| 11. |
- Gasull, Magda, et al.
(author)
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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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In: Environmental Research. - : Elsevier. - 0013-9351 .- 1096-0953. ; 169, s. 417-433
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Journal article (peer-reviewed)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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| 12. |
- Georgiadis, Panagiotis, et al.
(author)
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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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In: Environment International. - : Elsevier BV. - 0160-4120 .- 1873-6750. ; 126, s. 24-36
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Journal article (peer-reviewed)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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| 13. |
- Krauskopf, Julian, et al.
(author)
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MicroRNA profile for health risk assessment : environmental exposure to persistent organic pollutants strongly affects the human blood microRNA machinery
- 2017
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In: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 7
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Journal article (peer-reviewed)abstract
- Persistent organic pollutants (POPs) are synthetic chemical substances that accumulate in our environment. POPs such as polychlorinated biphenyls (PCBs), hexachlorobenzene (HCB) and dichlorodiphenyltrichloroethane (DDT) have been classified as carcinogenic to humans and animals. Due to their resistance to biodegradation humans are still exposed to these compounds worldwide. We aim to evaluate the miRNA and transcriptomic response of a human population exposed to POPs. The miRNA and transcriptomic response was measured in blood of healthy subjects by microarray technology and associated with the serum concentrations of six PCB congeners, DDE (a common DDT metabolite), and HCB. A total of 93 miRNA levels appeared significantly associated with the POP-exposure (FDR < 0.05). The miRNA profile includes four tumor suppressor miRNAs, namely miR-193a-3p, miR-152, miR-31-5p and miR-34a-5p. Integration of the miRNA profile with the transcriptome profile suggests an interaction with oncogenes such as MYC, CCND1, BCL2 and VEGFA. We have shown that exposure to POPs is associated with human miRNA and transcriptomic responses. The identified miRNAs and target genes are related to various types of cancer and involved in relevant signaling pathways like wnt and p53. Therefore, these miRNAs may have great potential to contribute to biomarker-based environmental health risk assessment.
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| 14. |
- Lavogina, Darja, et al.
(author)
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Endocrine disrupting chemicals interfere with decidualization of human primary endometrial stromal cells in vitro
- 2022
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In: Frontiers in Endocrinology. - : Frontiers Media S.A.. - 1664-2392. ; 13
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Journal article (peer-reviewed)abstract
- Multiple studies have shown associations between exposure to endocrine disrupting chemicals (EDCs) and reduced fertility in women. However, little is known about the target organs of chemical disruption of female fertility. Here, we focus on the hormone-sensitive uterine lining, the endometrium, as a potential target. Decidualization is the morphological and functional change that endometrial stromal cells undergo to support endometrial receptivity, which is crucial for successful implantation, placentation, and pregnancy. We investigated the effect of nine selected EDCs on primary human endometrial stromal cell decidualization in vitro. The cells were exposed to a decidualization-inducing mixture in the presence or absence of 1 mu M of nine different EDCs for nine days. Extent of decidualization was assessed by measuring the activity of cAMP dependent protein kinase, Rho-associated coiled-coil containing protein kinase, and protein kinase B in lysates using photoluminescent probes, and secretion of prolactin into the media by using ELISA. Decidualization-inducing mixture upregulated activity of protein kinases and prolactin secretion in cells derived from all women. Of the tested chemicals, dichlorodiphenyldichloroethylene (p,p'-DDE), hexachlorobenzene (HCB) and perfluorooctanesulfonic acid (PFOS) significantly reduced decidualization as judged by the kinase markers and prolactin secretion. In addition, bisphenol A (BPA) reduced prolactin secretion but did not significantly affect activity of the kinases. None of the EDCs was cytotoxic, based on the assessment of total protein content or activity of the viability marker casein kinase 2 in lysates. These results indicate that EDCs commonly present in the blood circulation of reproductive-aged women can reduce decidualization of human endometrial stromal cells in vitro. Future studies should focus on detailed hazard assessment to define possible risks of EDC exposure to endometrial dysfunction and implantation failure in women.
