Dioxin(-like)-Related Biological Effects through Integrated Chemical-wide and Metabolome-wide Analyses.

Dioxin(-like) exposures are linked to adverse health effects, including cancer. However, metabolic alterations induced by these chemicals remain largely unknown. Beyond known dioxin(-like) compounds, we leveraged a chemical-wide approach to assess chlorinated co-exposures and parent compound products [termed dioxin(-like)-related compounds] among 137 occupational workers. Endogenous metabolites were profiled by untargeted metabolomics, namely, reversed-phase chromatography with negative electrospray ionization (C18-negative) and hydrophilic interaction liquid chromatography with positive electrospray ionization (HILIC-positive). We performed a metabolome-wide association study to select dioxin(-like) associated metabolic features using a 20% false discovery rate threshold. Metabolic features were then characterized by pathway enrichment analyses. There are no significant features associated with polychlorinated dibenzo-p-dioxins (PCDDs), a subgroup of known dioxin(-like) compounds. However, 3,110 C18-negative and 2,894 HILIC-positive features were associated with at least one of the PCDD-related compounds. Abundant metabolic changes were also observed for polychlorinated dibenzofuran-related and polychlorinated biphenyl-related compounds. These metabolic features were primarily enriched in pathways of amino acids, lipid and fatty acids, carbohydrates, cofactors, and nucleotides. Our study highlights the potential of chemical-wide analysis for comprehensive exposure assessment beyond targeted chemicals. Coupled with advanced endogenous metabolomics, this approach allows for an in-depth exploration of metabolic alterations induced by environmental chemicals.

The association between genetically elevated polyunsaturated fatty acids and risk of cancer.

BACKGROUND: The causal relevance of polyunsaturated fatty acids (PUFAs) for risk of site-specific cancers remains uncertain. METHODS: Using a Mendelian randomization (MR) framework, we assessed the causal relevance of PUFAs for risk of cancer in European and East Asian ancestry individuals. We defined the primary exposure as PUFA desaturase activity, proxied by rs174546 at the FADS locus. Secondary exposures were defined as omega 3 and omega 6 PUFAs that could be proxied by genetic polymorphisms outside the FADS region. Our study used summary genetic data on 10 PUFAs and 67 cancers, corresponding to 562,871 cases and 1,619,465 controls, collected by the Fatty Acids in Cancer Mendelian Randomization Collaboration. We estimated odds ratios (ORs) for cancer per standard deviation increase in genetically proxied PUFA exposures. FINDINGS: Genetically elevated PUFA desaturase activity was associated (P < 0.0007) with higher risk (OR [95% confidence interval]) of colorectal cancer (1.09 [1.07-1.11]), esophageal squamous cell carcinoma (1.16 [1.06-1.26]), lung cancer (1.06 [1.03-1.08]) and basal cell carcinoma (1.05 [1.02-1.07]). There was little evidence for associations with reproductive cancers (OR = 1.00 [95% CI: 0.99-1.01]; Pheterogeneity = 0.25), urinary system cancers (1.03 [0.99-1.06], Pheterogeneity = 0.51), nervous system cancers (0.99 [0.95-1.03], Pheterogeneity = 0.92) or blood cancers (1.01 [0.98-1.04], Pheterogeneity = 0.09). Findings for colorectal cancer and esophageal squamous cell carcinoma remained compatible with causality in sensitivity analyses for violations of assumptions. Secondary MR analyses highlighted higher omega 6 PUFAs (arachidonic acid, gamma-linolenic acid and dihomo-gamma-linolenic acid) as potential mediators. PUFA biosynthesis is known to interact with aspirin, which increases risk of bleeding and inflammatory bowel disease. In a phenome-wide MR study of non-neoplastic diseases, we found that genetic lowering of PUFA desaturase activity, mimicking a hypothetical intervention to reduce cancer risk, was associated (P < 0.0006) with increased risk of inflammatory bowel disease but not bleeding. INTERPRETATION: The PUFA biosynthesis pathway may be an intervention target for prevention of colorectal cancer and esophageal squamous cell carcinoma but with potential for increased risk of inflammatory bowel disease. FUNDING: Cancer Resesrch UK (C52724/A20138, C18281/A19169). UK Medical Research Council (MR/P014054/1). National Institute for Health Research (NIHR202411). UK Medical Research Council (MC_UU_00011/1, MC_UU_00011/3, MC_UU_00011/6, and MC_UU_00011/4). National Cancer Institute (R00 CA215360). National Institutes of Health (U01 CA164973, R01 CA60987, R01 CA72520, U01 CA74806, R01 CA55874, U01 CA164973 and U01 CA164973).

