In utero versus adult cadmium exposure: impacts on retinal structure, function, and ocular gene expression

Abstract

Purpose : Industrial and agricultural practices have contributed to an increased risk for exposure to the toxic heavy metal cadmium (Cd). In humans, exposure to Cd in both childhood and adulthood is associated with risk of visual dysfunction and retinal diseases. The causative effect of Cd exposure on retinal disease susceptibility has not been defined. This study tested the hypothesis that Cd exposure impacts retinal and ocular health when administered in utero versus during adulthood.

Methods : Cd was administered via drinking water, to females throughout pregnancy (in utero; 50mg/L) or for 1 year starting at 8 weeks of age (adult; 100mg/L). Retinal health was assessed in adults (optomotor reflex, full-field light-and dark-adapted electroretinography (ERG), and optical coherence tomography (OCT)(n=5/group)). Post-mortem, RNA was extracted from eyes from postnatal day 0 (P0) and adult male mice (n=4/group/age). Using suitable quality RNA, directional libraries were made, then sequencing performed to a predicted read depth of 30 million reads/sample using 150 base-pair paired end reads, followed by bioinformatics and pathway analysis. Retinal thickness was assessed in early postnatal eyes (P0 and P21) by histology on cryosections (n=3/group/age).

Results : Compared to unexposed mice, Cd exposed mice had no difference in water consumption and body weight. Adult Cd exposure had minimal effects on optomotor reflex, ERG amplitudes and OCT retinal layer thicknesses. In utero Cd exposure increased outer nuclear layer thickness at P0 and P21. RNA-Seq number of reads was 23.9±standard deviation (SD) 8.6 million paired end reads/sample, out of which 79.7±SD 4.7% were mapped. In utero Cd exposure resulted in 705 significantly differentially expressed genes (DEGs) in the eye, whereas adult exposure resulted in only 29 significantly DEGs. In utero pathways included downregulation of immune activity and upregulation of histone acetylation and apoptosis. There were no shared biological pathways between in utero and adult Cd exposed mice.

Conclusions : Early ocular development is more sensitive to Cd exposure than exposure during adulthood. In utero exposure impacts gene expression, and we have supporting evidence for direct epigenetic effects of Cd exposure in the eye, modifying retinal development.

This abstract was presented at the 2024 ARVO Annual Meeting, held in Seattle, WA, May 5-9, 2024.