Abstract
Purpose :
Redox homeostasis plays an important role in modulating retinal physiology and photoreceptor (PR) viability during early developmental stages. Prenatal alcohol exposure is associated with maternal antioxidant depletion and disrupted adolescent circadian rhythms, as observed in fetal alcohol spectrum disorders (FASD). Developmental ethanol (EtOH) exposure produces damaging effects on visual function and is associated with proteostasis dysfunction in a zebrafish model of FASD. The purpose of this study was to investigate the connection between ethanol damage, time-of-day vulnerability to damage, and the interaction between redox homeostasis and proteostasis in retinal dysfunction.
Methods :
Zebrafish entrained to a 12:12 light–dark (LD) cycle were exposed to either daytime or nighttime treatments of 1% EtOH from 5-7 days post-fertilization. The functional effects of EtOH were assessed by optomotor response (OMR) assays and electroretinogram (ERG) recordings in intact zebrafish larvae at 2- and 3 days post-exposure. Whole eyes samples (n=8-10) were collected at zeitgeber time (ZT) 6 and 18 at 2 days post-exposure to determine time-of-day differences in gene expression via RT-qPCR.
Results :
Exposure to repeated daytime bouts of 1% EtOH significantly reduced OMR visual performance compared to control and nighttime exposure. After recovery, the maximum b-wave amplitudes for daytime exposure were attenuated by 39±10% and 50±8% compared to control and nighttime exposure (p<0.05, n=4, respectively. We also observed transcript differences at ZT6 and ZT18 in whole eye tissue for a subset of genes related to redox homeostasis known to display diurnal rhythms, specifically: cellular regulator of oxidant level and oxidant signaling, nrf2 (p<0.05, n=4), ubiquitin E3 ligase, park2 (p<0.05, n=4), and the melatonin synthesis enzyme, aanat2 (p<0.05, n=4). Co-treatment with 10 μM melatonin during daytime bouts protected against some damaging effects of EtOH on visual function revealed by OMR visual performance.
Conclusions :
Altogether, these results demonstrate that time-of-day vulnerability to EtOH damage in retinal neurons is influenced by redox homeostasis and may involve mechanisms associated with melatonin signaling and modulation of proteostasis under oxidative stress.
This abstract was presented at the 2024 ARVO Annual Meeting, held in Seattle, WA, May 5-9, 2024.