Design and quality control of large-scale two-sample Mendelian randomization studies.

Background: Mendelian randomization (MR) studies are susceptible to metadata errors (e.g. incorrect specification of the effect allele column) and other analytical issues that can introduce substantial bias into analyses. We developed a quality control (QC) pipeline for the Fatty Acids in Cancer Mendelian Randomization Collaboration (FAMRC) that can be used to identify and correct for such errors. Methods: We collated summary association statistics from fatty acid and cancer genome-wide association studies (GWAS) and subjected the collated data to a comprehensive QC pipeline. We identified metadata errors through comparison of study-specific statistics to external reference data sets (the National Human Genome Research Institute-European Bioinformatics Institute GWAS catalogue and 1000 genome super populations) and other analytical issues through comparison of reported to expected genetic effect sizes. Comparisons were based on three sets of genetic variants: (i) GWAS hits for fatty acids, (ii) GWAS hits for cancer and (iii) a 1000 genomes reference set. Results: We collated summary data from 6 fatty acid and 54 cancer GWAS. Metadata errors and analytical issues with the potential to introduce substantial bias were identified in seven studies (11.6%). After resolving metadata errors and analytical issues, we created a data set of 219 842 genetic associations with 90 cancer types, generated in analyses of 566 665 cancer cases and 1 622 374 controls. Conclusions: In this large MR collaboration, 11.6% of included studies were affected by a substantial metadata error or analytical issue. By increasing the integrity of collated summary data prior to their analysis, our protocol can be used to increase the reliability of downstream MR analyses. Our pipeline is available to other researchers via the CheckSumStats package (https://github.com/MRCIEU/CheckSumStats).

Association between anthropometry and lifestyle factors and risk of B-cell lymphoma: An exposome-wide analysis.

To better understand the role of individual and lifestyle factors in human disease, an exposome-wide association study was performed to investigate within a single-study anthropometry measures and lifestyle factors previously associated with B-cell lymphoma (BCL). Within the European Prospective Investigation into Cancer and nutrition study, 2402 incident BCL cases were diagnosed from 475 426 participants that were followed-up on average 14 years. Standard and penalized Cox regression models as well as principal component analysis (PCA) were used to evaluate 84 exposures in relation to BCL risk. Standard and penalized Cox regression models showed a positive association between anthropometric measures and BCL and multiple myeloma/plasma cell neoplasm (MM). The penalized Cox models additionally showed the association between several exposures from categories of physical activity, smoking status, medical history, socioeconomic position, diet and BCL and/or the subtypes. PCAs confirmed the individual associations but also showed additional observations. The PC5 including anthropometry, was positively associated with BCL, diffuse large B-cell lymphoma (DLBCL) and MM. There was a significant positive association between consumption of sugar and confectionary (PC11) and follicular lymphoma risk, and an inverse association between fish and shellfish and Vitamin D (PC15) and DLBCL risk. The PC1 including features of the Mediterranean diet and diet with lower inflammatory score showed an inverse association with BCL risk, while the PC7, including dairy, was positively associated with BCL and DLBCL risk. Physical activity (PC10) was positively associated with DLBCL risk among women. This study provided informative insights on the etiology of BCL.

Mediating effect of soluble B-cell activation immune markers on the association between anthropometric and lifestyle factors and lymphoma development.

