{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T00:40:42Z","timestamp":1759970442157,"version":"build-2065373602"},"reference-count":34,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2025,1,17]],"date-time":"2025-01-17T00:00:00Z","timestamp":1737072000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"US Environmental Protection Agency"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biology"],"abstract":"<jats:p>Advancing our understanding of pancreatic toxicity and metabolic disorders caused by environmental exposures requires innovative approaches. The pancreas, a vital organ for glucose regulation, is increasingly recognized as a target of harm from environmental chemicals and dietary factors. Traditional toxicological methods, while foundational, often fail to address the mechanistic complexities of pancreatic dysfunction, particularly under real-world conditions involving multiple exposures. New Approach Methodologies (NAMs)\u2014including high-throughput screening (HTS), OMICS technologies, computational modeling, and advanced in vitro systems\u2014offer transformative tools to tackle these challenges. NAMs enable the identification of mechanistic pathways, improve testing efficiency, and reduce reliance on animal testing. This commentary explores the integration of NAMs into pancreatic toxicity screening, addresses critical gaps in evaluating the cumulative risks of chemical and dietary exposures, and proposes solutions for integrating the pancreas into toxicity screening through NAMs. By highlighting recent advancements and emphasizing their adoption in environmental toxicity assessment frameworks, this work demonstrates the potential of NAMs to revolutionize environmental health research, inspire interdisciplinary collaboration, and protect public health.<\/jats:p>","DOI":"10.3390\/biology14010085","type":"journal-article","created":{"date-parts":[[2025,1,17]],"date-time":"2025-01-17T03:33:02Z","timestamp":1737084782000},"page":"85","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Integrating New Approach Methodologies to Address Environmental Pancreatic Toxicity and Metabolic Disorders"],"prefix":"10.3390","volume":"14","author":[{"given":"Yue","family":"Ge","sequence":"first","affiliation":[{"name":"Center for Computational Toxicology and Exposure, US Environmental Protection Agency, Research Triangle Park, NC 27711, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,1,17]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"e219","DOI":"10.1038\/emm.2016.6","article-title":"Pancreatic regulation of glucose homeostasis","volume":"48","author":"Wu","year":"2016","journal-title":"Exp. Mol. Med."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"319","DOI":"10.1186\/s13046-018-0963-4","article-title":"Pancreatic cancer associated with obesity and diabetes: An alternative approach for its targeting","volume":"37","author":"Pothuraju","year":"2018","journal-title":"J. Exp. Clin. Cancer Res."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"53","DOI":"10.1016\/j.ejca.2020.11.040","article-title":"A review of lifestyle and environmental risk factors for pancreatic cancer","volume":"145","author":"Zanini","year":"2021","journal-title":"Eur. J. Cancer"},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Soriano, S., Alonso-Magdalena, P., Garc\u00eda-Ar\u00e9valo, M., Novials, A., Muhammed, S.J., Salehi, A., Gustafsson, J.A., Quesada, I., and Nadal, A. (2012). Rapid insulinotropic action of low doses of bisphenol-A on mouse and human islets of Langerhans: Role of estrogen receptor \u03b2. PLoS ONE, 7.","DOI":"10.1371\/journal.pone.0031109"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"30","DOI":"10.1016\/j.taap.2005.11.015","article-title":"Sodium arsenite impairs insulin secretion and transcription in pancreatic beta-cells","volume":"214","author":"Hiriart","year":"2006","journal-title":"Toxicol. Appl. Pharmacol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"52","DOI":"10.1186\/s12940-016-0136-x","article-title":"The association between phthalates and metabolic syndrome: The National Health and Nutrition Examination Survey 2001\u20132010","volume":"15","author":"Huang","year":"2016","journal-title":"Environ. Health"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"167","DOI":"10.1530\/JOE-13-0386","article-title":"High-fat diet aggravates glucose homeostasis disorder caused by chronic exposure to bisphenol A","volume":"221","author":"Ding","year":"2014","journal-title":"J. Endocrinol."