Putative adverse outcome pathways of the male reproductive toxicity derived from toxicological studies of perfluoroalkyl acids.

Adverse outcome pathway (AOP) as a conceptual framework is a powerful tool in the field of toxicology to connect seemingly discrete events at different levels of biological organizations into an organized pathway from molecular interactions to whole organism toxicity. Based on numerous toxicological studies, eight AOPs for reproductive toxicity have been endorsed by the Organization for Economic Co-operation and Development (OECD) Task Force on Hazard Assessment. We have conducted a literature survey on the mechanistic studies on male reproductive toxicity of perfluoroalkyl acids (PFAAs), a class of global environmental contaminants with high persistence, bioaccumulation and toxicity. Using the AOP development strategy, five new AOPs for male reproductive toxicity were proposed here, namely (1) changes in membrane permeability leading to reduced sperm motility, (2) disruption of mitochondrial function leading to sperm apoptosis, (3) decreased gonadotropin-releasing hormone (GnRH) expression in hypothalamus leading to reduced testosterone production in male rats, (4) activation of the p38 signaling pathway leading to disruption of BTB in mice, (5) inhibition of p-FAK-Tyr407 activity leading to the destruction of BTB. The molecular initiating events in the proposed AOPs are different from those in the endorsed AOPs, which are either receptor activation or enzyme inhibition. Although some of the AOPs are still incomplete, they can serve as a building block upon which full AOPs can be developed and applied to not only PFAAs but also other chemical toxicants with male reproductive toxicity.