Abstract
Purpose :
Both correlational and causal evidence support a connection between increased ocular retinoic acid (RA) concentrations and myopic axial elongation in mammals; however, RA’s effects on scleral biomechanics, influential to eye size, are not known. Here, we treated mice with all-trans RA (atRA) to test the hypothesis that exogenous atRA alters scleral biomechanics and causes myopia in mice.
Methods :
Male C57BL/6J mice (n=10) were trained to voluntarily ingest sugar pellets and were fed daily (2.5 g pellet/kg) from P29 to P44/45. Pellets dosed with atRA (added at a 1:100 ratio prior to forming pellets) were introduced between P30-31 in a randomly selected subset of animals (n=6 atRA, n=4 control), yielding a daily 25 mg atRA/kg dose. Refractive error (RE) was measured once per week beginning prior to atRA treatment. From a subset of animals (n=8), one eye per animal was randomly selected for biomechanical measurements (n=4 control, n=4 atRA). After sacrifice, sclerae were isolated for biomechanical quantification of tensile stiffness and permeability using unconfined compression and a biphasic material model.
Results :
All animals voluntarily ingested the pellets. Oral atRA treatment significantly influenced RE development (interaction: treatment*age, p<0.001), leading to relative myopia at 1 week compared to the control mice (mean±STD, 0.3±2.7 vs 4.3±0.4D, p=0.024), with the difference increasing at 2 weeks (-1.0±2.6 vs 6.3±0.1D, p<0.001). Changes in RE were accompanied by significantly altered scleral biomechanical properties. Sclerae from atRA fed animals were significantly less stiff compared to control sclerae (95% CI, [83.8, 118] vs [131.6, 186]kPa, p<0.001). Permeability trended towards increasing with atRA treatment but did not reach significance (95% CI, [3.9, 7.4] vs [2.9, 5.5]m2 *10-18, p=0.18).
Conclusions :
Exogenous atRA is highly myopigenic in mice, a novel result that corroborates previous findings in guinea pigs. Further, we show for the first time that atRA affects scleral biomechanics, indicative of scleral remodeling. The decreased tensile stiffness of the sclera accompanying the atRA-induced myopia is comparable to that measured in mammals experiencing sustained myopigenic visual cues, e.g., form deprivation and lens defocus. This work motivates additional study into the role of RA in the retinoscleral signaling cascade that enables myopigenic visual cues to influence eye size.
This is a 2021 ARVO Annual Meeting abstract.