The decline in human fertility rates has drawn considerable concern (1, 2). Accumulating evidence suggests that human semen quality has decreased worldwide over the past few decades (3–9). Although the causative factors remain to be fully discovered, exposure to environmental pollutants is considered to be a major contributor for impaired male fecundity (2, 10–12). Per- and polyfluoroalkyl substances (PFASs) are a family of fluorinated synthetic chemicals that have been extensively used in industry and consumer products since the 1950s. As emerging persistent organic contaminants, PFASs are extremely resistant to environmental degradation and metabolic clearance due to their unique and stable physicochemical properties (13). Consequently, these compounds are ubiquitous and persistent in the environment and accumulate in the food chain (14, 15), posing a serious threat to ecological and human health worldwide. A variety of PFASs have been detected in the semen of human (16–19), implying a potential hazard of PFASs to male fecundity. Hence, this review briefly summarizes the epidemiological and experimental evidence regarding the toxic effects of PFAS exposure on male reproduction, focusing on sperm quality.

Accumulating evidence has revealed that humans are universally exposed to PFASs (20–24). The intake of polluted food and drinking water, inhalation of indoor air and dust, and dermal contact are claimed as the major routes of human exposure to PFASs (14, 25–27). Perfluorooctanoic acid (PFOA) and perfluorooctane sulfonic acid (PFOS) are the most predominant and frequently detected PFASs in human blood (28). Their serum half-lives were estimated to be 3.8 and 5.4 years in human body, respectively (29). In human plasma, PFASs primarily bind to albumin and are transferred through the body (30). Epidemiological investigations have indicated a possible association between PFAS exposure and adverse health outcomes, such as liver function abnormality (31), glucose homeostasis disturbance (32), dyslipidemia (33), cardiovascular diseases (34), fetal growth restriction (35), and bone mineral density reduction (36).

Due to the environmental persistence and pervasive presence, there is growing concern regarding the toxicities of PFASs to male fertility. Numerous studies have suggested that PFASs induce testicular toxicity. For example, exposure to PFOA repressed the expression of blood-testis barrier (BTB) proteins and increased TNFα content and p-p38/p38 MAPK ratio in mouse testis and cultured Sertoli cells (54). Similarly, hexafluoropropylene oxides and PFOS disturbed BTB by activating p38 MAPK/MMP9 pathway (55, 56). These results indicate that p38 MAPK signaling may contribute to PFASs-induced BTB disruption. Proteomic profile analysis also indicated that PFOA treatment altered blood-testis barrier remodeling in mouse testis (57). Furthermore, PFOS exposure promoted the generation of reactive oxygen species (ROS) and suppressed the activities of antioxidases in the testes, thereby impairing testicular physiology and spermatogenesis in rats (50). Oral PFOA administration resulted in the destruction of the seminiferous epithelium, induced oxidative stress, inhibited NRF2-mediated antioxidant response, and led to apoptosis in the testis of mice (49, 58). However, studies found that supplement with flavonoids rutin and pachypodol attenuated testicular damage caused by PFOA and PFOS through alleviating oxidative stress, respectively (49, 50). Additionally, maternal exposure to PFOA reduced serum testosterone levels, disrupted testis development, damaged testicular structure, and caused testicular apoptosis in the offspring mice (59, 60). These results suggest that exposure to PFASs can result in the disruption of testicular structure and function, which may be partly responsible for PFASs-caused reduction of sperm count. Moreover, antioxidative intervention with flavonoids may be a promising strategy for preventing and rescuing PFASs-induced spermatogenic impairment.

Hormones in the hypothalamic-pituitary-gonadal axis are important regulators in the reproductive process. Intratesticular testosterone plays an important role in sperm number and sperm motility, and abnormal testosterone generation impairs spermatogenesis in humans (61). PFASs have been identified to act as endocrine disruptors affecting male reproductive health. A cross-sectional study reported that higher serum levels of PFASs are negatively associated with testosterone concentrations among male adolescents (62). The negative association between serum PFOS and testosterone levels was also observed in healthy young Danish men (63). In laboratorial experiments, PFOS exposure disrupted the hypothalamic-pituitary-testis axis activity (64, 65), and reduced luteinizing hormone, follicle-stimulating hormone and testosterone levels in adult male rats (50). Furthermore, both PFOA and PFOS significantly decreased the expression of steroidogenic enzymes and the concentrations of testosterone in male mice (48, 66), and the mechanisms may be involved in developmental inhibition, oxidative stress and apoptosis in Leydig cells (67–70). Inversely, low-dose PFOA stimulated steroid hormone synthesis by enhancing fatty acid metabolism and steroidogenic activation in Leydig cells (71). These results suggested that exposure to PFASs disordered testosterone biosynthesis, which may be correlated with the impaired semen quality.

Normal sperm function is crucial for male fertility. Some epidemiological and experimental investigations also showed a negative association between PFAS exposure and semen parameters, such as sperm count, morphology and motility, implying that PFASs have an adverse influence on sperm quality ( Tables 1 and 2 ). Nevertheless, the toxicological mechanisms remain largely unelucidated. Rodent studies demonstrated that PFOA could accumulate in the epididymis and cause morphological change in epididymal epithelium (47, 49), suggesting that the epididymis is a potential target and PFOA may exert direct toxicity to spermatozoa. Lu et al. (47) found that PFOA exposure activated AKT/AMPK signaling pathway, altered polyunsaturated fatty acid composition, and triggered oxidative stress in the epididymis of mice (47). Furthermore, in vitro treatment with PFOA augmented ROS production and reduced sperm viability (47). The study implied that oxidative stress and membrane polyunsaturated fatty acid alteration may be involved in PFOA-induced sperm toxicity. Moreover, PFOA incubation resulted in accumulation in sperm membrane, and perturbed plasma membrane fluidity, mitochondrial respiratory activity and electrochemical potential, indicating that PFOA impacts human sperm motility by plasma membrane disruption (44). Our previous study showed that in vitro PFOA exposure compromised the penetration ability of human spermatozoa by inducing oxidative stress, evoking CatSper-mediated Ca²⁺ influx, and compromising progesterone-induced response (43). Testicular transcriptome profiling revealed that PFOS exposure led to alterations in microtubule-based movement, microtubule motor activity, cilium movement, cytoskeleton and spermatid development (51). In addition, PFOS altered sperm membrane lipid composition reflected by elevated ratio of cholesterol to phospholipids in male zebrafish (53), suggesting that PFOS may sperm function through disrupting membrane fluidity. These findings may help explain the abnormalities in sperm morphology and motility caused by PFASs.

We have summarized the toxicological effects of PFASs on sperm using recent epidemiological and experimental data. Increasing evidence suggests that exposure to PFASs is adversely associated with sperm quality, and their mechanisms of toxicity might be involved in testicular and epididymal damage, testosterone synthesis disorder, and oxidative stress, membrane lipid composition alteration and Ca²⁺ influx in sperm. However, due to the limited number of epidemiological studies, the reproductive health risk of human exposure to PFASs, especially their emerging alternatives, needs further investigation.

ZS and YW: Writing-original draft preparation, writing-review and editing. BW and SD: Writing-review & editing. FZ and ZF: Data collection, conceptualization. YY: Writing-review & editing, conceptualization. DZ: Supervision, writing-review and editing, funding acquisition. All authors contributed to the article and approved the submitted version.