},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"P\u00e1nico, P., Velasco, M., Salazar, A.M., Picones, A., Ortiz-Huidobro, R.I., Guerrero-Palomo, G., Salgado-Bernab\u00e9, M.E., Ostrosky-Wegman, P., and Hiriart, M. (2022). Is arsenic exposure a risk factor for metabolic syndrome? A review of the potential mechanisms. Front. Endocrinol., 13.","DOI":"10.3389\/fendo.2022.878280"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1048900","DOI":"10.3389\/ftox.2022.1048900","article-title":"Chemical testing using new approach methodologies (NAMs)","volume":"4","author":"Stucki","year":"2022","journal-title":"Front. Toxicol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"105470","DOI":"10.1016\/j.envint.2020.105470","article-title":"High-throughput screening tools facilitate calculation of a combined exposure-bioactivity index for chemicals with endocrine activity","volume":"137","author":"Wegner","year":"2020","journal-title":"Environ. Int."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"216","DOI":"10.1007\/s00125-007-0886-7","article-title":"The mechanisms of alloxan- and streptozotocin-induced diabetes","volume":"51","author":"Lenzen","year":"2008","journal-title":"Diabetologia"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"64","DOI":"10.1001\/jama.1974.03240010032024","article-title":"Liver damage and angiosarcoma in vinyl chloride workers: A systematic detection program","volume":"230","author":"Makk","year":"1974","journal-title":"JAMA"},{"key":"ref_13","first-page":"167","article-title":"Mortality and cancer morbidity in a group of Swedish VCM and PCV production workers","volume":"17","author":"Byren","year":"1976","journal-title":"Environ. Health Perspect."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"E527","DOI":"10.1152\/ajpendo.00233.2011","article-title":"Developmental exposure to di(2-ethylhexyl) phthalate impairs endocrine pancreas and leads to long-term adverse effects on glucose homeostasis in the rat","volume":"301","author":"Lin","year":"2011","journal-title":"Am. J. Physiol.-Endocrinol. Metab."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"E2643","DOI":"10.1210\/jc.2014-1683","article-title":"Polychlorinated biphenyl exposure and glucose metabolism in 9-year-old Danish children","volume":"99","author":"Jensen","year":"2014","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"245","DOI":"10.1016\/j.envres.2008.01.004","article-title":"Relationship between insulin sensitivity and exposure to dioxins and polychlorinated biphenyls in pregnant women","volume":"107","author":"Chen","year":"2008","journal-title":"Environ. Res."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"56","DOI":"10.1016\/j.scitotenv.2014.09.085","article-title":"Associations between exposure to polycyclic aromatic hydrocarbons and glucose homeostasis as well as metabolic syndrome in nondiabetic adults","volume":"505","author":"Hu","year":"2015","journal-title":"Sci. Total. Environ."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"3983","DOI":"10.1016\/j.apsb.2021.05.018","article-title":"A small molecule UPR modulator for diabetes identified by high throughput screening","volume":"11","author":"Marrocco","year":"2021","journal-title":"Acta Pharm. Sin. B"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"316","DOI":"10.1016\/j.slasd.2023.07.003","article-title":"Automated high-throughput, high-content 3D imaging of intact pancreatic islets","volume":"28","author":"McCarty","year":"2023","journal-title":"SLAS Discov."},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Lytrivi, M., Ghaddar, K., Lopes, M., Rosengren, V., Piron, A., Yi, X., Johansson, H., Lehti\u00f6, J., Igoillo-Esteve, M., and Cunha, D.A. (2020). Combined transcriptome and proteome profiling of the pancreatic \u03b2-cell response to palmitate unveils key pathways of \u03b2-cell lipotoxicity. BMC Genom., 21.","DOI":"10.1186\/s12864-020-07003-0"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1194","DOI":"10.1016\/j.cmet.2017.04.003","article-title":"Deciphering pancreatic islet \u03b2 cell and \u03b1 cell maturation pathways and characteristic features at the single-cell level","volume":"25","author":"Qiu","year":"2017","journal-title":"Cell Metab."