Implications of Lead (Pb)-Induced Transcriptomic and Phenotypic Alterations in the Aged Zebrafish ().

Lead (Pb) is a well-known neurotoxin with established adverse effects on the neurological functions of children and younger adults, including motor, learning, and memory abilities. However, its potential impact on older adults has received less attention. Using the zebrafish model, our study aims to characterize the dose-response relationship between environmentally relevant Pb exposure levels and their effects on changes in behavior and transcriptomics during the geriatric periods. We exposed two-year-old zebrafish to waterborne lead acetate (1, 10, 100, 1000, or 10,000 µg/L) or a vehicle (DMSO) for 5 days. While lower concentrations (1-100 µg/L) reflect environmentally relevant Pb levels, higher concentrations (1000-10,000 µg/L) were included to assess acute toxicity under extreme exposure scenarios. We conducted adult behavior assessment to evaluate the locomotor activity following exposure. The same individual fish were subsequently sacrificed for brain dissection after a day of recovery in the aquatic system. RNA extraction and sequencing were then performed to evaluate the Pb-induced transcriptomic changes. Higher (1000-10,000 ug/L) Pb levels induced hyperactive locomotor patterns in aged zebrafish, while lower (10-100 ug/L) Pb levels resulted in the lowest locomotor activity compared to the control group. Exposure to 100 µg/L led to the highest number of differentially expressed genes (DEGs), while 10,000 µg/L induced larger fold changes in both directions. The neurological pathways impacted by Pb exposure include functions related to neurotransmission, such as cytoskeletal regulation and synaptogenesis, and oxidative stress response, such as mitochondrial dysfunction and downregulation of heat shock protein genes. These findings emphasize a U-shape dose-response relationship with Pb concentrations in locomotor activity and transcriptomic changes in the aging brain.