diabetes in other populations. We compared organochlorine (OC) pesticide concentrations in South Asian immigrants and European whites to determine whether the disease was positively associated with OC pesticides in South Asians.

Research Design And Methods: South Asians of Tamil or Telugu descent (n = 120) and European whites (n = 72) were recruited into the London Life Sciences Population Study cohort. Blood samples as well as biometric, clinical, and survey data were collected. Plasma levels of -dichlorodiphenyldichloroethylene (DDE), - dichlorodiphenyltrichloroethane, -hexachlorohexane (HCH), and polychlorinated biphenyl-118 were analyzed by gas chromatography-mass spectrometry. South Asian cases and controls were categorized by binary exposure (above vs below the 50th percentile) to perform logistic regression.

Results: Tamils had approximately threefold to ninefold higher levels of OC pesticides, and Telugus had ninefold to 30-fold higher levels compared with European whites. The odds of exposure to -DDE above the 50th percentile was significantly greater in South Asian diabetes cases than in controls (OR: 7.00; 95% CI: 2.22, 22.06). The odds of exposure to -HCH above the 50th percentile was significantly greater in the Tamil cases than in controls (OR: 9.35; 95% CI: 2.43, 35.97).

Conclusions: South Asian immigrants have a higher body burden of OC pesticides than European whites. Diabetes mellitus is associated with higher -DDE and -HCH concentrations in this population. Additional longitudinal studies of South Asian populations should be performed.
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http://dx.doi.org/10.1210/js.2017-00480DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6041775PMC
August 2018

BMI1 enhancer polymorphism underlies chromosome 10p12.31 association with childhood acute lymphoblastic leukemia.

Int J Cancer 2018 12 3;143(11):2647-2658. Epub 2018 Oct 3.

Department of Epidemiology and Biostatistics, University of California San Francisco, San Francisco, CA.

Genome-wide association studies of childhood acute lymphoblastic leukemia (ALL) have identified regions of association at PIP4K2A and upstream of BMI1 at chromosome 10p12.31-12.2. The contribution of both loci to ALL risk and underlying functional variants remain to be elucidated. We carried out single nucleotide polymorphism (SNP) imputation across chromosome 10p12.31-12.2 in Latino and non-Latino white ALL cases and controls from two independent California childhood leukemia studies, and additional Genetic Epidemiology Research on Aging study controls. Ethnicity-stratified association analyses were performed using logistic regression, with meta-analysis including 3,133 cases (1,949 Latino, 1,184 non-Latino white) and 12,135 controls (8,584 Latino, 3,551 non-Latino white). SNP associations were identified at both BMI1 and PIP4K2A. After adjusting for the lead PIP4K2A SNP, genome-wide significant associations remained at BMI1, and vice-versa (p < 10 ), supporting independent effects. Lead SNPs differed by ethnicity at both peaks. We sought functional variants in tight linkage disequilibrium with both the lead Latino SNP among Admixed Americans and lead non-Latino white SNP among Europeans. This pinpointed rs11591377 (p = 2.1 x 10 ) upstream of BMI1, residing within a hematopoietic stem cell enhancer of BMI1, and which showed significant preferential binding of the risk allele to MYBL2 (p = 1.73 x 10 ) and p300 (p = 1.55 x 10 ) transcription factors using binomial tests on ChIP-Seq data from a SNP heterozygote. At PIP4K2A, we identified rs4748812 (p = 1.3 x 10 ), which alters a RUNX1 binding motif and demonstrated chromosomal looping to the PIP4K2A promoter. Fine-mapping chromosome 10p12 in a multi-ethnic ALL GWAS confirmed independent associations and identified putative functional variants upstream of BMI1 and at PIP4K2A.
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http://dx.doi.org/10.1002/ijc.31622DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6235695PMC
December 2018

Exposure to Formaldehyde Perturbs the Mouse Gut Microbiome.

Genes (Basel) 2018 Apr 3;9(4). Epub 2018 Apr 3.

Division of Environmental Health Sciences, School of Public Health, University of California, Berkeley, CA 94720, USA.

Exposure to Formaldehyde (FA) results in many pathophysiological symptoms, however the underlying mechanisms are not well understood. Given the complicated modulatory role of intestinal microbiota on human health, we hypothesized that interactions between FA and the gut microbiome may account for FA's toxicity. Balb/c mice were allocated randomly to three groups: a control group, a methanol group (0.1 and 0.3 ng/mL MeOH subgroups), and an FA group (1 and 3 ng/mL FA subgroups). Groups of either three or six mice were used for the control or experiment. We applied high-throughput sequencing of 16S ribosomal RNA (rRNA) gene approaches and investigated possible alterations in the composition of mouse gut microbiota induced by FA. Changes in bacterial genera induced by FA exposure were identified. By analyzing KEGG metabolic pathways predicted by PICRUSt software, we also explored the potential metabolic changes, such as alpha-Linolenic acid metabolism and pathways in cancer, associated with FA exposure in mice. To the best of our knowledge, this preliminary study is the first to identify changes in the mouse gut microbiome after FA exposure, and to analyze the relevant potential metabolisms. The limitation of this study: this study is relatively small and needs to be further confirmed through a larger study.
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http://dx.doi.org/10.3390/genes9040192DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5924534PMC
April 2018

Assessing health risks from multiple environmental stressors: Moving from G×E to I×E.

