Aluminum Induced Higher Neurotoxicity than Nano-Alumina During Early Development in Zebrafish, Exacerbated by Trem2 Knockdown.

Early exposure to toxic substances is a known risk factor for neurotoxicity. The present study is aimed at exploring the neurotoxicity of nano-alumina (AlNPs) and aluminum chloride (AlCl3) in zebrafish at 144 h post-fertilization (hpf) and at investigating the role of the type II triggering receptor expressed on myeloid cells (trem2) among them. Zebrafish embryos within the four-cell stage were exposed to control, negative control, trem2 knockdown, AlCl3, AlCl3 + trem2 knockdown, AlNPs, and AlNPs + trem2 knockdown until 144 hpf. 500 pL of lentivirus containing trem2 inhibitor at 5 × 108 TU/mL was microinjected into the yolk sacs to achieve trem2 knockdown. AlCl3 and AlNPs were applied at 50 mg/L. Neurobehavior, AChE and SOD levels, and the expression of trem2 and neurodevelopmental genes were measured. AlNPs significantly increased the average speed while decreasing the absolute angle compared to AlCl3. Upon trem2 knockdown, time spent in the outer zone, distance travelled, and accelerated speed were further reduced in both AlCl3 and AlNPs groups. The trem2 loss also exacerbated the suppression of AChE and SOD levels, trem2, α1-tubulin, and mbp gene levels in the AlCl3 and AlNPs groups. In conclusion, AlCl3 induced higher neurotoxicity than AlNPs, and these effects were intensified by trem2 knockdown. Studying larvae allows us to capture neurodevelopmental disturbances during critical stages of brain formation, offering a more comprehensive assessment of the risks and therapeutic potential of targeting trem2 in Al- and AlNPs-induced neurotoxicity.