Chemical Exacerbation of Light-induced Retinal Degeneration in F344/N Rats in National Toxicology Program Rodent Bioassays

Abstract

Retinal degeneration due to chronic ambient light exposure is a common spontaneous age-related finding in albino rats, but it can also be related to exposures associated with environmental chemicals and drugs. Typically, light induced retinal degeneration has a central/hemispherical localization where as chemical induced retinal degeneration has a diffuse localization. This study was conducted to identify National Toxicology Program (NTP) rodent bioassays with treatment-related retinal degeneration, and to characterize the retinal lesions related to these retinal toxicities. A total of 3 chronic bioassays in F344/N rats were identified that had treatment-related increases in retinal degeneration (kava kava extract, acrylamide, and leucomalachite green). A retrospective light-microscopic evaluation of the retinas from rats in these three studies showed a dose-related increase in the frequencies of retinal degeneration, beginning with the loss of photoreceptor cells, followed by the inner nuclear layer cells. These dose-related increased frequencies of degenerative retinal lesions localized within the central/hemispherical region are suggestive of exacerbation of light-induced retinal degeneration.

Reduced Disc Shedding and Phagocytosis of Photoreceptor Outer Segment Contributes to Kava Kava Extract–induced Retinal Degeneration in F344/N Rats

“…Pramipexole dihydrochloride, a dopamine agonist, induces retinal degeneration in albino rats by reducing the rate of phagocytosis, and its severity is increased by enhanced light intensity (FDA 1997a(FDA , 2013. A retrospective evaluation of rat retinas from the 2-year NTP KKE bioassay indicated that chronic KKE exposure exacerbated light-induced retinal degeneration since the frequency of retinal degeneration was increased in a dose-dependent manner and the distribution and morphology (but not severity) of retinal degeneration was similar to the changes observed in light-induced retinal degeneration reported in albino rats (Yamashita et al 2016). In this study, phagocytosis of photoreceptor outer segment was decreased only in the superior retina, which is more sensitive to light damage than the inferior retina (Tanito et al 2008).…”

“…The degeneration consisted of a thinning and loss of the external retinal layers, such as the photoreceptors and external nuclear layers, with a decreased cellularity and disorganization of the remaining retinal layers (NTP 2012). A retrospective evaluation of rat retinas from the 2-year NTP KKE bioassay indicated the distribution and morphology of retinal degeneration was similar to the changes observed in light-induced retinal degeneration reported in albino rats (Yamashita et al 2016). Therefore, it was hypothesized that KKE has the potential to exacerbate the lightinduced retinal degeneration.…”

“…Frequency of Retinal Degeneration in Male and Female F344/N Rats Treated with Kava Kava Extract by Gavage for Two Years(Yamashita et al 2016).…”

Conflict of interest: the authors declare no conflict of interest.

“…У пигментированных животных после длительного воздействия света не обнаруживаются какие-либо морфологические изменения, в то время как у альбиносов развивается дегенерация сетчатки. Интересным является тот факт, что воздействие света может дополнитель- но усиливать дегенеративные процессы в сетчатке как у химически-индуцированных моделей, так и у генетических моделей [29,40,41,48].…”

Is It Adverse, Nonadverse, Adaptive, or Artifact?

“…Retinal degeneration due to light exposure is a common spontaneous finding in albino rodents. However, the finding can be seen as a xenobiotic-induced exacerbation (Yamashita et al ., 2016). In general, light-induced retinal degeneration is manifested as localized lesion and is limited to superior-temporal regions, especially when not in the advanced stage of lesion development; whereas xenobiotic induced retinal degeneration is more diffuse (De Vera Mudry et al ., 2013).…”