| 1. |
- Espín-Pérez, Almudena, et al.
(författare)
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Identification of Sex-Specific Transcriptome Responses to Polychlorinated Biphenyls (PCBs)
- 2019
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Ingår i: Scientific Reports. - : Nature Publishing Group. - 2045-2322. ; 9
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Tidskriftsartikel (refereegranskat)abstract
- PCBs are classified as xenoestrogens and carcinogens and their health risks may be sex-specific. To identify potential sex-specific responses to PCB-exposure we established gene expression profiles in a population study subdivided into females and males. Gene expression profiles were determined in a study population consisting of 512 subjects from the EnviroGenomarkers project, 217 subjects who developed lymphoma and 295 controls were selected in later life. We ran linear mixed models in order to find associations between gene expression and exposure to PCBs, while correcting for confounders, in particular distribution of white blood cells (WBC), as well as random effects. The analysis was subdivided according to sex and development of lymphoma in later life. The changes in gene expression as a result of exposure to the six studied PCB congeners were sex- and WBC type specific. The relatively large number of genes that are significantly associated with PCB-exposure in the female subpopulation already indicates different biological response mechanisms to PCBs between the two sexes. The interaction analysis between different PCBs and WBCs provides only a small overlap between sexes. In males, cancer-related pathways and in females immune system-related pathways are identified in association with PCBs and WBCs. Future lymphoma cases and controls for both sexes show different responses to the interaction of PCBs with WBCs, suggesting a role of the immune system in PCB-related cancer development.
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| 2. |
- Gasull, Magda, et al.
(författare)
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Methodological issues in a prospective study on plasma concentrations of persistent organic pollutants and pancreatic cancer risk within the EPIC cohort
- 2019
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Ingår i: Environmental Research. - : Elsevier. - 0013-9351 .- 1096-0953. ; 169, s. 417-433
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: The use of biomarkers of environmental exposure to explore new risk factors for pancreatic cancer presents clinical, logistic, and methodological challenges that are also relevant in research on other complex diseases.OBJECTIVES: First, to summarize the main design features of a prospective case-control study -nested within the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort- on plasma concentrations of persistent organic pollutants (POPs) and pancreatic cancer risk. And second, to assess the main methodological challenges posed by associations among characteristics and habits of study participants, fasting status, time from blood draw to cancer diagnosis, disease progression bias, basis of cancer diagnosis, and plasma concentrations of lipids and POPs. Results from etiologic analyses on POPs and pancreatic cancer risk, and other analyses, will be reported in future articles.METHODS: Study subjects were 1533 participants (513 cases and 1020 controls matched by study centre, sex, age at blood collection, date and time of blood collection, and fasting status) enrolled between 1992 and 2000. Plasma concentrations of 22 POPs were measured by gas chromatography - triple quadrupole mass spectrometry (GC-MS/MS). To estimate the magnitude of the associations we calculated multivariate-adjusted odds ratios by unconditional logistic regression, and adjusted geometric means by General Linear Regression Models.RESULTS: There were differences among countries in subjects' characteristics (as age, gender, smoking, lipid and POP concentrations), and in study characteristics (as time from blood collection to index date, year of last follow-up, length of follow-up, basis of cancer diagnosis, and fasting status). Adjusting for centre and time of blood collection, no factors were significantly associated with fasting status. Plasma concentrations of lipids were related to age, body mass index, fasting, country, and smoking. We detected and quantified 16 of the 22 POPs in more than 90% of individuals. All 22 POPs were detected in some participants, and the smallest number of POPs detected in one person was 15 (median, 19) with few differences by country. The highest concentrations were found for p,p'-DDE, PCBs 153 and 180 (median concentration: 3371, 1023, and 810 pg/mL, respectively). We assessed the possible occurrence of disease progression bias (DPB) in eight situations defined by lipid and POP measurements, on one hand, and by four factors: interval from blood draw to index date, tumour subsite, tumour stage, and grade of differentiation, on the other. In seven of the eight situations results supported the absence of DPB.CONCLUSIONS: The coexistence of differences across study centres in some design features and participant characteristics is of relevance to other multicentre studies. Relationships among subjects' characteristics and among such characteristics and design features may play important roles in the forthcoming analyses on the association between plasma concentrations of POPs and pancreatic cancer risk.
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| 3. |
- Georgiadis, Panagiotis, et al.
