A toxicity pathway-based approach for modeling the mode of action framework of lead-induced neurotoxicity

The underlying mechanisms of lead (Pb) toxicity are not fully understood, which makes challenges to the traditional risk assessment. There is growing use of the mode of action (MOA) for risk assessment by integration of experimental data and system biology. The current study aims to develop a new pathway-based MOA for assessing Pb-induced neurotoxicity.

The available Comparative Toxicogenomic Database (CTD) was used to search genes associated with Pb-induced neurotoxicity followed by developing toxicity pathways using Ingenuity Pathway Analysis (IPA). The spatiotemporal sequence of disturbing toxicity pathways and key events (KEs) were identified by upstream regulator analysis. The MOA framework was constructed by KEs in biological and chronological order.

There were a total of 71 references showing the relationship between lead exposure and neurotoxicity, which contained 2331 genes. IPA analysis showed that the neuroinflammation signaling pathway was the core toxicity pathway in the enriched pathways relevant to Pb-induced neurotoxicity. The upstream regulator analysis demonstrated that the aryl hydrocarbon receptor (AHR) signaling pathway was the upstream regulator of the neuroinflammation signaling pathway (11.76% overlap with upstream regulators, |Z-score|=1.451). Therefore, AHR activation was recognized as the first key event (KE1) in the MOA framework. The following downstream molecular and cellular key events were also identified. The pathway-based MOA framework of Pb-induced neurotoxicity was built starting with AHR activation, followed by an inflammatory response and neuron apoptosis.

Our toxicity pathway-based approach not only advances the development of risk assessment for Pb-induced neurotoxicity but also brings new insights into constructing MOA frameworks of risk assessment for new chemicals.