Assessment of the Emerging Threat Posed by Perfluoroalkyl and Polyfluoroalkyl Substances to Male Reproduction in Humans

Abstract

Per-fluoroalkyl and polyfluoroalkyl substances (PFAS) are a diverse group of synthetic fluorinated chemicals used widely in industry and consumer products. Due to their extensive use and chemical stability, PFAS are ubiquitous environmental contaminants and as such, form an emerging risk factor for male reproductive health. The long half-lives of PFAS is of particular concern as the propensity to accumulate in biological systems prolong the time taken for excretion, taking years in many cases. Accordingly, there is mounting evidence supporting a negative association between PFAS exposure and an array of human health conditions. However, inconsistencies among epidemiological and experimental findings have hindered the ability to definitively link negative reproductive outcomes to specific PFAS exposure. This situation highlights the requirement for further investigation and the identification of reliable biological models that can inform health risks, allowing sensitive assessment of the spectrum of effects of PFAS exposure on humans. Here, we review the literature on the biological effects of PFAS exposure, with a specific focus on male reproduction, owing to its utility as a sentinel marker of general health. Indeed, male infertility has increasingly been shown to serve as an early indicator of a range of co-morbidities such as coronary, inflammatory, and metabolic diseases. It follows that adverse associations have been established between PFAS exposure and the incidence of testicular dysfunction, including pathologies such as testicular cancer and a reduction in semen quality. We also give consideration to the mechanisms that render the male reproductive tract vulnerable to PFAS mediated damage, and discuss novel remediation strategies to mitigate the negative impact of PFAS contamination and/or to ameliorate the PFAS load of exposed individuals.

Keywords: PFAS; male fertility; male infertility; male reproduction; perfluoroalkyl and polyfluoroalkyl substances; sperm; toxicants.

Figure 1

Basic structure of perfluoroalkyl substances (PFAS), using perfluorooctanesulfonic acid (PFOS) as an example. Outlined in blue is the perfluoroalkyl tail (carbon/fluoride chain) and the functional group is outlined in red. All PFAS share these general features, with variation in the carbon chain length and functional group. Figure adapted from Blake and Fenton 2020 (51).

Figure 2

Schematic diagram illustrating the routes of human PFAS exposure. Following production, PFAS are used in consumer products such as food packaging, cookware, water repellent clothing and non-stick fry pans. PFAS are also a main component in firefighting foam, which can leach into the environment, or are otherwise disposed of as industrial waste. Human exposure may occur through use of consumer products or from contaminated water supplies. Accordingly, environmental exposure can occur as a result of waste products contaminating waterways and soil through leaching of firefighting foam and waste from industry and consumers.

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.

Figure 4

Schematic diagram of three possible treatment mechanisms for PFAS contaminated water. (A) Carbon-rich sorbents such as granular activated carbon (GAC) have a long history of being utilised to remove a variety of organic contaminants from water and as such are by far the best studied and most widely used sorption technology for treating PFAS contaminated water sources (208). Granular activated carbon has been shown to reliably remove PFOS with over 90% efficiency (59, 210) and is thus now the reference point for comparison of all new PFAS water sorption technologies. This technology can be employed to treat water before it reaches consumers, either as a single strategy, or as part of an integrated treatment programme. This treatment often involves the pump and treat method in which groundwater is extracted and filtered (208, 211), with the sorbent then being disposed of in landfill sites, provided certain risk criteria are met and the chemicals remain sequestered. International conventions state that waste materials containing > 50 mg/kg of PFAS must be treated in such a way as to destroy these chemicals, which is often accomplished by incinerating at high temperatures (over 1100°C) (208, 212). (B) Ion exchange uses anion exchange to target a wider range of PFAS, allowing for more efficient removal. Removal occurs via electrostatic interactions between the charged functional groups of PFAS chemicals and ions supported on an immobilized synthetic structure (213). In comparison to activated carbon treatment, this method has been shown to be more effective in removing PFAS, particularly the short chain variants (205). However, the efficiency of ion exchange technologies is dependent on several factors, such as the chemical composition of PFAS functional group, PFAS chain length and the ion exchange functional groups (the more hydrophobic, the better the sorption capacity of all chain lengths) (213). The success of almost all remediation strategies employed has been shown to depend on the perfluoroalkyl chain length, with increased efficacy seen with smaller chain length (214). (C) However, simply removing PFAS from water does not destroy the chemical, hence why further processing or incineration is required, making removal techniques lengthy and potentially hazardous. Sonochemical degradation has been shown to destroy aqueous PFOA and PFOA in laboratory conditions (213), demonstrating sonic irradiation can be effectively employed to reduce PFAS contamination at environmentally relevant levels (215). The degradation patterns of PFAS chemicals are influenced by their functional groups and chain lengths as well as physical variables such as temperature and pH (216). Utilizing the method of groundwater pumping is seen as a potentially endless endeavor due to continual contamination from untreated water sources. This, in turn, raises questions as to whether the pump and treat method is sustainable in the long-term treatment of PFAS contamination due to extensive resources and energy required (208).