Proteome signatures of joint toxicity to arsenic (As) and lead (Pb) in human brain organoids with optic vesicles

Abstract

Arsenic (As) and lead (Pb) are toxins found in the natural surroundings, and the harmful health outcomes caused by the co-exposure of such toxins have become a considerable problem. However, the joint neurotoxicity of As and Pb to neurodevelopment and the underlying mechanisms remain unclear. Pluripotent stem cell-derived human brain organoids are emerging animal model alternatives for understanding neurological-related diseases. Therefore, we utilized brain organoids with optic vesicles (OVB-organoids) to systematically analyze the neurotoxicity of As and Pb. After 24 h of As and/or Pb exposure, hematoxylin-eosin staining revealed that As and Pb exposure could cause disorders in the structure of the ventricular zone and general cell disarrangement in OVB-organoids. Immunostaining displayed that OVB-organoids are more susceptible to As and Pb co-exposure than independent exposure in apoptosis, proliferation, and cell differentiation. Meanwhile, even though As and Pb could both hinder cell proliferation, contrary to Pb, As could induce an increasing proportion of mitotic (G2/M) cells. The proteome landscape of OVB-organoids illustrated that Pb synergized with As in G2/M arrest and the common role of As and Pb in carcinogenesis. Besides, proteomics analyses suggested the consequential role of autophagy and Wnt pathway in the neurotoxicity of As and Pb co-exposure. Overall, our findings provide penetrating insights into the cell cycle, carcinogenesis, autophagy, and Wnt pathway underlying the As and Pb binary exposure scenarios, which could enhance our understanding of the mixture neurotoxicity mechanisms.