Medium-chain perfluoroalkyl carboxylic acids exert male reproductive toxicity at environmental and human exposure levels by antagonizing androgen receptor mediated pathways.

Medium-chain perfluoroalkyl carboxylic acids (MC-PFCAs) are frequently detected at elevated concentrations in various environmental matrices and human samples worldwide. MC-PFCA exposure is associated with a number of adverse health effects including male reproductive toxicity, but their toxicological mechanisms remain unclear. This study investigated the male reproductive toxicity of MC-PFCAs and their molecular mechanisms by taking a combined approach of in vivo, in vitro and in silico studies at environmental and human exposure levels. Exposure of adult male zebrafish to perfluorononanoic acid (PFNA) and perfluorooctanoic acid (PFOA) induced testicular damage and altered androgen receptor (AR) pathway gene expression at 10, 100, and 1000 μg/L, whereas perfluoroheptanoic acid (PFHpA) induced testicular damage, disrupted sex hormone expression, and altered gene expression at 1000 μg/L. In cell assays PFCA inhibited the transcriptional activity of zebrafish AR with the lowest effect concentrations (LEC) of 10 nM-1 μM. They were docked favorably to the antagonistic conformation of zebrafish AR, indicating an important role of AR in the male reproductive toxicity of PFCAs. These compounds also inhibited the proliferation of human prostate cancer cells and transcriptional activity of human AR with similar LECs, and docked to the antagonistic conformation of human AR, suggesting potential toxicity on humans. Our study revealed a mechanism of male reproductive toxicity via antagonizing AR mediated pathways with implications on human health.