Figure 3.

Proposed mechanisms of PFAS action pertaining to the male reproductive system. PFAS have the potential to enter the body through multiple routes. Following entry, PFAS are capable of binding to fatty acid binding proteins and transport proteins in the blood such as human serum albumin (HSA) and thereafter are thought to be transported throughout the body eliciting harmful endocrine effects via two possible mechanisms: disturbing steroidogenesis (e.g. via allosteric inhibition of vital enzymes) or directly interfering with steroid hormone receptors. This results in altered levels of reproductive hormones such as luteinizing hormone (LH), follicle stimulating hormone (FSH), sex hormone binding globulin (SHBG), testosterone (T) and insulin-like peptide 3 (INSL3), which has subsequent effects on male reproductive processes. PFAS also accumulate in protein rich tissues, including the testes, which is facilitated by the high expression of fatty acid binding proteins. Here, PFAS impact testicular cell function, namely Leydig and Sertoli cells. Altered Leydig cell function leads to reduced testosterone production resulting in altered sexual development, increased incidence of hyperplasia and adenomas and increased risk of cryptorchidism in the fetus. This reduction in testosterone leads to attendant impacts on Sertoli cell function by reducing Sertoli cell differentiation and precipitating compromise of spermatogenesis, reduced sperm count and altered sexual development. Gap junctions between Sertoli cells and developing germ cells are also affected by PFAS, which reduces communication between the cells, negatively affecting spermatogenesis and resulting in a range of defects in the mature spermatozoa.