Chronic low-dose cadmium exposure induces neurodevelopmental impairment in hESC-derived retinal organoids

Cadmium, a heavy metal environmental toxin known for its neurotoxic effects on the central nervous system, is implicated in multiple eye diseases, including cataracts, glaucoma, and age-related macular degeneration. However, due to the lack of suitable experimental models, there is limited data on the impact of cadmium exposure on human retinal development. Human retinal organoids accurately mimic the 3D architecture of early fetal retinal tissue, making them suitable for investigating developmental retinal toxicity in the context of maternal cadmium exposure. This study found that cadmium exposure caused a dose- and time-dependent reduction in neural retina thickness and retinal organoid volume. And cadmium exposure specifically induced retinal cell apoptosis, inhibited retinal progenitor cell proliferation, and affected ganglion cell differentiation. After four weeks of cadmium exposure, retinal organoids exhibited abnormal cell distribution, disorganized neural retina structure, and generated rosette-like structures. Transcriptomic analysis revealed that cadmium exposure upregulated the expression of metallothioneins, profoundly disrupted ion homeostasis in retinal cells, and potentially suppressed the development of human retinal organoid by modulating pathways involved in environmental information processing. Overall, this study established a versatile and straightforward experimental model for assessing the influence of environmental toxic substances on human embryonic retinal development, and preliminarily elucidated the toxic effects and molecular mechanisms of long-term, low-dose cadmium exposure on the initial neurogenesis of the human retina.