Combining in vitro assays and mathematical modelling to study developmental neurotoxicity induced by chemical mixtures

• DOI: 10.1016/j.reprotox.2021.08.007
• Publication Date: 2021-08-26T15:32:23Z
• Authors: Francesca Pistollato; Donatella Carpi; Emilio Mendoza-de...; Alicia Paini; Stephanie K. Bopp; Andrew Worth; Anna Bal-Price
• Keywords: Neurotoxicity; Synaptogenesis; Neurite

Prenatal and postnatal co-exposure to multiple chemicals at the same time may have deleterious effects on developing nervous system. We previously showed that acting through similar mode of action (MoA) grouped based perturbation brain derived neurotrophic factor (BDNF), induced greater neurotoxic human pluripotent stem cell (hiPSC)-derived neurons astrocytes compared with dissimilar MoA. Here we assessed repeated dose (14 days) treatments mixtures containing six tested in our previous study (Bisphenol A, Chlorpyrifos, Lead(II) chloride, Methylmercury PCB138 Valproic acid) along 2,2'4,4'-tetrabromodiphenyl ether (BDE47), Ethanol, Vinclozolin 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)), hiPSC-derived neural cells undergoing differentiation toward mixed neurons/astrocytes up 21 days. Similar MoA caused an increase BDNF levels neurite outgrowth, a decrease synapse formation, which led inhibition electrical activity. Perturbations these endpoints are described as common key events adverse outcome pathways (AOPs) specific for DNT. When study, adding similarly (BDE47 EtOH) mixture resulted stronger downregulation synapses. A synergistic effect some synaptogenesis-related features (PSD95 particular) was hypothesized upon treatment mixtures, indicated by mathematical modelling. Our findings confirm use iPSC-derived neuronal/glial models applied battery vitro assays anchored DNT AOP networks, combined modelling, is suitable testing strategy assess chemical mixtures.