Sustained B-cell activation is an important mechanism contributing to B-cell lymphoma (BCL). We aimed to validate four previously reported B-cell activation markers predictive of BCL risk (sCD23, sCD27, sCD30, and CXCL13) and to examine their possible mediating effects on the association between anthropometric and lifestyle factors and major BCL subtypes. Pre-diagnostic serum levels were measured for 517 BCL cases and 525 controls in a nested case-control study. The odds ratios of BCL were 6.2 in the highest versus lowest quartile for sCD23, 2.6 for sCD30, 4.2 for sCD27, and 2.6 for CXCL13. Higher levels of all markers were associated with increased risk of chronic lymphocytic leukemia (CLL), follicular lymphoma (FL), and diffuse large B-cell lymphoma (DLBCL). Following mutual adjustment for the other immune markers, sCD23 remained associated with all subtypes and CXCL13 with FL and DLBCL. The associations of sCD23 with CLL and DLBCL and CXCL13 with DLBCL persisted among cases sampled > 9 years before diagnosis. sCD23 showed a good predictive ability (area under the curve = 0.80) for CLL, in particular among older, male participants. sCD23 and CXCL13 showed a mediating effect between body mass index (positive) and DLBCL risk, while CXCL13 contributed to the association between physical activity (inverse) and DLBCL. Our data suggest a role of B-cell activation in BCL development and a mediating role of the immune system for lifestyle factors.

Proteomic markers with prognostic impact on outcome of chronic lymphocytic leukemia patients under chemo-immunotherapy: results from the HOVON 109 study.

Despite recent identification of several prognostic markers, there is still a need for new prognostic parameters able to predict clinical outcome in chronic lymphocytic leukemia (CLL) patients. Here, we aimed to validate the prognostic ability of known (proteomic) markers measured pretreatment and to search for new proteomic markers that might be related to treatment response in CLL. To this end, baseline serum samples of 51 CLL patients treated with chemo-immunotherapy were analyzed for 360 proteomic markers, using Olink technology. Median event-free survival (EFS) was 23 months (range: 1.25-60.9). Patients with high levels of sCD23 (>11.27, p = 0.026), sCD27 (>11.03, p = 0.04), SPINT1 (>1.6, p = 0.001), and LY9 (>8.22, p = 0.0003) had a shorter EFS than those with marker levels below the median. The effect of sCD23 on EFS differed between immunoglobulin heavy chain variable gene-mutated and unmutated patients, with the shortest EFS for unmutated CLL patients with sCD23 levels above the median. Taken together, our results validate the prognostic impact of sCD23 and highlight SPINT1 and LY9 as possible promising markers for treatment response in CLL patients.

Healthy lifestyle and the risk of lymphoma in the European Prospective Investigation into Cancer and Nutrition study.

Limited evidence exists on the role of modifiable lifestyle factors on the risk of lymphoma. In this work, the associations between adherence to healthy lifestyles and risks of Hodgkin lymphoma (HL) and non-Hodgkin lymphoma (NHL) were evaluated in a large-scale European prospective cohort. Within the European Prospective Investigation into Cancer and Nutrition (EPIC), 2,999 incident lymphoma cases (132 HL and 2,746 NHL) were diagnosed among 453,808 participants after 15 years (median) of follow-up. The healthy lifestyle index (HLI) score combined information on smoking, alcohol intake, diet, physical activity and BMI, with large values of HLI expressing adherence to healthy behavior. Cox proportional hazards models were used to estimate lymphoma hazard ratios (HR) and 95% confidence interval (CI). Sensitivity analyses were conducted by excluding, in turn, each lifestyle factor from the HLI score. The HLI was inversely associated with HL, with HR for a 1-standard deviation (SD) increment in the score equal to 0.78 (95% CI: 0.66, 0.94). Sensitivity analyses showed that the association was mainly driven by smoking and marginally by diet. NHL risk was not associated with the HLI, with HRs for a 1-SD increment equal to 0.99 (0.95, 1.03), with no evidence for heterogeneity in the association across NHL subtypes. In the EPIC study, adherence to healthy lifestyles was not associated with overall lymphoma or NHL risk, while an inverse association was observed for HL, although this was largely attributable to smoking. These findings suggest a limited role of lifestyle factors in the etiology of lymphoma subtypes.

