Retinopathic effects of 2-aminooxy propionic acid derivatives in the rat

Abstract

Administration of methyl 2-(ureidooxy) propionate caused retinal lesions in male rats after 21 days of feeding at 2500 ppm (160 mg/kg/day). Retinal lesions were also apparent after 28 days of feeding at 1500 ppm (125 mg/kg/day), after 91 days of feeding at 1000 or 500 ppm (75 or 40 mg/kg/day), and after 10 intragastric intubations of 1000 mg/kg body wt/day. Single oral doses as high as 4000 mg/kg had no effect on the retina. Of three similar compounds tested in 20-day feeding studies for retinopathic activity, p-nitrophenyl 2-(aminooxy) propionate (2500 ppm, 230 mg/kg/day) was inactive. Methyl 2-(cinnamidooxy) propionate and methyl 2-(acetamidooxy) propionate at the same dose and duration produced lesions similar to those with methyl 2-(ureidooxy) propionate but differing in magnitude. With light microscopy, the lesions produced were characterized by focal migrations of the outer nuclear cells into outer photoreceptor segments. This migration appeared to be a result of displacement due to loss of the outer photoreceptor segments, since under electron microscopy, the primary target sites appeared to be the lamellar disks of the outer photoreceptor segments and the inner segments were less damaged. With electron microscopy, photoreceptor nuclei migrated into the area of destroyed outer segments and apposed to the pigment cells. Some photoreceptor nuclei showed pycnosis and karyorrhexis. Retinal pigment cells exhibited disruption of cytoplasmic processes, cytoplasmic vacuolation, and numerous phagosomes which contained the degraded outer photoreceptor segments.