Adverse outcome pathways of PBDEs inducing male reproductive toxicity

Polybrominated diphenyl ethers (PBDEs) are widely used brominated flame retardants, they are easily released into environment and causing adverse effects to the ecosystem and human health. This review aims to summarize the research status of PBDEs-induced male reproductive toxicity and its mechanisms at various levels such as molecular/cellular, tissue/organ and individual/population. The Adverse Outcome Pathways (AOPs) diagram showed that PBDEs-induced reactive oxygen species (ROS) production, disruptions of estrogen receptor-alpha (ER alpha) and antagonism of androgen receptor (AR) were defined as critical molecular initiating events (MIEs). They caused key events (KEs) at the molecular and cellular levels, including oxidative stress, increased DNA damage, damaging mitochondria, increased glycolipid levels and apoptosis, depletion of ectoplasmic specialization and decreased Leydig cells numbers. These in turn lead to followed KEs at the tissue or organ levels, such as the impaired spermatogenesis, impaired blood-testis barrier and reduced testosterone synthesis and function. As a result, reproductive system-related adverse outcomes (AOs) were reported, such as the decreased sperm quantity or quality, shorten male anogenital distance and cryptorchidism in individual and reduced reproduction of the population. This review assembled information on the mechanisms of male reproductive toxicity induced by PBDEs, and constructed a causal mechanism relationship diagram from different levels using the an AOP framework to provide theoretical basis for ecological risk assessment and environmental management of PBDEs. The AOP framework makes it possible to develop risk management strategies based on toxicity mechanisms and support for development of Integrated Approach to Testing and Assessment (IATA) which are available for regulatory purposes.