Pre-diagnostic blood immune markers, incidence and progression of B-cell lymphoma and multiple myeloma: Univariate and functionally informed multivariate analyses.

Recent prospective studies have shown that dysregulation of the immune system may precede the development of B-cell lymphomas (BCL) in immunocompetent individuals. However, to date, the studies were restricted to a few immune markers, which were considered separately. Using a nested case-control study within two European prospective cohorts, we measured plasma levels of 28 immune markers in samples collected a median of 6 years before diagnosis (range 2.01-15.97) in 268 incident cases of BCL (including multiple myeloma [MM]) and matched controls. Linear mixed models and partial least square analyses were used to analyze the association between levels of immune marker and the incidence of BCL and its main histological subtypes and to investigate potential biomarkers predictive of the time to diagnosis. Linear mixed model analyses identified associations linking lower levels of fibroblast growth factor-2 (FGF-2 p = 7.2 × 10-4 ) and transforming growth factor alpha (TGF-α, p = 6.5 × 10-5 ) and BCL incidence. Analyses stratified by histological subtypes identified inverse associations for MM subtype including FGF-2 (p = 7.8 × 10-7 ), TGF-α (p = 4.08 × 10-5 ), fractalkine (p = 1.12 × 10-3 ), monocyte chemotactic protein-3 (p = 1.36 × 10-4 ), macrophage inflammatory protein 1-alpha (p = 4.6 × 10-4 ) and vascular endothelial growth factor (p = 4.23 × 10-5 ). Our results also provided marginal support for already reported associations between chemokines and diffuse large BCL (DLBCL) and cytokines and chronic lymphocytic leukemia (CLL). Case-only analyses showed that Granulocyte-macrophage colony stimulating factor levels were consistently higher closer to diagnosis, which provides further evidence of its role in tumor progression. In conclusion, our study suggests a role of growth-factors in the incidence of MM and of chemokine and cytokine regulation in DLBCL and CLL.

Cam Deformity and Acetabular Dysplasia as Risk Factors for Hip Osteoarthritis.

OBJECTIVE: Cam deformity and acetabular dysplasia have been recognized as relevant risk factors for hip osteoarthritis (OA) in a few prospective studies with limited sample sizes. To date, however, no evidence is available from prospective studies regarding whether the magnitude of these associations differs according to sex, body mass index (BMI), and age. METHODS: Participants in the Rotterdam Study cohort including men and women ages 55 years or older without OA at baseline (n = 4,438) and a mean follow-up of 9.2 years were included in the study. Incident radiographic OA was defined as a Kellgren/Lawrence grade of ≥2 or a total hip replacement at follow-up. Alpha and center-edge angles were measured to determine the presence of cam deformity and acetabular dysplasia/pincer deformity, respectively. Odds ratios (ORs) were calculated to assess the associations between both deformities and the development of OA. RESULTS: Subjects with cam deformity (OR 2.11, 95% confidence interval [95% CI] 1.55-2.87) and those with acetabular dysplasia (OR 2.19, 95% CI 1.50-3.21) had a 2-fold increased risk of developing OA compared with subjects without deformity, while pincer deformity did not increase the risk of OA. Stratification analyses showed that the associations of cam deformity and acetabular dysplasia with OA were driven by younger individuals, whereas BMI did not influence the associations. Female sex appears to modify the risk of hip OA related to acetabular dysplasia. CONCLUSION: Individuals with cam deformity and those with acetabular dysplasia are predisposed to OA; these associations were independent of other well-known risk factors. Interestingly, both deformities predisposed to OA only in relatively young individuals. Therefore, early identification of these conditions is important.

