Publication:
Modulating Glutathione Thiol Status Alters Pancreatic β-cell Morphogenesis in the Developing Zebrafish (Danio rerio) Embryo

Simple item page
dc.contributor.authorRastogi, Archit
dc.contributor.authorSeverance, Emily G.
dc.contributor.authorJacobs, Haydee M.
dc.contributor.authorConlin, Sarah M.
dc.contributor.authorIslam, Sadia T.
dc.contributor.authorTimme-Laragy, Alicia R.
dc.contributor.departmentUniversity of Massachusetts Amherst
dc.contributor.departmentUniversity of Massachusetts Amherst
dc.contributor.departmentUniversity of Massachusetts Amherst
dc.contributor.departmentUniversity of Massachusetts Amherst
dc.contributor.departmentUniversity of Massachusetts Amherst
dc.contributor.departmentUniversity of Massachusetts Amherst
dc.date2023-09-24T09:19:48.000
dc.date.accessioned2024-04-26T16:35:37Z
dc.date.available2022-09-26T00:00:00Z
dc.date.issued2021-01-01
dc.description.abstractEmerging evidence suggests that redox-active chemicals perturb pancreatic islet development. To better understand potential mechanisms for this, we used zebrafish (Danio rerio) embryos to investigate roles of glutathione (GSH; predominant cellular redox buffer) and the transcription factor Nrf2a (Nfe2l2a; zebrafish Nrf2 coortholog) in islet morphogenesis. We delineated critical windows of susceptibility to redox disruption of beta-cell morphogenesis, interrogating embryos at 24, 48 and 72 h post fertilization (hpf) and visualized Nrf2a expression in the pancreas using whole-mount immunohistochemistry at 96 hpf. Chemical GSH modulation at 48 hpf induced significant islet morphology changes at 96 hpf. Pro-oxidant exposures to tert-butylhydroperoxide (77.6 mu M; 10-min at 48 hpf) or tert-butylhydroquinone (1 mu M; 48-56 hpf) decreased beta-cell cluster area at 96 hpf. Conversely, exposures to antioxidant N-acetylcysteine (bolsters GSH pools; 100 mu M; 48-72 hpf) or sulforaphane (activates Nrf2a; 20 mu M; 48-72 hpf) significantly increased islet areas. Nrf2a was also stabilized in beta-cells: 10-min exposures to 77.6 mu M tert-butylhydroperoxide significantly increased Nrf2a protein compared to control islet cells that largely lack stabilized Nrf2a; 10-min exposures to higher (776 mu M) tert-butylhydroperoxide concentration stabilized Nrf2a throughout the pancreas. Using biotinylated-GSH to visualize in situ protein glutathionylation, islet cells displayed high protein glutathionylation, indicating oxidized GSH pools. The 10-min high (776 mu M) tert-butylhydroperoxide exposure (induced Nrf2a globally) decreased global protein glutathionylation at 96 hpf. Mutant fish expressing inactive Nrf2a were protected against tert-butylhydroperoxide-induced abnormal islet morphology. Our data indicate that disrupted redox homeostasis and Nrf2a stabilization during pancreatic beta-cell development impact morphogenesis, with implications for disease states at later life stages. Our work identifies a potential molecular target (Nrf2) that mediates abnormal beta-cell morphology in response to redox disruptions. Moreover, our findings imply that developmental exposure to exogenous stressors at distinct windows of susceptibility could diminish the reserve redox capacity of beta-cells, rendering them vulnerable to later-life stresses and disease.
dc.description.sponsorshipNational Institutes of HealthUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USA [R01ES025748]
dc.identifier.doihttps://doi.org/10.1016/j.redox.2020.101788
dc.identifier.issn2213-2317
dc.identifier.orcidRastogi, Archit/0000-0002-2572-3227; Severance, Emily/0000-0002-1531-7575
dc.identifier.urihttps://hdl.handle.net/20.500.14394/22952
dc.relation.ispartofREDOX BIOLOGY
dc.relation.urlhttps://scholarworks.umass.edu/cgi/viewcontent.cgi?article=1034&context=ehs_faculty_pubs&unstamped=1
dc.rightsUMass Amherst Open Access Policy
dc.rights.urihttp://creativecommons.org/licenses/by-nc-nd/4.0/
dc.source.issue38
dc.source.statuspublished
dc.subjectREDOX DYNAMICS
dc.subjectNRF2
dc.subjectSTRESS
dc.subjectIDENTIFICATION
dc.subjectORGANOGENESIS
dc.subjectACTIVATION
dc.subjectINTERFACE
dc.subjectPROTEINS
dc.subjectEXPOSURE
dc.subjectSYSTEM
dc.subjectBiochemistry
dc.subjectMolecular Biology
dc.titleModulating Glutathione Thiol Status Alters Pancreatic β-cell Morphogenesis in the Developing Zebrafish (Danio rerio) Embryo
dc.typearticle
dc.typearticle
digcom.contributor.authorRastogi, Archit
digcom.contributor.authorSeverance, Emily G.
digcom.contributor.authorJacobs, Haydee M.
digcom.contributor.authorConlin, Sarah M.
digcom.contributor.authorIslam, Sadia T.
digcom.contributor.authorisAuthorOfPublication|email:aliciat@schoolph.umass.edu|institution:University of Massachusetts Amherst|Timme-Laragy, Alicia R.
digcom.date.embargo2022-09-26T00:00:00-07:00
digcom.identifierehs_faculty_pubs/35
digcom.identifier.contextkey31470038
digcom.identifier.submissionpathehs_faculty_pubs/35
dspace.entity.typePublication
relation.isAuthorOfPublication176d7f65-6c41-4ef7-adb1-64dc81d64eea
relation.isAuthorOfPublication.latestForDiscovery176d7f65-6c41-4ef7-adb1-64dc81d64eea
Files
Original bundle
Now showing 1 - 1 of 1
Thumbnail Image
Name:
1_s2.0_S2213231720309939_main.pdf
Size:
9.37 MB
Format:
Adobe Portable Document Format
Thumbnail Image
Name: 1_s2.0_S2213231720309939_main.pdf
Size: 9.37 MB
Kind: Adobe PDF
Collections
Environmental Health Sciences Faculty Publication Series