Construction and evaluation of an AOP framework to explore cobalt-induced nonalcoholic fatty liver disease

With the rapid advancements of the new energy industry, cobalt demand has risen substantially, raising concerns about associated health risks. Epidemiological investigations have identified cobalt exposure as a risk factor for nonalcoholic fatty liver disease (NAFLD), yet the underlying mechanisms remain elusive. This study aimed to investigate the relationship between cobalt exposure and NAFLD and to elucidate its underlying mechanisms. Analysis of the NHANES 2017-2020 data revealed a positive association between urinary cobalt levels and NAFLD. To evaluate the biological plausibility, in vivo mouse experiments were conducted, providing evidence that cobalt exposure contributes to NAFLD development. To further elucidate the mechanistic pathways, an adverse outcome pathway (AOP) framework for cobalt-induced NAFLD was developed and evaluated. The AOP framework proposed that the activation of the peroxisome proliferator-activated receptor gamma (PPARγ) serves as a potential molecular initiating event (MIE), while dysregulations of lipid metabolism pathways are potential key events (KEs). Finally, in vivo and in vitro models corroborated that cobalt exposure increased PPARγ protein and downstream genes expression, leading to dysregulation of lipid metabolism pathways and lipid accumulation, thereby supporting the proposed AOP framework. These findings provide mechanistic insights into cobalt-induced NAFLD and may inform future environmental risk assessments.