Bisphenols-enhanced platelet aggregation via TP, P2Y12, PAR1 and PAR4 receptors: a thrombotic legacy in a plastic-ubiquitous world

Background Cardiovascular diseases remain an urgent global health concern addressed by multiple clinical guidelines. Atherothrombosis is characterised by thrombus formation following disruption of atherosclerotic plaque, leading to major adverse cardiovascular events, such as myocardial infarction and stroke. Platelet hyperactivity is a key driver of these outcomes, leading causes of morbidity and mortality worldwide. Environmental xenobiotic exposure has been documented to contribute to atherosclerosis, endothelial dysfunction, and hypertension; however, its effects on thrombosis remain scarcely documented. In the present study, the effects of bisphenol A (BPA) and its most commonly used structural analogues on platelet aggregation were assessed using an ex vivo model. In silico analyses were also performed to identify potential receptors through which bisphenols may induce platelet aggregation. Additionally, our findings were contextualised within a systematic review spanning 10 years. Methods Platelet-rich plasma from healthy middle-aged men was incubated (30 min at 37°) with different bisphenols at concentrations ranging from 5 pM to 500 nM. Following incubation, platelet aggregation was induced with adenosine diphosphate (ADP) and measured with a Lumi-Aggregometer. Results were presented as standardised mean differences (SMD). A systematic review spanning 10 years was conducted to compare our findings. To explain our results, in silico analyses were conducted to evaluate the binding affinity and interaction models of bisphenols at platelet receptors relative to their reference agonists and antagonists. Receptors were selected based on the structural similarity between their cognate agonist and bisphenols. Binding affinity was assessed for the thromboxane A 2 (TP), the purinergic P2Y-subtype-12 (P2RY 12 ) and the protease-activated receptors 1 (PAR1) and 4 (PAR4). Results Bisphenols did not provoke platelet aggregation spontaneously. However, once ADP was added, they induced a strong and prolonged platelet aggregation (SMD: 1.90; 95% CI: 1.68–2.11) in the ex vivo model, with a potency ranking of BPF > TDF > BPS > BPA > BPAF. These findings were reinforced by the results from other studies in which human platelets were exposed ex vivo to bisphenols. The in silico analyses revealed that bisphenols exhibit favourable binding affinities for TP, which may explain the ex vivo findings. Bisphenols also showed binding affinity for P2Y 12 , PAR1, and PAR4. Conclusion Our study demonstrated that exposure to bisphenols enhanced and prolonged ADP-induced platelet aggregation and, for the first time, illuminated their interactions with key receptors involved in this complex process. Nonetheless, bisphenols may also exert other pleiotropic effects that further contribute to platelet aggregation. These results highlight the remarkable toxicity of these xenobiotics and their significant impact on haemostatic balance.