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| 15. |
- Porta, Miquel, et al.
(author)
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Plasma concentrations of persistent organic pollutants and pancreatic cancer risk
- 2022
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In: International Journal of Epidemiology. - : Oxford University Press. - 0300-5771 .- 1464-3685. ; 51:2, s. 479-490
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Journal article (peer-reviewed)abstract
- Background: Findings and limitations of previous studies on persistent organic pollutants (POPs) and pancreatic cancer risk support conducting further research in prospective cohorts.Methods: We conducted a prospective case-control study nested within the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort. Participants were 513 pancreatic cancer cases and 1020 matched controls. Concentrations of 22 POPs were measured in plasma collected at baseline.Results: Some associations were observed at higher concentrations of p, p'-DDT, trans-nonachlor, β-hexachlorocyclohexane and the sum of six organochlorine pesticides and of 16 POPs. The odds ratio (OR) for the upper quartile of trans-nonachlor was 1.55 (95% confidence interval 1.06-2.26; P for trend = 0.025). Associations were stronger in the groups predefined as most valid (participants having fasted >6 h, with microscopic diagnostic confirmation, normal weight, and never smokers), and as most relevant (follow-up ≥10 years). Among participants having fasted >6 h, the ORs were relevant for 10 of 11 exposures. Higher ORs were also observed among cases with microscopic confirmation than in cases with a clinical diagnosis, and among normal-weight participants than in the rest of participants. Among participants with a follow-up ≥10 years, estimates were higher than in participants with a shorter follow-up (for trans-nonachlor: OR = 2.14, 1.01 to 4.53, P for trend = 0.035). Overall, trans-nonachlor, three PCBs and the two sums of POPs were the exposures most clearly associated with pancreatic cancer risk.Conclusions: Individually or in combination, most of the 22 POPs analysed did not or only moderately increased the risk of pancreatic cancer.
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| 16. |
- Rantakokko, Panu, et al.
(author)
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A simple and fast liquid-liquid extraction method for the determination of 2,2 ',4,4 ',5,5 '-hexachlorobiphenyl (CB-153) and 1,1-dichloro-2,2-bis(p-chlorophenyl)-ethylene (p,p '-DDE) from human serum for epidemiological studies on type 2 diabetes
- 2009
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In: Journal of Chromatography A. - : Elsevier BV. - 0021-9673. ; 1216:6, s. 897-901
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Journal article (peer-reviewed)abstract
- A simple and fast method is presented to be used for example in studies on the relationship between serum levels of persistent organic pollutants and type 2 diabetes mellitus. Method is based on liquid-liquid extraction and gas chromatography coupled with high.-resolution mass spectrometry. In the sample pretreatment special attention was paid to minimize the number of sample manipulation steps and the amounts of organic solvents needed. Compounds analyzed were 2,2',4,4',5,5'-hexachlorobiphenyl (PCB-153) and 1,1-dichloro-2,2-bis (p-chlorophenyl)-ethylene (p,p'-DDE), the major metabolite of DDT. The method included extraction and cleanup of 0.2 rill of serum in a single test tube and subsequent analysis of the extract from 0.2 ml final volume. Validation was conducted to explore the performance of the method. The limits of detection for p,p'-DDE and PCB-153 based on the standard deviation of the blank samples were 4.3 and 3.1 pg/ml, respectively. Repeatability was less than 2.5% at three concentration levels tested and recovery from Certified Reference Material SRM 1589a was 84% for p,p'-DDE and 87% for PCB-153 of the certified values, respectively. Serum samples from the AMAP intercalibration round 2008-2 were also analyzed, and results were 101-116% of the assigned values. The presented method was used for an epidemiological study with more than 700 serum samples from a type 2 diabetes cohort from Sweden. (C) 2008 Elsevier B.V. All rights reserved.
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| 17. |
- Rignell-Hydbom, Anna, et al.
