Exogenous All-Trans Retinoic Acid Induces Myopia and Alters Scleral Biomechanics in Mice

• Type of Material: Article
• Authors: Dillon M Brown, Emory University; Jianshi Yu, University of Maryland School of Pharmacy; Praveen Kumar, University of Maryland School of Pharmacy; Quinn M Paulus, Atlanta Veterans Affairs Healthcare System; Michael A Kowalski, Emory University School of Medicine; Jay Patel, Emory University; Maureen A Kane, University of Maryland School of Pharmacy; Christopher Ethier, Emory University; Machelle Pardue, Emory University
• Language: English
• Date: 2023-05-01
• Publisher: Emory University Libraries
• Publication Version: Final Published Version
• Copyright Statement: 2023 The Authors
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1167/iovs.64.5.22
• Title of Journal or Parent Work: Investigative Ophthalmology and Visual Science
• Volume: 64
• Issue: 5
• Start Page: 22
• End Page: 22
• Keywords: Myopia; Male; Biomechanical Phenomena; Mice, Inbred C57BL; Mice; Refractive Errors; Sclera; Animals
• Research Categories: Engineering, Biomedical; Chemistry, Pharmaceutical

Abstract

PURPOSE. Ocular all-trans retinoic acid (atRA) levels are influenced by visual cues, and exogenous atRA has been shown to increase eye size in chickens and guinea pigs. However, it is not clear whether atRA induces myopic axial elongation via scleral changes. Here, we test the hypothesis that exogenous atRA will induce myopia and alter scleral biomechanics in the mouse. METHODS. Male C57BL/6J mice were trained to voluntarily ingest atRA + vehicle (1% atRA in sugar, 25 mg/kg) (RA: n = 16 animals) or vehicle only (Ctrl: n = 14 animals). Refractive error (RE) and ocular biometry were measured at baseline and after 1 and 2 weeks of daily atRA treatment. Eyes were used in ex vivo assays to measure scleral biomechanics (unconfined compression: n = 18), total scleral sulfated glycosaminoglycan (sGAG) content (dimethylmethylene blue: n = 23), and specific sGAGs (immunohistochemistry: n = 18). RESULTS. Exogenous atRA caused myopic RE and larger vitreous chamber depth (VCD) to develop by 1 week (RE: −3.7 ± 2.2 diopters [D], P < 0.001; VCD: +20.7 ± 15.1 μm, P < 0.001), becoming more severe by 2 weeks (RE: −5.7 ± 2.2 D, P < 0.001; VCD: +32.3 ± 25.8 μm, P < 0.001). The anterior eye biometry was unaffected. While scleral sGAG content was not measurably affected, scleral biomechanics were significantly altered (tensile stiffness: −30% ± 19.5%, P < 0.001; permeability: +60% ± 95.3%, P < 0.001). CONCLUSIONS. In mice, atRA treatment results in an axial myopia phenotype. Eyes developed myopic RE and larger VCD without the anterior eye being affected. The decrease in stiffness and increase in permeability of the sclera are consistent with the form-deprivation myopia phenotype.