PPARα Activation-Mediated Testosterone Reduction as the Key Adverse Outcome Pathway for Cd-Induced Male Infertility:...

Area of Science:

• Environmental Toxicology
• Reproductive Toxicology
• Network Toxicology

Background:

• Cadmium (Cd) is a known reproductive toxicant, but its precise mechanisms for inducing male infertility are not fully understood.
• A systematic construction of an adverse outcome pathway (AOP) network for Cd-induced male infertility has been lacking.

Purpose of the Study:

• To construct a comprehensive AOP network for Cd-induced male infertility.
• To identify the key AOP responsible for Cd-induced male infertility using an integrated approach.

Main Methods:

• Network toxicology, single-cell sequencing, National Health and Nutrition Examination Survey (NHANES) data analysis, animal experiments, and molecular modeling.
• Construction of an AOP network comprising 9 AOPs.
• Prioritization of key molecular initiating events (MIEs) and pathways.

Main Results:

• The study identified a key AOP: PPARα activation leads to testosterone reduction and subsequent male infertility.
• Single-cell sequencing revealed downregulation of testosterone synthesis genes in Cd-exposed Leydig cells.
• NHANES data indicated a threshold effect of blood Cd on serum testosterone levels, with higher levels reducing testosterone.

Conclusions:

• PPARα activation-mediated testosterone reduction is validated as the key pathway for Cd-induced male infertility.
• The study establishes a novel integrative paradigm for identifying key AOPs in environmental toxicology.
• This research provides critical insights into the mechanisms of Cd-induced male infertility and informs risk assessment.