(författare)
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DNA methylation profiling implicates exposure to PCBs in the pathogenesis of B-cell chronic lymphocytic leukemia
- 2019
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Ingår i: Environment International. - : Elsevier BV. - 0160-4120 .- 1873-6750. ; 126, s. 24-36
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVES: To characterize the impact of PCB exposure on DNA methylation in peripheral blood leucocytes and to evaluate the corresponding changes in relation to possible health effects, with a focus on B-cell lymphoma.METHODS: We conducted an epigenome-wide association study on 611 adults free of diagnosed disease, living in Italy and Sweden, in whom we also measured plasma concentrations of 6 PCB congeners, DDE and hexachlorobenzene.RESULTS: We identified 650 CpG sites whose methylation correlates strongly (FDR < 0.01) with plasma concentrations of at least one PCB congener. Stronger effects were observed in males and in Sweden. This epigenetic exposure profile shows extensive and highly statistically significant overlaps with published profiles associated with the risk of future B-cell chronic lymphocytic leukemia (CLL) as well as with clinical CLL (38 and 28 CpG sites, respectively). For all these sites, the methylation changes were in the same direction for increasing exposure and for higher disease risk or clinical disease status, suggesting an etiological link between exposure and CLL. Mediation analysis reinforced the suggestion of a causal link between exposure, changes in DNA methylation and disease. Disease connectivity analysis identified multiple additional diseases associated with differentially methylated genes, including melanoma for which an etiological link with PCB exposure is established, as well as developmental and neurological diseases for which there is corresponding epidemiological evidence. Differentially methylated genes include many homeobox genes, suggesting that PCBs target stem cells. Furthermore, numerous polycomb protein target genes were hypermethylated with increasing exposure, an effect known to constitute an early marker of carcinogenesis.CONCLUSIONS: This study provides mechanistic evidence in support of a link between exposure to PCBs and the etiology of CLL and underlines the utility of omic profiling in the evaluation of the potential toxicity of environmental chemicals.
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| 4. |
- Tornevi, Andreas, et al.
(författare)
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Chlorinated persistent organic pollutants and type 2 diabetes - A population-based study with pre- and post- diagnostic plasma samples
- 2019
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Ingår i: Environmental Research. - : Elsevier. - 0013-9351 .- 1096-0953. ; 174, s. 35-45
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Persistent organic pollutants (POPs) have been associated with type 2 diabetes (T2D), but causality is uncertain.OBJECTIVE: Within longitudinal population-based data from northern Sweden, we assessed how POPs associated with T2D prospectively and cross-sectionally, and further investigated factors related to individual changes in POP concentrations.METHODS: For 129 case-controls pairs matched by age, sex and date of sampling, plasma concentrations of hexachlorobenzene (HCB), dichlorodiphenyl-dichloroethylene (p,p'-DDE), dioxin-like (DL) polychlorinated biphenyl congeners (PCB-118 and PCB-156), and non-dioxin like (NDL-PCB: PCB-74, -99, -138 -153, -170, -180, -183 and PCB-187) were analyzed twice (baseline and follow-up, 9-20 years apart). The cases received their T2D diagnose between baseline and follow-up. Prospective (using baseline data) and cross-sectional (using follow-up data) odds ratios (ORs) for T2D on lipid standardized POPs (HCB, p,p'-DDE, ∑DL-PCBs, ∑NDL-PCBs) were estimated using conditional logistic regression, adjusting for body mass index (BMI) and plasma lipids. The influence of BMI, weight-change, and plasma lipids on longitudinal changes in POP concentrations were evaluated among non-diabetic individuals (n = 306).RESULTS: POPs were associated with T2D in both the prospective and cross-sectional assessments. Of a standard deviation increase in POPs, prospective ORs ranged 1.42 (95% CI: 0.99, 2.06) for ∑NDL-PCBs to 1.55 (95% CI: 1.01, 2.38) for HCB (p < 0.05 only for HCB), and cross-sectional ORs ranged 1.62 (95% CI: 1.13; 2.32) for p,p'-DDE to 2.06 (95% CI: 1.29, 3.28) for ∑DL-PCBs (p < 0.05 for all POPs). In analyses of non-diabetic individuals, higher baseline BMI, decreased weight and decreased plasma lipid concentrations were associated with a slower decrease of POPs. Cases had, besides a higher BMI, reduced cholesterol and weight gain at follow-up compared to controls, which can explain the higher ORs in the cross-sectional assessments.DISCUSSION: The association between POPs and T2D was confirmed, but an indication that individuals body fat history might influence POP-T2D associations weakens the epidemiological support for a causal association. It also warrants studies based on other exposure metrics than biomonitoring. In addition, we note that a cross-sectional design overestimates the ORs if T2D cases have successfully intervened on weight and/or blood lipids, as changes in these factors cause changes in POPs.
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