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Despite evidence of their toxicity, whether these vitamin A cycle byproducts contribute to retinal disease, are symptoms, beneficial, or benign has been debated. We delivered a representative vitamin A byproduct, A2E, to the rat's retina and monitored electrophysiological, histological, proteomic, and transcriptomic changes. We show that the vitamin A cycle byproduct is sufficient alone to damage the RPE, photoreceptor inner and outer segments, and the outer plexiform layer, cause the formation of sub-retinal debris, alter transcription and protein synthesis, and diminish retinal function. The presented data are consistent with the theory that the formation of vitamin A byproducts during the vitamin A cycle is neither benign nor beneficial but may be sufficient alone to cause the most prevalent forms of retinal disease. Retarding the formation of vitamin A byproducts could potentially address the root cause of several retinal diseases to eliminate the threat of irreversible blindness for millions of people.<\/jats:p>","DOI":"10.1242\/bio.058600","type":"journal-article","created":{"date-parts":[[2021,11,29]],"date-time":"2021-11-29T10:12:10Z","timestamp":1638180730000},"source":"Crossref","is-referenced-by-count":6,"title":["Vitamin A cycle byproducts explain retinal damage and molecular changes thought to initiate retinal degeneration"],"prefix":"10.1242","volume":"10","author":[{"given":"Dan","family":"Zhang","sequence":"first","affiliation":[{"name":"Columbia University Medical Center, Ophthalmology, New York, NY 10032, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Doina M.","family":"Mihai","sequence":"additional","affiliation":[{"name":"Columbia University Medical Center, Ophthalmology, New York, NY 10032, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2238-7918","authenticated-orcid":false,"given":"Ilyas","family":"Washington","sequence":"additional","affiliation":[{"name":"Columbia University Medical Center, Ophthalmology, New York, NY 10032, USA"},{"name":"biOOrg3.14, Buffalo, WY 82834, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"237","published-online":{"date-parts":[[2021,11,29]]},"reference":[{"key":"2021120611360971000_BIO058600C1","doi-asserted-by":"publisher","first-page":"425","DOI":"10.1172\/JCI69404","article-title":"Melanocyte-secreted fibromodulin promotes an angiogenic microenvironment","volume":"124","author":"Adini","year":"2014","journal-title":"J. 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