(author)
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Exposure to p,p'-DDE: a risk factor for type 2 diabetes.
- 2009
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In: PLoS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 4:10
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Journal article (peer-reviewed)abstract
- BACKGROUND: Persistent organic pollutants (POPs), such as PCBs, DDT and dioxins have in several cross-sectional studies shown strong associations with type 2 diabetes mellitus. Reversed causality can however not be excluded. The aim of this case-control study was to evaluate whether POPs concentration is a risk factor for type 2 diabetes. METHODOLOGY/PRINCIPAL FINDINGS: A case-control study was performed within a well-defined cohort of women, age 50-59 years, from the Southern part of Sweden. Biomarkers for POP exposure, 2,2',4,4',5,5'-hexachlorobiphenyl (CB-153) and 1,1-dichloro-2,2-bis (p-chlorophenyl)-ethylene (p,p'-DDE) were analyzed in stored serum samples, which were collected at the baseline examination when the cohort was established. For 107 out of the 371 cases, serum samples were stored at least three years before their type 2 diabetes was diagnosed. In this data set, CB-153 and p,p'-DDE were not associated with an increased risk to develop type 2 diabetes. However, when only the cases (n = 39) that were diagnosed more than six years after the baseline examination and their controls were studied, the women in the highest exposed quartile showed an increased risk to develop type 2 diabetes (OR of 1.6 [95% 0.61, 4.0] for CB-153 and 5.5 [95% CI 1.2, 25] for p,p'-DDE). CONCLUSIONS/SIGNIFICANCE: The results from the present case-control study, including a follow-up design, confirms that p,p'-DDE exposure can be a risk factor for type 2 diabetes.
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| 18. |
- Schillemans, Tessa, et al.
(author)
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Omics signatures linking persistent organic pollutants to cardiovascular disease in the Swedish mammography cohort
- 2024
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In: Environmental Science and Technology. - : American Chemical Society (ACS). - 0013-936X .- 1520-5851. ; 58:2, s. 1036-1047
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Journal article (peer-reviewed)abstract
- Cardiovascular disease (CVD) development may be linked to persistent organic pollutants (POPs), including organochlorine compounds (OCs) and perfluoroalkyl and polyfluoroalkyl substances (PFAS). To explore underlying mechanisms, we investigated metabolites, proteins, and genes linking POPs with CVD risk. We used data from a nested case-control study on myocardial infarction (MI) and stroke from the Swedish Mammography Cohort - Clinical (n = 657 subjects). OCs, PFAS, and multiomics (9511 liquid chromatography-mass spectrometry (LC-MS) metabolite features; 248 proteins; 8110 gene variants) were measured in baseline plasma. POP-related omics features were selected using random forest followed by Spearman correlation adjusted for confounders. From these, CVD-related omics features were selected using conditional logistic regression. Finally, 29 (for OCs) and 12 (for PFAS) unique features associated with POPs and CVD. One omics subpattern, driven by lipids and inflammatory proteins, associated with MI (OR = 2.03; 95% CI = 1.47; 2.79), OCs, age, and BMI, and correlated negatively with PFAS. Another subpattern, driven by carnitines, associated with stroke (OR = 1.55; 95% CI = 1.16; 2.09), OCs, and age, but not with PFAS. This may imply that OCs and PFAS associate with different omics patterns with opposite effects on CVD risk, but more research is needed to disentangle potential modifications by other factors.
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| 19. |
- Svensson, Katherine, et al.