Mutat Res 2018 Jan - Mar;775:11-20. Epub 2017 Nov 24.

Office of Environmental Health Hazard Assessment, California Environmental Protection Agency, Oakland, CA 94612, USA.

Research on disease causation often attempts to isolate the effects of individual factors, including individual genes or environmental factors. This reductionist approach has generated many discoveries, but misses important interactive and cumulative effects that may help explain the broad range of variability in disease occurrence observed across studies and individuals. A disease rarely results from a single factor, and instead results from a broader combination of factors, characterized here as intrinsic (I) and extrinsic (E) factors. Intrinsic vulnerability or resilience emanates from a variety of both fixed and shifting biological factors including genetic traits, while extrinsic factors comprise all biologically-relevant external stressors encountered across the lifespan. The I×E concept incorporates the multi-factorial and dynamic nature of health and disease and provides a unified, conceptual basis for integrating results from multiple areas of research, including genomics, G×E, developmental origins of health and disease, and the exposome. We describe the utility of the I×E concept to better understand and characterize the cumulative impact of multiple extrinsic and intrinsic factors on individual and population health. New research methods increasingly facilitate the measurement of multifactorial and interactive effects in epidemiological and toxicological studies. Tiered or indicator-based approaches can guide the selection of potentially relevant I and E factors for study and quantification, and exposomics methods may eventually produce results that can be used to generate a response function over the life course. Quantitative data on I×E interactive effects should generate a better understanding of the variability in human response to environmental factors. The proposed I×E concept highlights the role for broader study design in order to identify extrinsic and intrinsic factors amenable to interventions at the individual and population levels in order to enhance resilience, reduce vulnerability and improve health.
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http://dx.doi.org/10.1016/j.mrrev.2017.11.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5863617PMC
October 2018

Adductomic signatures of benzene exposure provide insights into cancer induction.

Carcinogenesis 2018 05;39(5):661-668

Division of Environmental Health Sciences, School of Public Health, University of California, Berkeley, CA, USA.

Although benzene has long been recognized as a cause of human leukemia, the mechanism by which this simple molecule causes cancer has been problematic. A complicating factor is benzene metabolism, which produces many reactive intermediates, some specific to benzene and others derived from redox processes. Using archived serum from 20 nonsmoking Chinese workers, 10 with and 10 without occupational exposure to benzene (exposed: 3.2-88.9 ppm, controls: 0.002-0.020 ppm), we employed an adductomic pipeline to characterize protein modifications at Cys34 of human serum albumin, a nucleophilic hotspot in extracellular fluids. Of the 47 measured human serum albumin modifications, 39 were present at higher concentrations in benzene-exposed workers than in controls and many of the exposed-control differences were statistically significant. Correlation analysis identified three prominent clusters of adducts, namely putative modifications by benzene oxide and a benzene diolepoxide that grouped with other measures of benzene exposure, adducts of reactive oxygen and carbonyl species, and Cys34 disulfides of small thiols that are formed following oxidation of Cys34. Benzene diolepoxides are potent mutagens and carcinogens that have received little attention as potential causes of human leukemia. Reactive oxygen and carbonyl species-generated by redox processes involving polyphenolic benzene metabolites and by Cyp2E1 regulation following benzene exposure-can modify DNA and proteins in ways that contribute to cancer. The fact that these diverse human serum albumin modifications differed between benzene-exposed and control workers suggests that benzene can increase leukemia risks via multiple pathways involving a constellation of reactive molecules.
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http://dx.doi.org/10.1093/carcin/bgy042DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5932554PMC
May 2018

Formaldehyde, Hematotoxicity, and Chromosomal Changes-Response.

Cancer Epidemiol Biomarkers Prev 2018 01;27(1):120-121

Occupational and Environmental Epidemiology Branch, Division of Cancer, Epidemiology and Genetics, Department of Health and Human Services, NCI (NIH), Bethesda, Maryland.

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http://dx.doi.org/10.1158/1055-9965.EPI-17-0804DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6980366PMC
January 2018

Assessment of the Endocrine-Disrupting Effects of Trichloroethylene and Its Metabolites Using in Vitro and in Silico Approaches.