},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Li, X., Du, Y., Jiang, W., Dong, S., Li, W., Tang, H., Yi, J., Zhou, W., and Zhang, H. (2023). Integrated transcriptomics, proteomics, and metabolomics-based analysis uncover TAM2-associated glycolysis and pyruvate metabolic remodeling in pancreatic cancer. Front. Immunol., 14.","DOI":"10.3389\/fimmu.2023.1170223"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"e2412040","DOI":"10.1001\/jamanetworkopen.2024.12040","article-title":"Prenatal exposure to chemical mixtures and metabolic syndrome risk in children","volume":"7","author":"Stratakis","year":"2024","journal-title":"JAMA Netw. Open."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"14235","DOI":"10.1038\/s41598-024-65161-7","article-title":"Machine-learning-guided recognition of \u03b1 and \u03b2 cells from label-free infrared micrographs of living human islets of Langerhans","volume":"14","author":"Azzarello","year":"2024","journal-title":"Sci. Rep."},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"MacFarlane, E.M., and Bruin, J.E. (2021). Human pluripotent stem cells: A unique tool for toxicity testing in pancreatic progenitor and endocrine cells. Front. Endocrinol., 11.","DOI":"10.3389\/fendo.2020.604998"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"705","DOI":"10.1242\/dev.086165","article-title":"Human pluripotent stem cells: An emerging model in developmental biology","volume":"140","author":"Zhu","year":"2013","journal-title":"Development"},{"key":"ref_27","first-page":"344","article-title":"Toxicity of organic and inorganic nickel in pancreatic cell cultures: Comparison to cadmium","volume":"70","author":"Wallace","year":"2020","journal-title":"Arch. Pharm."},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Essaouiba, A., Okitsu, T., Kinoshita, R., Jellali, R., Shinohara, M., Danoy, M., Legallais, C., Sakai, Y., and Leclerc, E. (2020). Development of a pancreas-liver organ-on-chip coculture model for organ-to-organ interaction studies. Biochem. Eng. J., 164.","DOI":"10.1016\/j.bej.2020.107783"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"447","DOI":"10.1016\/j.clnu.2004.02.006","article-title":"Dietary fat, insulin sensitivity, and the metabolic syndrome","volume":"23","author":"Riccardi","year":"2004","journal-title":"Clin. Nutr."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"528","DOI":"10.1111\/jdi.13976","article-title":"Can lipophilic pollutants in adipose tissue explain weight change-related risk in type 2 diabetes mellitus?","volume":"14","author":"Lee","year":"2023","journal-title":"J. Diabetes Investig."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"103","DOI":"10.1093\/toxsci\/kfad024","article-title":"Vinyl chloride enhances high-fat diet-induced proteome alterations in the mouse pancreas related to metabolic dysfunction","volume":"193","author":"Ge","year":"2023","journal-title":"Toxicol. Sci."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"194","DOI":"10.12688\/openreseurope.18439.1","article-title":"Unmasking metabolic disruptors: The NEMESIS project\u2019s quest for novel biomarkers, evidence on adverse effects, and efficient methodologies","volume":"4","author":"Levonen","year":"2024","journal-title":"Open Res. Eur."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"101735","DOI":"10.1016\/j.nantod.2022.101735","article-title":"Systems toxicology to advance human and environmental hazard assessment: A roadmap for advanced materials","volume":"48","author":"Amorim","year":"2023","journal-title":"Nano Today."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"tfae044","DOI":"10.1093\/toxres\/tfae044","article-title":"New approach methodologies (NAMs): Identifying and overcoming hurdles to accelerated adoption","volume":"13","author":"Sewell","year":"2024","journal-title":"Toxicol. Res."}],"container-title":["Biology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2079-7737\/14\/1\/85\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,8]],"date-time":"2025-10-08T10:30:26Z","timestamp":1759919426000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2079-7737\/14\/1\/85"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,1,17]]},"references-count":34,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2025,1]]}},"alternative-id":["biology14010085"],"URL":"https:\/\/doi.org\/10.3390\/biology14010085","relation":{},"ISSN":["2079-7737"],"issn-type":[{"type":"electronic","value":"2079-7737"}],"subject":[],"published":{"date-parts":[[2025,1,17]]}}}