Association between biomarkers of tissue inflammation and progression of osteoarthritis: evidence from the Rotterdam study cohort.

BACKGROUND: We aimed to investigate the prognostic value of two biomarkers of tissue inflammation, matrix metalloproteinase-dependent degradation of C-reactive protein (CRPM) and connective tissue type I collagen turnover (C1M), on the incidence and progression of radiographic osteoarthritis (OA) in the Rotterdam Study, a prospective cohort. Moreover, the independent effect of these biomarkers with respect to the established biomarkers of OA progression, like urinary type II collagen degradation (uCTX-II) and serum cartilage oligomeric protein (COMP), was evaluated. METHODS: Serum levels of C1M, CRPM, COMP and CRP of 1335 participants aged >55 years were measured in fasting serum using ELISA. The commercial ELISA detecting CTX-II was used in urine. Radiographs at baseline and 5-year follow-up were scored for OA stage by Kellgren-Lawrence grade. The associations between progression and incidence of OA and the baseline biomarkers were examined using logistic regression and generalized estimating equations adjusted for age, sex, BMI, and possible other confounders. RESULTS: The uCTX-II, COMP, and CRP concentrations were associated with the incidence and progression of OA. Moreover, OA progression was positively associated with CRPM (OR = 1.3, p = 0.01) and CRP (OR = 1.3, p = 0.01) levels with similar effect size as uCTX-II (OR = 1.3, p = 0.01) and COMP (OR = 1.2, p = 0.02). CRPM had prognostic value for progression of OA independent from the uCTX-II and COMP. CONCLUSIONS: Our study confirmed the associations between uCTX-II and COMP concentrations and OA progression. Importantly, we showed for the first time that CRPM predicts the risk of OA progression independent of the established biomarkers uCTX-II and COMP.

Dietary intakes and risk of lymphoid and myeloid leukemia in the European Prospective Investigation into Cancer and Nutrition (EPIC).

The etiology of leukemias cannot entirely be explained by known risk factors, including ionizing radiation, benzene exposure, and infection with human T cell leukemia virus. A number of studies suggested that diet influences the risk of adult leukemias. However, results have been largely inconsistent. We examined the potential association between dietary factors and risk of leukemias among participants of the European Prospective Investigation into Cancer and Nutrition study. Among the 477,325 participants with mean follow-up of 11.34 yr (SD = 2.47), 773 leukemias (373 and 342 cases of lymphoid and myeloid leukemia, respectively) were identified. Diet over the previous 12 mo was assessed at baseline using a validated country-specific dietary questionnaire. Cox proportional hazards regression was used to explore the association between dietary factors that have previously been associated with leukemia risk, including red and processed meat, poultry, offal, fish, dairy products, vegetables, fruits, and seeds/nuts, and risk of both lymphoid and myeloid leukemias. No significant associations were observed between dietary measures and total, lymphoid, and myeloid leukemias. Additional subtype analyses showed no dietary association with risk of major subtypes of leukemias. In summary, this study did not support a possible link between selected dietary factors and risk of leukemias.

Circulating soluble CD27 and CD30 in workers exposed to 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD).

Previous studies suggest that 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) exposure may be associated with non-Hodgkin lymphoma (NHL) but findings remain inconclusive. There is a need for mechanistic studies to evaluate the biologic plausibility of this association. In this cross-sectional study, we investigated changes in plasma levels of interleukin 1 receptor antagonist (IL1RA) and soluble (s)CD27 and sCD30 which have been found to be predictive of lymphoma, among workers of a cohort occupationally exposed to TCDD. Eighty-five workers who had been exposed to TCDD more than 30 years before blood collection were included in the current investigation. Plasma level of the markers was measured by ELISA. Current plasma levels of TCDD were determined by high-resolution gas chromatography/isotope dilution high-resolution mass spectrometry. TCDD blood levels at time of last exposure were estimated using a one-compartment first order kinetic model. Exposure-response analyses showed no significant association between blood levels of sCD27, and sCD30 and current and estimated TCDD levels at time of last exposure. IL1RA showed a borderline significant decrease with increasing plasma TCDD levels (P = 0.07), which reached formal statistical significance when excluding subjects with chronic diseases. In conclusion, no clear dose-response relationship was observed between the measured markers and TCDD level. However, there was a suggestion that markers in particular IL1RA tended to decrease with increasing TCDD levels. This observation is consistent with our earlier observation on decreasing cytokine levels, suggesting immunosuppression, with increasing exposures. These findings possibly provide new insights in the etiology of NHL and the mechanisms through which TCDD can increase lymphoma risk.

