title: Deviant development of pancreatic beta cells from embryonic exposure to PCB-126 in zebrafish.
abstract: Exposures to co-planar PCBs and dioxins have been associated with diabetes in epidemiologic studies. Individuals may be predisposed to diseases such as diabetes as a result of exposure to environmental contaminants during early life, resulting in dysmorphic pancreatic islets or metabolically fragile β-cells. We tested the hypothesis that embryonic exposure to a model Ahr-ligand, PCB-126 would cause structural and/or functional alterations to the developing primary pancreatic islet in the zebrafish (Danio rerio). To assess β-cell development, transgenic zebrafish embryos (Tg(ins:GFP) and Tg(ins:mcherry) were exposed to nominal concentrations of 2 or 5nM PCB-126 or DMSO from 24-48h post fertilization (hpf), and imaged via time-lapse microscopy from 80-102hpf. We identified defects including hypomorphic islets, altered islet migration, islet fragmentation, and formation of ectopic β-cells. As we recently showed the transcription factor Nrf2a is protective in PCB-126 embryotoxicity, we then assessed the transcriptional function of the islets in wildtype and nrf2a(fh318/fh318) mutant embryos. We measured gene expression of preproinsulin a, somatostatin2, pdx1, ghrelin, and glucagon. Expression of preproinsulin a increased with PCB treatment in wildtype embryos, while expression of all measured pancreas genes was altered by the nrf2a mutant genotype, suggesting misregulation of the glucose homeostasis axis in those embryos, independent of PCB treatment. This study shows that embryonic exposure to PCB-126 can result in deviant development of the pancreatic islet and suggests that Nrf2a plays a role in regulating glucose homeostasis during development.
authors.affiliation: Department of Environmental Health Science, School of Public Health and Health Sciences, University of Massachusetts Amherst, Amherst, MA, 01003, USA. Electronic address: aliciat@umass.edu.
authors.forename: Alicia R
authors.initials: AR
authors.lastname: Timme-Laragy
authors.affiliation: Department of Environmental Health Science, School of Public Health and Health Sciences, University of Massachusetts Amherst, Amherst, MA, 01003, USA. Electronic address: ksant@umass.edu.
authors.forename: Karilyn E
authors.initials: KE
authors.lastname: Sant
authors.affiliation: Department of Environmental Health Science, School of Public Health and Health Sciences, University of Massachusetts Amherst, Amherst, MA, 01003, USA. Electronic address: merousse@umass.edu.
authors.forename: Michelle E
authors.initials: ME
authors.lastname: Rousseau
authors.affiliation: Department of Environmental Health Science, School of Public Health and Health Sciences, University of Massachusetts Amherst, Amherst, MA, 01003, USA.
authors.forename: Philip J
authors.initials: PJ
authors.lastname: diIorio
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified / Q000196:embryology; D004625:Embryo, Nonmammalian / Q000187:drug effects / Q000196:embryology; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects; D054439:Ghrelin / Q000235:genetics; D005934:Glucagon / Q000235:genetics; D018398:Homeodomain Proteins / Q000235:genetics; D050417:Insulin-Secreting Cells / Q000187:drug effects / Q000502:physiology; D051267:NF-E2-Related Factor 2; D011078:Polychlorinated Biphenyls / Q000009:adverse effects; D015534:Trans-Activators / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics; D015027:Zebrafish / Q000196:embryology; D029961:Zebrafish Proteins / Q000235:genetics
chemical_list: C023035:3,4,5,3',4'-pentachlorobiphenyl; D054439:Ghrelin; D005934:Glucagon; D018398:Homeodomain Proteins; D051267:NF-E2-Related Factor 2; C495638:nfe2l2a protein, zebrafish; C084010:pancreatic and duodenal homeobox 1 protein; D011078:Polychlorinated Biphenyls; D015534:Trans-Activators; D014157:Transcription Factors; D029961:Zebrafish Proteins
keywords: Ahr; Embryo; Endocrine; Gene expression; Insulin; Islet; Nrf2; Time-lapse