A1 Vertaisarvioitu alkuperäisartikkeli tieteellisessä lehdessä
The effect of polychlorinated biphenyls on type 2 diabetes risk is mediated via DNA methylation
Tekijät: Kartiosuo, Noora; Auranen, Kari; Mansell, Toby; Novakovic, Boris; Nevalainen, Jaakko; Pahkala, Katja; Rovio, Suvi; Mykkänen, Juha; Viikari, Jorma; Juonala, Markus; Rantakokko, Panu; Kiviranta, Hannu; Kaikkonen, Jari; Lehtimäki, Terho; Raitoharju, Emma; Mishra, Pashupati P.; Kähönen, Mika; Ponsonby, Anne-Louise; Tanner, Sam; Burgner, David; Raitakari, Olli; Saffery, Richard
Kustantaja: Elsevier Ltd
Julkaisuvuosi: 2025
Journal: Environment International
Artikkelin numero: 109779
Vuosikerta: 203
ISSN: 0160-4120
eISSN: 1873-6750
DOI: https://doi.org/10.1016/j.envint.2025.109779
Verkko-osoite: https://doi.org/10.1016/j.envint.2025.109779
Rinnakkaistallenteen osoite: https://research.utu.fi/converis/portal/detail/Publication/499971225
Polychlorinated biphenyls (PCBs) have been identified as diabetogens and potential epigenetic regulators. Epigenetic variation is implicated in the pathogenesis of type 2 diabetes (T2D) and is therefore a potential mechanism linking PCB exposure and T2D. We here investigate the effect of PCB exposure on T2D risk and the extent to which this is mediated via DNA methylation (DNAm) using two epigenome-wide association studies and mediation analysis. Exposure to PCBs, especially congeners 74, 99, 118, 138 and 183, increased the risk of T2D (range of ORs 1.38-1.54). Five CpG sites were identified as potential mediators. Together, methylation at these sites was estimated to mediate 40 % (95 % CI: 20, 60 %) of the effect of PCBs on T2D. The strongest evidence was obtained for cg00574958, located in the first intron of the CPT1A gene. This study is among the largest to date assessing the link between PCBs and T2D, and the first to investigate the mediation by DNAm. The evidence for methylation at cg00574958 as a mediator of the PCB-T2D relationship supports the widely-replicated link of CPT1A DNA methylation to a range of metabolic phenotypes including obesity, dyslipidemia and T2D and indicates a possible future target for epigenetic intervention.
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The Young Finns Study has been financially supported by the Academy of Finland: grants 356405, 322098, 286284, 134309 (Eye), 126925, 121584, 124282, 129378 (Salve), 117797 (Gendi), and 141071 (Skidi); the Social Insurance Institution of Finland; Competitive State Research Financing of the Expert Responsibility area of Kuopio, Tampere and Turku University Hospitals (grant X51001); Juho Vainio Foundation; Paavo Nurmi Foundation; Finnish Foundation for Cardiovascular Research; Finnish Cultural Foundation; The Sigrid Juselius Foundation; Tampere Tuberculosis Foundation; Emil Aaltonen Foundation; Yrjö Jahnsson Foundation; Signe and Ane Gyllenberg Foundation; Diabetes Research Foundation of Finnish Diabetes Association; EU Horizon 2020 (grant 755320 for TAXINOMISIS and grant 848146 for To Aition); European Research Council (grant 742927 for MULTIEPIGEN project); Tampere University Hospital Supporting Foundation; Finnish Society of Clinical Chemistry; the Cancer Foundation Finland; pBETTER4U_EU (Preventing obesity through Biologically and bEhaviorally Tailored inTERventions for you; project number: 101080117); CVDLink (EU grant nro. 101137278) and the Jane and Aatos Erkko Foundation. Noora Kartiosuo has been supported by the Emil Aaltonen Foundation, University of Turku Graduate School and the Alfred Kordelin foundation. Katja Pahkala is supported by Research Council of Finland (grant: 322112). Pashupati Mishra is supported by Research Council of Finland (grant: 349708). Emma Raitoharju is supported by Research Council of Finland (grant: 330809, 338395), Laboratoriolääketieteen edistämissäätiö sr., Signe och Ane Gyllenbergs stiftelse, State funding for university-level health research, Tampere University Hospital, Wellbeing services county of Pirkanmaa and Fimlab Oy, Yrjö Jahnsson Foundation and Finnish Foundation for Cardiovascular Research. Jari Kaikkonen has been funded by the Research Committee of the Kuopio University Hospital Catchment Area (State Research Funding, 5031364). Research at MCRI is supported by the Victorian Government’s Operational Infrastructure Support Program. DB is supported by an NHMRC Investigator Grant (GTN1175744).