Serum metabolomic pertubations among workers exposed to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD).

Exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) has been associated with multiple health effects. Mechanistic studies using metabolomics could provide supporting evidence for such associations by identifying relevant biological pathways. In this study, we investigated metabolic perturbations in a cohort of TCDD exposed workers to better understand TCDD related health effects. Eighty one workers who had been exposed to TCDD in the past and 63 nonexposed workers were included in the study. Serum metabolites were detected using ultra high pressure liquid chromatography coupled online to a Q-TOF Premier mass spectrometer with a scan range of 70-1,000 m/z. Current plasma levels of TCDD were determined by high-resolution gas chromatography/isotope dilution high resolution mass spectrometry. TCDD blood levels at the time of last exposure were estimated using a one-compartment first order kinetic model. Differentially expressed metabolites were identified using linear regression models, partial least squares regression (PLSr) and a regression-based Bayesian variable selection approach. Features that were present in all quality control samples and had a coefficient of variation <30% were included in the analyses (n = 421 features). Adjusted linear regression analysis showed several significant perturbations (n = 27; P < 0.05) but these observations did not survive multiple testing correction (q value > 0.05). PLSr analyses and Bayesian variable selection regression analyses revealed no obvious metabolic perturbations associated with TCDD levels. This is the first metabolomic analysis related to TCDD exposure in humans. No significant metabolic features were identified. It is concluded that TCDD exposure at levels present in this study does not lead to significant perturbations of the serum metabolome.

Occupation and risk of lymphoid and myeloid leukaemia in the European Prospective Investigation into Cancer and Nutrition (EPIC).

OBJECTIVES: Established risk factors for leukaemia do not explain the majority of leukaemia cases. Previous studies have suggested the importance of occupation and related exposures in leukaemogenesis. We evaluated possible associations between job title and selected hazardous agents and leukaemia in the European Prospective Investigation into Cancer and Nutrition. METHODS: The mean follow-up time for 241 465 subjects was 11.20 years (SD 2.42 years). During the follow-up period, 477 incident cases of myeloid and lymphoid leukaemia occurred. Data on 52 occupations considered a priori to be at high risk of developing cancer were collected through standardised questionnaires. Occupational exposures were estimated by linking the reported occupations to a job exposure matrix. Cox proportional hazard models were used to explore the association between occupation and related exposures and risk of leukaemia. RESULTS: The risk of lymphoid leukaemia significantly increased for working in chemical laboratories (HR 8.35, 95% CI 1.58 to 44.24), while the risk of myeloid leukaemia increased for working in the shoe or other leather goods industry (HR 2.54, 95% CI 1.28 to 5.06). Exposure-specific analyses showed a non-significant increased risk of myeloid leukaemias for exposure to benzene (HR 1.15, 95% CI 0.75 to 1.40; HR=1.60, 95% CI 0.95 to 2.69 for the low and high exposure categories, respectively). This association was present both for acute and chronic myeloid leukaemia at high exposure levels. However, numbers were too small to reach statistical significance. CONCLUSIONS: Our findings suggest a possible role of occupational exposures in the development of both lymphoid and myeloid leukaemia. Exposure to benzene seemed to be associated with both acute and chronic myeloid leukaemia.

Anthropometric characteristics and risk of lymphoid and myeloid leukemia in the European Prospective Investigation into Cancer and Nutrition (EPIC).