Environ Sci Technol 2018 02 19;52(3):1542-1550. Epub 2018 Jan 19.

Division of Environmental Health Sciences, School of Public Health, University of California Berkeley , Berkeley, California 94720, United States.

Trichloroethylene (TCE) is a ubiquitous environmental contaminant, which may have effects on both ecosystem and human health. TCE has been reported to cause several toxic effects, but little effort has been made to assess the ecological risks of TCE or its major metabolites: trichloroethanol (TCOH), trichloroacetic acid, and oxalic acid (OA). In this study, the endocrine-disrupting potential of TCE and its metabolites were investigated using in vitro and in silico approaches. We examined alterations in the steroidogenesis pathway using the NCI-H295R cell line and utilized receptor-mediated luciferase reporter cell lines to identify effects on estrogen and androgen receptors. Molecular docking was also used to explore chemical interactions with these receptors. All test chemicals except OA significantly increased 17β-estradiol production which can be attributed to an up-regulation of 17β-hydroxysteroid dehydrogenase. Moreover, TCOH exhibited significant antiestrogenic activity with a RIC (20% relative inhibitory concentration) of 3.7 × 10 M. Molecular docking simulation supported this finding with lower docking scores for TCOH, indicating that hydrogen bonds may stabilize the interaction between TCOH and the estrogen receptor binding pocket. These findings suggest that TCE contamination poses an endocrine-disrupting threat, which has implications for both ecological and human health.
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http://dx.doi.org/10.1021/acs.est.7b04832DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6290898PMC
February 2018

Response to letter to the editor of Carcinogenesis by Pira et al., 2017.

Carcinogenesis 2017 12;38(12):1253-1255

Division of Environmental Health Sciences, School of Public Health, University of California at Berkeley, USA.

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http://dx.doi.org/10.1093/carcin/bgx111DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5862264PMC
December 2017

Marine ecological risk assessment methods for radiation accidents.

J Environ Radioact 2017 Dec 13;180:65-76. Epub 2017 Oct 13.

Department of Earth and Environmental Studies, Montclair State University, Montclair, NJ 07043, USA.

Ecological risk assessment (ERA) is a powerful technical tool that can be used to analyze potential and extreme adverse environmental impacts. With the rapid development of nuclear power plants in coastal areas around the world, the establishment of approaches and methodologies for marine ERA with a focus on radiation accidents is an urgent requirement for marine environmental management. In this study, the approaches and methodologies for ERA pertaining to marine radiation accidents (MRA) are discussed and summarized with applications in case studies, such as the nuclear accident in Fukushima, Japan, and a hypothetical accident in Daya Bay, China. The concepts of ERA and Risk Degree of ERA on MRA are defined for the first time to optimize the ERA system. The results of case studies show that the ERA approach and methodology for MRA are scientifically sound and effective in both the early and late stage of MRAs along with classic ERA Approach and the ERICA Integrated Approach. The results can be useful in the decision-making processes and the risk management at the beginning of accident as well as the ecological restoration after the accident.
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http://dx.doi.org/10.1016/j.jenvrad.2017.09.024DOI Listing
December 2017

Editor's Highlight: High-Throughput Functional Genomics Identifies Modulators of TCE Metabolite Genotoxicity and Candidate Susceptibility Genes.

Toxicol Sci 2017 Nov;160(1):111-120

Department of Nutritional Sciences and Toxicology, University of California, Berkeley, California 94720.

Trichloroethylene (TCE), an industrial chemical and environmental contaminant, is a human carcinogen. Reactive metabolites are implicated in renal carcinogenesis associated with TCE exposure, yet the toxicity mechanisms of these metabolites and their contribution to cancer and other adverse effects remain unclear. We employed an integrated functional genomics approach that combined functional profiling studies in yeast and avian DT40 cell models to provide new insights into the specific mechanisms contributing to toxicity associated with TCE metabolites. Genome-wide profiling studies in yeast identified the error-prone translesion synthesis (TLS) pathway as an import mechanism in response to TCE metabolites. The role of TLS DNA repair was further confirmed by functional profiling in DT40 avian cell lines, but also revealed that TLS and homologous recombination DNA repair likely play competing roles in cellular susceptibility to TCE metabolites in higher eukaryotes. These DNA repair pathways are highly conserved between yeast, DT40, and humans. We propose that in humans, mutagenic TLS is favored over homologous recombination repair in response to TCE metabolites. The results of these studies contribute to the body of evidence supporting a mutagenic mode of action for TCE-induced renal carcinogenesis mediated by reactive metabolites in humans. Our approach illustrates the potential for high-throughput in vitro functional profiling in yeast to elucidate toxicity pathways (molecular initiating events, key events) and candidate susceptibility genes for focused study.
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http://dx.doi.org/10.1093/toxsci/kfx159DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5837773PMC
November 2017