PMID- 35303528 OWN - NLM STAT- MEDLINE DCOM- 20220426 LR - 20220915 IS - 1873-6750 (Electronic) IS - 0160-4120 (Linking) VI - 163 DP - 2022 May TI - Associations between persistent organic pollutants and type 1 diabetes in youth. PG - 107175 LID - S0160-4120(22)00101-5 [pii] LID - 10.1016/j.envint.2022.107175 [doi] AB - BACKGROUND: Diabetes affects millions of people worldwide with a continued increase in incidence occurring within the pediatric population. The potential contribution of persistent organic pollutants (POPs) to diabetes in youth remains poorly known, especially regarding type 1 diabetes (T1D), generally the most prevalent form of diabetes in youth. OBJECTIVES: We investigated the associations between POPs and T1D in youth and studied the impacts of POPs on pancreatic beta-cell function and viability in vitro. METHODS: We used data and plasma samples from the SEARCH for Diabetes in Youth Case Control Study (SEARCH-CC). Participants were categorized as Controls, T1D with normal insulin sensitivity (T1D/IS), and T1D with insulin resistance (T1D/IR). We assessed plasma concentrations of polychlorinated biphenyls (PCBs) and organochlorine pesticides and estimated the odds of T1D through multivariable logistic regression. In addition, we performed in vitro experiments with the INS-1E pancreatic beta-cells. Cells were treated with PCB-153 or p,p'-DDE at environmentally relevant doses. We measured insulin production and secretion and assessed the mRNA expression of key regulators involved in insulin synthesis (Ins1, Ins2, Pdx1, Mafa, Pcsk1/3, and Pcsk2), glucose sensing (Slc2a2 and Gck), and insulin secretion (Abcc8, Kcnj11, Cacna1d, Cacna1b, Stx1a, Snap25, and Sytl4). Finally, we assessed the effects of PCB-153 and p,p'-DDE on beta-cell viability. RESULTS: Among 442 youths, 112 were controls, 182 were classified with T1D/IS and 148 with T1D/IR. The odds ratios (OR) of T1D/IS versus controls were statistically significant for p,p'-DDE (OR 2.0, 95% confidence interval (CI) 1.0, 3.8 and 2.4, 95% CI 1.2, 5.0 for 2nd and 3rd tertiles, respectively), trans-nonachlor (OR 2.5, 95% CI 1.3, 5.0 and OR 2.3, 95% CI 1.1, 5.1 for 2nd and 3rd tertiles, respectively), and PCB-153 (OR 2.3, 95% CI 1.1, 4.6 for 3rd tertile). However, these associations were not observed in participants with T1D/IR. At an experimental level, treatment with p,p'-DDE or PCB-153, at concentrations ranging from 1 x 10(-15) M to 5 x 10(-6) M, impaired the ability of pancreatic beta-cells to produce and secrete insulin in response to glucose. These failures were paralleled by impaired Ins1 and Ins2 mRNA expression. In addition, among different targeted genes, PCB-153 significantly reduced Slc2a2 and Gck mRNA expression whereas p,p'-DDE mainly affected Abcc8 and Kcnj11. While treatment with PCB-153 or p,p'-DDE for 2 days did not affect beta-cell viability, longer treatment progressively killed the beta-cells. CONCLUSION: These results support a potential role of POPs in T1D etiology and demonstrate a high sensitivity of pancreatic beta-cells to POPs. CI - Copyright (c) 2022 The Authors. Published by Elsevier Ltd.. All rights reserved. FAU - Bresson, Sophie E AU - Bresson SE AD - Department of Molecular Medicine, Institute of Basic Medical Sciences, Faculty of Medicine, University of Oslo, Oslo, Norway. FAU - Isom, Scott AU - Isom S AD - Wake Forest School of Medicine, Winston-Salem, NC, USA. FAU - Jensen, Elizabeth T AU - Jensen ET AD - Wake Forest School of Medicine, Winston-Salem, NC, USA. FAU - Huber, Sandra AU - Huber S AD - Department of Laboratory Medicine, University Hospital