Revealing an adverse outcome pathway network for reproductive toxicity induced by atrazine, via oxidative stress

Abstract

Adverse outcome pathway AOPs are conceptual frameworks that organize scientific knowledge about how stressors disrupt specific biological targets, pathways. AOP network consists of two or more AOPs that share common key events (KEs), including crucial events like molecular initiating events (MIEs) and adverse outcomes (AOs), which offer the opportunity to link toxicological pathways. Thus, to better understand the sequential series of KEs involved in the AOP 492 (https://aopwiki.org/aops/492), which is triggered by atrazine (ATZ), we first generated a Reproductive Toxicity via Oxidative Stress (RTOS) AOP network from individual AOPs published in the AOP-Wiki database, using this AOP as a seed. The KEs “Increased, Reactive oxygen species” and “Apoptosis” were considered the most common/highly connected KE within this network and an important point of divergence. Furthermore, “Increased, DNA damage and mutations” is a critical KE within the network, as it is highly connected and central, and represents a point of divergence. This suggests that these three KEs have a high predictive value and could, for example, serve as a basis for the development/selection of in vitro assays to assess reproductive toxicity. The in silico analyses revealed that the pivotal target proteins for ATZ-induced infertility via oxidative stress in humans are Tp53, Bcl2, Esr1, and Nos3, which interact indirectly with ATZ via intermediary factors such as Mapk3, Mapk1, and Cyp19a1. Further, the gene enrichment analyses indicate that these entities are involved in several biological processes and pathways directly associated with oxidative stress, DNA damage and apoptosis, further reinforcing the developed network.