The journal Frontiers in Microbiology published a study that examined the influence of bisphenols on vascular calcification, including data from humans and an animal-based experiment. Given its widely recognized role as an endocrine disruptor, bisphenol A (BPA) has been replaced in many plastic products with other bisphenols, including bisphenol S (BPS), bisphenol F (BPF), and bisphenol AF (BPAF), though they too have been shown to have similar mechanisms of action as well as a magnitude of effect. Yet because most toxicity data exists for BPA, the other bisphenols do not receive as much public attention, and are below the radar of many individuals who look for “BPA-free” products. This study attempted to specifically evaluate BPF’s role in vascular calcification.
Fifty-seven consecutive patients presenting with chest pain were enrolled in the study, 30 of whom had vascular calcification as determined by diagnostic CT imaging. Although bisphenols are typically measured in the urine, this study measured fecal bisphenol levels. Unfortunately, very little is known about the fecal elimination of BPF in humans; in animal studies, only 15-20% is eliminated in feces (variation exists between animals and humans as well as bisphenols), and it is unclear why the researchers did not include measurement of urinary bisphenol levels. Nonetheless, in this study, BPA, BPS, and BPF were all found in significantly higher levels among patients with vascular calcification compared to those without. Other significant differences include older age, higher rates of smoking, and a lower eGFR among people with vascular calcification. It’s certainly possible that these variables may also be relevant to bisphenol exposure; for example, tobacco smoke has previously been linked to higher urinary BPA levels. Of the bisphenols, BPF was the most predictive of calcification in this study.
Analysis of the gut microbiome was also done, which found significant differences between those with calcification and those without, such as a higher abundance of Escherichia-Shigella, Anaerovibrio, Prevotella, etc., among those with calcification, with abundance also associated with all 3 bisphenols and inversely with short-chain fatty acids (acetate, propionate, and butyrate levels).
An animal experiment was also conducted, which found that BPF could induce vascular calcification in healthy animals and exacerbate it among animals with previously induced calcification. BPF disrupted the gut microbiota, including enrichment of Escherichia-Shigella, and was associated with an increase in several inflammatory signals, including LPS (endotoxin), IL-6, IL-1β, and TNF-α. Next, the researchers performed a fecal transplant from animals with calcification (also exposed to BPF) to those with calcification but not BPF exposure, and found an exacerbation in calcification. This and related experiments prompted the authors to conclude that BPF promotes vascular calcification through its effects on the gut microbiota.
Currently, the effects of BPF on the human microbiome are unknown. This is despite an NHANES 2013–2014 study which found that roughly 2/3 of urine samples of adults and children in the U.S. had detectable levels of BPF, while 96% had detectable BPA, and almost 90% had detectable BPS. Given how underappreciated the hazards of BPF are compared to BPA, it’s likely this exposure has only increased since then.
A 2024 review of bisphenols and phthalates suggested that the weight of the evidence favors their playing a role in the obesity epidemic, mediated through at least 6 mechanisms, including dysregulating the gut microbiome and promoting a pro-inflammatory milieu. While primarily focused on BPA, this review describes a disruption of gut microbiota and increases in intestinal permeability and inflammation, as well as alterations in glucose and lipid homeostasis from exposure.
A 2023 review of BPA cardiovascular toxicity concluded that BPA may induce dysfunction in multiple tissues, including blood vessels, the heart, kidneys, and liver. It points to a growing body of evidence suggesting that urinary or blood levels of BPA are associated with the incidence of heart attack, stroke, and coronary artery disease. This review included a 2020 analysis published in Ecotoxicology and Environmental Safety, which cited a 73% higher risk for myocardial infarction, 61% higher risk for stroke when comparing quintiles of exposure, as well as positive associations with heart failure, coronary heart disease, and angina pectoris. It also included mention of a 2021 analysis of young adults, which found that higher BPA levels were associated with pro-inflammatory signals, including higher C-reactive protein levels, blood pressure, and pro-inflammatory gene expression. Another study with nearly 900 participants found a higher risk of subclinical atherosclerosis (thicker carotid artery intima-media thickness) and endothelial dysfunction among young adults (aged 12-30) with greater BPA exposure.
While the vascular toxicity of BPF is not conclusively shown in humans, the suggestion that its toxicity is mediated by changes to gut microbiota may influence possible therapeutics. For example, Akkermansia muciniphila has emerged as a likely beneficial probiotic and was shown to remove approximately 48% of BPF via biotransformation; similarly, Faecalibacterium prausnitzii removed up to 87% of tetramethylbisphenol F (TMBPF) in vitro. Regardless of mechanism, it may be warranted to at least occasionally screen for elevated bisphenol exposure (not just BPA), and identify contributing sources.