(author)
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EDC mixtures during pregnancy and body fat at 7 years of age in a Swedish cohort, the SELMA study
- 2024
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In: Environmental Research. - : Elsevier. - 0013-9351 .- 1096-0953. ; 48
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Journal article (peer-reviewed)abstract
- Background: Some endocrine disrupting chemicals (EDC), are “obesogens” and have been associated withoverweight and obesity in children. Daily exposure to different classes of EDCs demands for research withmixtures approach.Objectives: This study evaluates the association, considering sex-specific effects, between prenatal exposure toEDC mixture and children’s body fat at seven years of age.Methods: A total of 26 EDCs were assessed in prenatal urine and serum samples from first trimester in pregnancyfrom 737 mother-child pairs participating in the Swedish Environmental Longitudinal, Mother and child, Asthmaand allergy (SELMA) study. An indicator for children’s “overall body fat” was calculated, using principalcomponent analysis (PCA), based on BMI, percent body fat, waist, and skinfolds measured at seven years of age.Weighted quantile sum (WQS) regression was used to assess associations between EDC mixture and children’sbody fat.Results: Principal component (PC1) represented 83.6 % of the variance, suitable as indicator for children’s“overall body fat”, with positive loadings of 0.40–0.42 for each body fat measure. A significant interaction term,WQS*sex, confirmed associations in the opposite direction for boys and girls. Higher prenatal exposure to EDCmixture was borderline significant with more “overall body fat” for boys (Mean β = 0.20; 95 % CI: − 0.13, 0.53)and less for girls (Mean β = − 0.23; 95 % CI: − 0.58, 0.13). Also, higher prenatal exposure to EDC mixture wasborderline significant with more percent body fat (standardized score) for boys (Mean β = 0.09; 95 % CI: − 0.04,0.21) and less for girls (Mean β = − 0.10 (− 0.26, 0.05). The chemicals of concern included bisphenols, phthalates, PFAS, PAH, and pesticides with different patterns for boys and girls.Discussion: Borderline significant associations were found between prenatal exposure to a mixture of EDCs andchildren’s body fat. The associations in opposite directions suggests that prenatal exposure to EDCs may presentsex-specific effects on children’s body fat.
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| 20. |
- Svensson, Katherine, et al.
(author)
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Prenatal exposures to mixtures of endocrine disrupting chemicals and sex-specific associations with children’s BMI and overweight at 5.5 years of age in the SELMA study
- 2023
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In: Environment International. - : Elsevier. - 0160-4120 .- 1873-6750. ; 179
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Journal article (peer-reviewed)abstract
- Background: Prenatal exposure to mixtures of endocrine disrupting chemicals (EDC) has the potential to disrupt human metabolism. Prenatal periods are especially sensitive as many developmental processes are regulated by hormones. Prenatal exposure to EDCs has inconsistently been associated with children’s body mass index (BMI) and obesity. The objective of this study was to investigate if prenatal exposure to a mixture of EDCs was associated with children’s BMI and overweight (ISO-BMI ≥ 25) at 5.5 years of age, and if there were sex-specific effects. Methods: A total of 1,105 mother–child pairs with complete data on prenatal EDCs concentrations (e.g., phthalates, non-phthalate plasticizers, phenols, PAH, pesticides, PFAS, organochlorine pesticides, and PCBs), children’s measured height and weight, and selected covariates in the Swedish Environmental Longitudinal, Mother and child, Asthma and allergy (SELMA) study were included in this analysis. The mixture effect of EDCs with children’s BMI and overweight was assessed using WQS regression with 100 repeated holdouts. A positively associated WQS index with higher BMI and odds of overweight was derived. Models with interaction term and stratified weights by sex was applied in order to evaluate sex-specific associations. Results: A significant WQS*sex interaction term was identified and associations for boys and girls were in opposite directions. Higher prenatal exposure to a mixture of EDCs was associated with lower BMI (Mean β = -0.19, 95%CI: −0.40, 0.01) and lower odds of overweight (Mean OR = 0.72, 95%CI: 0.48, 1.04) among girls with borderline significance. However, the association among boys did not reach statistical significance. Among girls, the possible chemicals of concern were MEP, 2-OHPH, BPF, BPS, DPP and PFNA. Conclusion: Prenatal exposure to a mixture of EDCs was associated with lower BMI and overweight among girls, and non-significant associations among boys. Chemicals of concern for girls included phthalates, non-phthalate plasticizers, bisphenols, PAHs, and PFAS.
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