PURPOSE: Overweight and obesity have been suggested as a risk factor for leukemia. Impaired immune function associated with obesity, increased insulin-like growth factor-I activity and stimulating effects of leptin suggest a possible biological link between anthropometric measures and leukemia. However, evidence from epidemiological studies has been inconsistent. We examined the potential association between prospective measurements of body size and risk of leukemia among participants of the European Prospective Investigation into Cancer and Nutrition (EPIC). METHODS: During follow-up (mean = 11.52 years, standard deviation = 2.63), 671 leukemia (lymphoid leukemia = 50.1 %, myeloid leukemia = 43.2 %) cases were identified. Anthropometric measures including weight, height, body mass index (BMI), waist circumference (WC), hip circumference, and waist-to-hip ratio (WHR) were measured. Cox proportional hazard models were used to explore the association between anthropometric measures and risk of leukemia. RESULTS: No associations were observed between anthropometric measures and total leukemia, and lymphoid leukemia. Risk of myeloid leukemia significantly increased for higher categories of BMI and WC among women. Analyses by subtype of myeloid leukemia showed an increased risk of acute myeloid leukemia (AML) for higher categories of WHR among women. This association seemed to be reversed for chronic myeloid leukemia. No association between anthropometric measures and myeloid leukemia were observed among men except an increased risk of AML with height. CONCLUSION: The study showed no associations between anthropometric measures and total leukemia, and lymphoid leukemia among men and women. A possible association between BMI as general obesity and WC as abdominal obesity and increased risk of myeloid leukemia among women were observed.

Changes in lymphocyte subsets in workers exposed to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD).

OBJECTIVES: 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is known to have toxic effects on the haematopoietic system in animals but epidemiological studies in humans have shown inconsistent results. In this cross-sectional study we investigated changes in peripheral blood cell counts and lymphocyte subsets among workers from a Dutch historical cohort occupationally exposed to chlorophenoxy herbicides and contaminants including TCDD. METHODS: Forty-seven workers who had been exposed to high levels of TCDD in the past and 38 low-exposed workers were included in the current investigation. Complete blood counts and differential and major lymphocyte subsets were analysed. Current plasma levels of TCDD (TCDD(current)) were determined by high-resolution gas chromatography/isotope-dilution high resolution mass spectrometry. TCDD blood levels at the time of last exposure (TCDD(max)) were estimated using a one-compartment first order kinetic model. RESULTS: Cell counts and lymphocyte subsets were similar between high- and low-exposed workers, except for a non-dose dependent increase in CD4/CD8 ratio among high-exposed workers. Interestingly, most lymphocyte subsets, in particular the B cell compartment, showed a decrease with increasing levels of both TCDD(current) and TCDD(max). CONCLUSIONS: Overall, our study showed that plasma TCDD levels had no effect on white blood cell counts and major subsets. However, a non-significant decrease in most lymphocyte subsets was noted, with the strongest effect for B cells. The latter finding may suggest that dioxin exposure might have an adverse impact on the haematopoietic system and lends some support to B cell lymphoma induction by dioxin.

Plasma Cytokine Concentrations in Workers Exposed to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD).

OBJECTIVES: Few epidemiological studies have studied the effect of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) on blood cytokine levels. In this study we investigated changes in plasma levels of a large panel of cytokines, chemokines, and growth factors among workers from a Dutch historical cohort occupationally exposed to chlorophenoxy herbicides and contaminants including TCDD. METHODS: Eighty-five workers who had been exposed to either high (n = 47) or low (n = 38) TCDD levels more than 30 years before serum collection were included in the current investigation. Plasma level of 16 cytokines, 10 chemokines, and 6 growth factors were measured. Current plasma levels of TCDD (TCDD(current)) were determined by high-resolution gas chromatography/isotope-dilution high-resolution mass spectrometry. TCDD blood levels at the time of last exposure (TCDD(max)) were estimated using a one-compartment first order kinetic model. RESULTS: Blood levels of most analytes had a negative association with current and estimated past maximum TCDD levels. These decreases reached formal statistical significance for fractalkine, transforming growth factor alpha (TGF-α), and fibroblast growth factor 2 (FGF2) with increasing TCDD levels. CONCLUSION: Our study showed a general reduction in most analyte levels with the strongest effects for fractalkine, FGF2, and TGF-α. These findings suggest that TCDD exposure could suppress the immune system and that chemokine and growth factor-dependent cellular pathway changes by TCDD may play role in TCDD toxicity and associated health effects.