of North Norway, Tromso, Norway. FAU - Oulhote, Youssef AU - Oulhote Y AD - Department of Biostatistics and Epidemiology, School of Public Health and Health Sciences, University of Massachusetts, Amherst, MA, USA. FAU - Rigdon, Joseph AU - Rigdon J AD - Wake Forest School of Medicine, Winston-Salem, NC, USA. FAU - Lovato, James AU - Lovato J AD - Wake Forest School of Medicine, Winston-Salem, NC, USA. FAU - Liese, Angela D AU - Liese AD AD - Department of Epidemiology and Biostatistics, Arnold School of Public Health, SC, USA. FAU - Pihoker, Catherine AU - Pihoker C AD - Department of Pediatrics, University of Washington, Seattle, WA, USA. FAU - Dabelea, Dana AU - Dabelea D AD - Lifecourse Epidemiology of Adiposity and Diabetes (LEAD) Center and Department of Epidemiology, Colorado School of Public Health, University of Colorado Anschutz Medical Campus, Aurora, CO, USA. FAU - Ehrlich, Shelley AU - Ehrlich S AD - Division of Biostatistics and Epidemiology, Cincinnati Children's Hospital Medical center, Cincinnati, OH, USA; Department of Environmental Health, University of Cincinnati College of Medicine, Cincinnati, OH, USA. FAU - Ruzzin, Jerome AU - Ruzzin J AD - Department of Molecular Medicine, Institute of Basic Medical Sciences, Faculty of Medicine, University of Oslo, Oslo, Norway. Electronic address: jerome.ruzzin@medisin.uio.no. LA - eng GR - U01 DP000244/DP/NCCDPHP CDC HHS/United States GR - U18 DP006139/DP/NCCDPHP CDC HHS/United States GR - U01 DP000250/DP/NCCDPHP CDC HHS/United States GR - U18 DP002714/DP/NCCDPHP CDC HHS/United States GR - U01 DP000248/DP/NCCDPHP CDC HHS/United States GR - U18 DP002709/DP/NCCDPHP CDC HHS/United States GR - U18 DP006136/DP/NCCDPHP CDC HHS/United States GR - U01 DP000246/DP/NCCDPHP CDC HHS/United States GR - U01 DP000254/DP/NCCDPHP CDC HHS/United States GR - U18 DP002710/DP/NCCDPHP CDC HHS/United States GR - U18 DP006138/DP/NCCDPHP CDC HHS/United States GR - U18 DP002708/DP/NCCDPHP CDC HHS/United States GR - U18 DP006131/DP/NCCDPHP CDC HHS/United States GR - U18 DP006134/DP/NCCDPHP CDC HHS/United States GR - UC4 DK108173/DK/NIDDK NIH HHS/United States GR - U18 DP006133/DP/NCCDPHP CDC HHS/United States GR - U01 DP000247/DP/NCCDPHP CDC HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural DEP - 20220316 PL - Netherlands TA - Environ Int JT - Environment international JID - 7807270 RN - 0 (Environmental Pollutants) RN - 0 (Hydrocarbons, Chlorinated) RN - 0 (Insulin) RN - 0 (Pesticides) RN - 0 (RNA, Messenger) RN - 4M7FS82U08 (Dichlorodiphenyl Dichloroethylene) RN - DFC2HB4I0K (Polychlorinated Biphenyls) RN - IY9XDZ35W2 (Glucose) SB - IM MH - Adolescent MH - Case-Control Studies MH - Child MH - *Diabetes Mellitus, Type 1/epidemiology MH - Dichlorodiphenyl Dichloroethylene MH - *Environmental Pollutants/adverse effects MH - Glucose MH - Humans MH - *Hydrocarbons, Chlorinated/analysis MH - Insulin MH - *Insulin Resistance MH - Persistent Organic Pollutants MH - *Pesticides MH - *Polychlorinated Biphenyls MH - RNA, Messenger OTO - NOTNLM OT - Organochlorine Pesticides OT - Persistent Organic Pollutants OT - Polychlorinated Biphenyls OT - Type 1 Diabetes OT - Youths EDAT- 2022/03/19 06:00 MHDA- 2022/04/27 06:00 CRDT- 2022/03/18 20:09 PHST- 2021/11/26 00:00 [received] PHST- 2022/02/08 00:00 [revised] PHST- 2022/03/07 00:00 [accepted] PHST- 2022/03/19 06:00 [pubmed] PHST- 2022/04/27 06:00 [medline] PHST- 2022/03/18 20:09 [entrez] AID - S0160-4120(22)00101-5 [pii] AID - 10.1016/j.envint.2022.107175 [doi] PST - ppublish SO - Environ Int. 2022 May;163:107175. doi: 10.1016/j.envint.2022.107175. Epub 2022 Mar 16.