They’re called ‘forever chemicals’ because they linger in both the environment and in our bodies with an unsettling persistence. Polyfluoroalkyl substances (PFAS) such as perfluorooctanoic acid (PFOA) are ubiquitous in many consumer items, being used extensively for their non-stick and water-repellent properties.
But these compounds have also insidiously infiltrated our water supply, food and even our bodies, where they’ve been linked to cancer, hormone disruptions and fetal growth impairment.
James Chan, a Junior Principal Investigator at A*STAR’s Singapore Institute of Food and Biotechnology Innovation (SIFBI) and the A*STAR Skin Research Labs (A*SRL) explained that our understanding of how PFOA affects the body over time, known as toxicokinetics, is still in its infancy.
Chan said that as a strongly charged molecule, PFOA cannot readily enter or exit human cells as the cell membrane blocks the passage of charged molecules; instead, transporters ferry PFOA into cells. The complexity and multitude of transporters which regulate the entry and exit of PFOA makes it difficult to predict its behaviour and long-term health effects. To address this challenge, Chan collaborated with experts from SIFBI, A*SRL and the National University of Singapore and pioneered a computational model to simulate how the human body handles and eliminates PFOA.
The virtual model integrated physiologically-based toxicokinetic (PBTK) frameworks, in vitro transporter kinetics and quantitative proteomics to unravel the interplay between PFOA transporters and provide deep insight on the biological handling of PFOA exposure.
The study uncovered a novel protein called monocarboxylate transporter 1 that is likely involved in distributing PFOA into various tissues, thereby allowing PFOA to disrupt tissue function. Additionally, the researchers proposed a pivotal role for kidney transporters in controlling PFOA clearance, which would account for the wide variability in estimates of how long PFOA remains in the human body, ranging from months to years.
“All the known transporters of PFOA were responsible for pumping PFOA into kidney cells, but none were documented to pump it out. This would theoretically result in massive accumulation of PFOA in the kidney. We therefore hypothesised that there must be an efflux transporter that acts as a release valve to pump PFOA out of the kidney cells and back into the blood,” Chan explained. This discovery is instrumental in identifying how the body retains PFOA, as its efflux back into the blood ensures that PFOA is almost completely reabsorbed into circulation. This does not come as a complete surprise, because PFOA chemically resembles the fatty acids that our kidneys recognise as essential nutrients to be retained.
The synthesis of PBTK modelling and targeted cellular assays devised by Chan's team provides a robust methodology for appraising the toxicokinetics of PFAS, which can contribute to future evaluations of risk and the formulation of public health directives.
“Most importantly, these models can be used as a safer alternative to human studies and avoid ethical concerns with intentional PFAS exposure. We also intend to use our findings to guide the rational design of next-generation PFAS replacements that do not possess these undesirable behaviours. This turns a problem into an opportunity,” said Chan.
Since the study, the team has established strategic alliances, including those with Health Canada and Accelerating the Pace of Chemical Risk Assessment, with the goal of unifying global initiatives to mitigate the public health challenges presented by PFAS contamination.
The A*STAR-affiliated researchers contributing to this research are from the Singapore Institute of Food and Biotechnology Innovation (SIFBI) and A*STAR Skin Research Labs (A*SRL).
