Dataset Information

OMICs Signatures Linking Persistent Organic Pollutants to Cardiovascular Disease in the Swedish Mammography Cohort.

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.

SUBMITTER: Schillemans T

PROVIDER: S-EPMC10795192 | biostudies-literature | 2024 Jan

REPOSITORIES: biostudies-literature

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OMICs Signatures Linking Persistent Organic Pollutants to Cardiovascular Disease in the Swedish Mammography Cohort.

Schillemans Tessa T Yan Yingxiao Y Ribbenstedt Anton A Donat-Vargas Carolina C Lindh Christian H CH Kiviranta Hannu H Rantakokko Panu P Wolk Alicja A Landberg Rikard R Åkesson Agneta A Brunius Carl C

Environmental science & technology 20240104 2

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 (<i>n</i> = 657 subjects). OCs, PFAS, and multiomics (9511 l ...[more]

PMID: 38174696

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Project description:Exposure to persistent organic pollutants (POPs), such as dichlorodiphenyltrichloroethane (DDT) and polychlorinated biphenyls (PCBs), has historically been linked to population collapses in wildlife. Despite international regulations, these legacy chemicals are still currently detected in women of reproductive age, and their levels correlate with reduced ovarian reserve, longer time-to-pregnancy, and higher risk of infertility. However, the specific modes of action underlying these associations remain unclear. Here, we examined the effects of five commonly occurring POPs − hexachlorobenzene (HCB), p,p'-dichlorodiphenyldichloroethylene (DDE), 2,3,3′,4,4′,5-hexachlorobiphenyl (PCB156), 2,2′,3,4,4′,5,5′-heptachlorobiphenyl (PCB180), perfluorooctane sulfonate (PFOS) − and their mixture on human ovaries in vitro. We exposed human ovarian cancer cell lines COV434, KGN, and PA1 as well as primary ovarian cells for 24 h, and ovarian tissue containing unilaminar follicles for 6 days. RNA-sequencing of samples exposed to concentrations covering epidemiologically relevant levels revealed significant gene expression changes related to central energy metabolism in the exposed cells, indicating glycolysis, oxidative phosphorylation, fatty acid metabolism, and reactive oxygen species as potential shared targets of POP exposures in ovarian cells. Alpha-enolase (ENO1), lactate dehydrogenase A (LDHA), cytochrome C oxidase subunit 4I1 (COX4I1), ATP synthase F1 subunit alpha (ATP5A), and glutathione peroxidase 4 (GPX4) were validated as targets through qPCR in additional cell culture experiments in KGN. In ovarian tissue cultures, we observed significant effects of exposure on follicle growth and atresia as well as protein expression. All POP exposures, except PCB180, decreased unilaminar follicle proportion and increased follicle atresia. Immunostaining confirmed altered expression of LDHA, ATP5A, and GPX4 in the exposed tissues. Moreover, POP exposures modified ATP production in KGN and tissue culture. In conclusion, our results demonstrate the disruption of cellular energy metabolism as a novel mode of action underlying POP-mediated interference of follicle growth in human ovaries.

Project description:BackgroundAnimal and human studies suggest certain persistent organic pollutants (POPs) may impact glucose metabolism; however, few epidemiologic studies have examined environmental determinants of glycemic outcomes during pregnancy. Our objective is to evaluate associations between exposures to individual and mixture of POPs and measures of prenatal fasting glucose, insulin, and insulin resistance during pregnancy in overweight women.MethodsA cohort of overweight and obese pregnant women (N = 95) was recruited from California. Blood samples were collected during late first or second trimester (median = 16 weeks' gestation; range = 10-24 weeks). Exposures included serum concentrations of polybrominated diphenyl ethers (PBDEs) and hydroxylated metabolites (OH-PBDEs), polychlorinated biphenyls (PCBs), and poly- and perfluoroalkyl substances (PFASs). Outcomes included serum concentrations of fasting plasma glucose, fasting plasma insulin, and calculated homeostatic model assessment of insulin resistance (HOMA-IR). Generalized linear models were used to evaluate cross-sectional associations between individual and aggregate POPs and mean percent difference in fasting glucose, fasting insulin, and HOMA-IR. Bayesian kernel machine regression (BKMR) was used to assess the relative importance of each exposure to the association with our outcomes, using conditional and group posterior inclusion probabilities (PIPs).ResultsStudy participants were racially/ethnically diverse and nearly half were below the federal poverty level. Across PBDEs and OH-PBDEs, the direction of associations with fasting glucose, fasting insulin and HOMA-IR were varied. A doubling of PCB-138, PCB-153, PCB-180, and ∑PCBs concentrations was associated with a 2.10% mmol/L (95%CI: 0.49%, 3.74%), 2.10% mmol/L (95%CI: -0.14%, 4.39%), 2.10% mmol/L (95%CI: 0.12%, 4.12%), and 2.81% mmol/L (95%CI: 0.38%, 5.31%) increase in fasting glucose, respectively. Exposure to individual PCBs was positively associated with both fasting insulin and HOMA-IR. All PFAS were inversely associated with fasting glucose, fasting insulin, and HOMA-IR. In BKMR models of fasting glucose, all four chemical classes were important contributors to the overall mixture, with PFASs identified as the most important contributor.DiscussionPrenatal PCB exposure was positively associated while certain PBDE and PFAS analytes were inversely associated with fasting glucose concentrations in overweight women. Further examination of the relationship between POPs exposure and glycemic functioning in a larger study population of women during pregnancy is warranted.

Dataset Information

OMICs Signatures Linking Persistent Organic Pollutants to Cardiovascular Disease in the Swedish Mammography Cohort.

Publications

OMICs Signatures Linking Persistent Organic Pollutants to Cardiovascular Disease in the Swedish Mammography Cohort.

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