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Occupational exposure to trichloroethylene (TCE) has been associated with alterations in B-cell activation factors and an increased risk of non-Hodgkin's lymphoma (NHL). Here, we aimed to examine the biological processes influenced by TCE exposure to understand the underlying molecular mechanisms. This cross-sectional molecular epidemiology study included data of 1317 targeted proteins in the serum from 42 TCE exposed and 34 unexposed factory workers in Guangdong, China. We used multivariable linear regressions to identify proteins associated with TCE exposure and examined their exposure-response relationship across categories of TCE exposure (unexposed, low exposed: <10 ppm, high exposed: ≥10 ppm). We further examined pathway enrichment of TCE-related proteins to understand their biological response. Occupational exposure to TCE was associated with lower levels of tumor necrosis factor receptor superfamily member 17 (TNFRSF17; β = -.08; p-value = .0003) and kynureninase (KYNU; β = -.10, p-value = .002). These proteins also showed a significant exposure-response relation across the unexposed, low exposed, and high exposed workers (all p-trends < .001, false discovery rate [FDR] < 0.20). Pathway analysis of TCE-related proteins showed significant enrichment (FDR < 0.05) for several inflammatory and immune pathways. TCE exposure was associated with TNFRSF17, a key B-cell maturation antigen that mediates B-cell survival and KYNU, an enzyme that plays a role in T-cell mediated immune response. Given that altered immunity is an established risk factor for NHL, our findings support the biological plausibility of linking TCE exposure with NHL., (© 2022 Environmental Mutagen Society. This article has been contributed to by U.S. Government employees and their work is in the public domain in the 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 trend = 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.

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 p -value = 3.75e-3) and in 25 CpG sites at a genome-wide significance level (Bonferroni p -value < 0.05). We identified a 609 basepair region in the TRIM68 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 ( p -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.

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., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2019. No commercial re-use. See rights and permissions. Published by BMJ.)

Benzene, formaldehyde (FA) and trichloroethylene (TCE) are ubiquitous chemicals in workplaces and the general environment. Benzene is an established myeloid leukemogen and probable lymphomagen. FA is classified as a myeloid leukemogen but has not been associated with non-Hodgkin lymphoma (NHL), whereas TCE has been associated with NHL but not myeloid leukemia. Epidemiologic associations between FA and myeloid leukemia, and between benzene, TCE and NHL are, however, still debated. Previously, we showed that these chemicals are associated with hematotoxicity in cross-sectional studies of factory workers in China, which included extensive personal monitoring and biological sample collection. Here, we compare and contrast patterns of hematotoxicity, monosomy 7 in myeloid progenitor cells (MPCs), and B-cell activation biomarkers across these studies to further evaluate possible mechanisms of action and consistency of effects with observed hematologic cancer risks. Workers exposed to benzene or FA, but not TCE, showed declines in cell types derived from MPCs, including granulocytes and platelets. Alterations in lymphoid cell types, including B cells and CD4+ T cells, and B-cell activation markers were apparent in workers exposed to benzene or TCE. Given that alterations in myeloid and lymphoid cell types are associated with hematological malignancies, our data provide biologic insight into the epidemiological evidence linking benzene and FA exposure with myeloid leukemia risk, and TCE and benzene exposure with NHL risk., (Published by Oxford University Press 2016.)

To evaluate the immunotoxicity of trichloroethylene (TCE), we conducted a cross-sectional molecular epidemiology study in China of workers exposed to TCE. We measured serum levels of IL-6, IL-10, and TNF-α, which play a critical role in regulating various components of the immune system, in 71 exposed workers and 78 unexposed control workers. Repeated personal exposure measurements were taken in workers before blood collection using 3 M organic vapor monitoring badges. Compared to unexposed workers, the serum concentration of IL-10 in workers exposed to TCE was decreased by 70% (P = 0.001) after adjusting for potential confounders. Further, the magnitude of decline in IL-10 was >60% and statistically significant in workers exposed to <12 ppm as well as in workers with exposures ≥ 12 ppm of TCE, compared to unexposed workers. No significant differences in levels of IL-6 or TNF-α were observed among workers exposed to TCE compared to unexposed controls. Given that IL-10 plays an important role in immunologic processes, including mediating the Th1/Th2 balance, our findings provide additional evidence that TCE is immunotoxic in humans., (© 2013 Wiley Periodicals, Inc.)

Trichloroethylene (TCE) has been associated with a variety of immunotoxic effects and may be associated with an increased risk of non-Hodgkin lymphoma (NHL). Altered serum immunoglobulin (Ig) levels have been reported in NHL patients and in animals exposed to TCE. Recently, we reported that occupational exposure to TCE is associated with immunosuppressive effects and immune dysfunction, including suppression of B-cell counts and activation, even at relatively low levels. We hypothesized that TCE exposure would also affect Ig levels in humans. We measured serum levels of IgG, IgM and IgE, by enzyme-linked immunosorbent assay, in TCE-exposed workers (n = 80) and unexposed controls (n = 45), matched by age and gender, in a cross-sectional, molecular epidemiology study of occupational exposure to TCE in Guangdong, China. Exposed workers had about a 17.5% decline in serum levels of IgG compared with unexposed controls (P = 0.0002). Similarly, serum levels of IgM were reduced by about 38% in workers exposed to TCE compared with unexposed controls (P < 0.0001). Serum levels of both IgG and IgM were significantly decreased in workers exposed to TCE levels below 12 p.p.m., the median exposure level. Adjustment for B-cell counts had minimal impact on our findings. IgE levels were not significantly different between exposed and control subjects. These results provide further evidence that TCE is immunotoxic at relatively low exposure levels and provide additional biologic plausibility for the reported association of TCE with NHL.