Reproductive toxicity of PFOA, PFOS and their substitutes: A review based on epidemiological and toxicological evidence

Per- and polyfluoroalkyl substances (PFAS) have already drawn a lot of attention for their accumulation and reproductive toxicity in organisms. Perfluorooctanoic acid (PFOA) and perfluorooctanoic sulfonate (PFOS), two representative PFAS, are toxic to humans and animals. Due to their widespread use in environmental media with multiple toxicities, PFOA and PFOS have been banned in numerous countries, and many substitutes have been produced to meet market requirements. Unfortunately, most alternatives to PFOA and PFOS have proven to be cumulative and highly toxic. Of the reported multiple organ toxicities, reproductive toxicity deserves special attention. It has been confirmed through epidemiological studies that PFOS and PFOA are not only associated with reduced testosterone levels in humans, but also with an association with damage to the integrity of the blood testicular barrier. In addition, for women, PFOA and PFOS are correlated with abnormal sex hormone levels, and increase the risk of infertility and abnormal menstrual cycle. Nevertheless, there is controversial evidence on the epidemiological relationship that exists between PFOA and PFOS as well as sperm quality and reproductive hormones, while the evidence from animal studies is relatively consistent. Based on the published papers, the potential toxicity mechanisms for PFOA, PFOS and their substitutes were reviewed. For males, PFOA and PFOS may produce reproductive toxicity in the following five ways: (1) Apoptosis and autophagy in spermatogenic cells; (2) Apoptosis and differentiation disorders of Leydig cells; (3) Oxidative stress in sperm and disturbance of Ca2+ channels in sperm membrane; (4) Degradation of delicate intercellular junctions between Sertoli cells; (5) Activation of brain nuclei and shift of hypothalamic metabolome. For females, PFOA and PFOS may produce reproductive toxicity in the following five ways: (1) Damage to oocytes through oxidative stress; (2) Inhibition of corpus luteum function; (3) Inhibition of steroid hormone synthesis; (4) Damage to follicles by affecting gap junction intercellular communication (GJIC); (5) Inhibition of placental function. Besides, PFAS substitutes show similar reproductive toxicity with PFOA and PFOS, and are even more toxic to the placenta. Finally, based on the existing knowledge, future developments and direction of efforts in this field are suggested.