PFOS-induced Sertoli cell injury through c-Jun N-terminal kinase (JNK) - a study by RNA-Seq

Per- and polyfluoroalkyl substances (PFAS) are a family of "forever chemicals" including PFOS (perfluorooctane sulfonate). These toxic chemicals do not break down in the environment nor in our bodies. In the human body, PFOS and PFOA (perfluoroctanoic acid) have a half-life (T_1/2) of about 4-5 years so low daily consumption of these chemicals can accumulate in the human body to a harmful level over a long period. Although the use of PFOS in consumer products was banned in the U.S. in 2022/2023, this forever chemical remains detectable in our tap water and food products. Every American tested has a high level of PFAS in their blood (https://cleanwater.org/pfas-forever-chemicals). In this report, we used a Sertoli cell blood-testis barrier (BTB) model with primary Sertoli cells cultured in vitro with an established functional tight junction (TJ)-permeability barrier that mimicked the BTB in vivo. Treatment of Sertoli cells with PFOS was found to perturb the TJ-barrier, which was the result of cytoskeletal disruption across the cell cytoplasm, disrupting actin and microtubule polymerization. These changes thus affected the proper localization of BTB-associated proteins at the BTB. Using RNA-Seq transcriptome profiling, bioinformatics analysis, and pertinent biochemical and Cell Biology techniques, it was discovered that PFOS-induced Sertoli cell toxicity through the c-Jun N-terminal kinase (JNK; also known as stress-activated protein kinase, SAPK) and its phosphorylated/active form p-JNK signaling pathway. More importantly, KB-R7943 mesylate (KB), a JNK/p-JNK activator, was capable of blocking PFOS-induced Sertoli cell injury, supporting the notion that PFOS-induced cell injury can possibly be therapeutically managed.

Environmental toxicants; PFOS; Sertoli cells; spermatogenesis; testes.