Long-term effects on humoral immunity among workers exposed to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD).

OBJECTIVES: Epidemiological studies have shown inconsistent effects on immunological parameters in subjects exposed to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). In this study we investigated changes in humoral immunity and prevalence of atopic diseases among workers from a Dutch historical cohort occupationally exposed to chlorophenoxy herbicides and contaminants including TCDD. METHODS: 45 workers who had been exposed to high levels of TCDD in the past and 108 non-exposed workers (39 from the same factory as the exposed subjects (internal control group) and 69 from a comparable factory but without TCDD exposure (external control group)) were included in the study. Blood immunoglobulin (Ig) and complement factor (C) concentrations and specific IgE antibodies to a panel of common allergens were measured using quantitative nephelometry or ELISA. TCDD plasma levels were measured and back-extrapolated to the time of last exposure (TCDDmax) using a one-compartment first order kinetic model. RESULTS: A borderline significant negative association between both current and predicted TCDD levels and C4 was found in multivariate analyses (ß = -0.020; 95% CI = -0.040-0.010 and ß = -0.020; 95% CI = -0.030-0.00, respectively). History of eczema was significantly associated with current TCDD levels in both crude (OR = 1.5; 95% CI = 1.03-2.2) and adjusted models (OR = 1.7; 95% CI = 1.08-2.7). CONCLUSIONS: Our results do not support an association between TCDD exposure and markers of humoral immunity except possibly C4. Interestingly, decreased levels of C4 have been linked to lymphoma risk, which provides some support to the putative link between TCDD and non-Hodgkin lymphoma.

Plasma cytokines and future risk of non-Hodgkin lymphoma (NHL): a case-control study nested in the Italian European Prospective Investigation into Cancer and Nutrition.

BACKGROUND: Recently, biological markers related to the immune system such as cytokines have been studied to further understand the etiology of non-Hodgkin Lymphoma (NHL). However, to date, there are no studies that have studied cytokine levels prospectively in relation to NHL risk in the general population. METHODS: Using bead-based immunoassays, plasma levels of 11 cytokines, 4 chemokines, and 1 adhesion molecules were measured in prediagnostic blood samples of 86 NHL cases and 86 matched controls (average time between blood collection and diagnosis, 4.5 y). Conditional logistic regression adjusted for body mass index and alcohol consumption was used to analyze the association between individual plasma cytokine levels and the risk of developing NHL. RESULTS: In multivariate models, excluding cases diagnosed within 2 years after inclusion, we observed a significant association for interleukin 2 (IL2; P trend = 0.004), interferon (IFN)-gamma (P trend = 0.05), and intercellular adhesion molecule (ICAM) (P trend = 0.04). Subanalyses of B-cell NHL patients showed a significant association with IL2 (P trend = 0.003), tumor necrosis factor-alpha (TNF-alpha; P trend = 0.03), and ICAM (P trend = 0.04) and a borderline association with IL5 (P trend = 0.07) and IFN-gamma (P trend = 0.08). CONCLUSIONS: The results of this study suggest, in a prospective setting, a possible association between plasma levels of IL2, ICAM, IFN-gamma, and TNF-alpha with NHL risk and provide some evidence that risk of NHL might be related to a downregulation of T helper 1 cytokines. IMPACT: Identification of subtle changes in immune response regulation quantified by plasma cytokine levels possibly provides new insights in the etiology of NHL.