{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,29]],"date-time":"2026-07-29T13:35:52Z","timestamp":1785332152024,"version":"3.55.0"},"reference-count":87,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,6,22]],"date-time":"2026-06-22T00:00:00Z","timestamp":1782086400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003141","name":"Secretar\u00eda de Ciencia, Humanidades, Tecnolog\u00eda e Innovaci\u00f3n","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100003141","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Pharmacol."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>\n                      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\n                      <jats:italic>ex vivo<\/jats:italic>\n                      model.\n                      <jats:italic>In silico<\/jats:italic>\n                      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\u00a0years.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      Platelet-rich plasma from healthy middle-aged men was incubated (30\u00a0min at 37\u00b0) with different bisphenols at concentrations ranging from 5\u00a0pM to 500\u00a0nM. 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\u00a0years was conducted to compare our findings. To explain our results,\n                      <jats:italic>in silico<\/jats:italic>\n                      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\n                      <jats:sub>2<\/jats:sub>\n                      (TP), the purinergic P2Y-subtype-12 (P2RY\n                      <jats:sub>12<\/jats:sub>\n                      ) and the protease-activated receptors 1 (PAR1) and 4 (PAR4).\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Bisphenols did not provoke platelet aggregation spontaneously. However, once ADP was added, they induced a strong and prolonged platelet aggregation (SMD: 1.90;\n                      <jats:sub>95%<\/jats:sub>\n                      CI: 1.68\u20132.11) in the\n                      <jats:italic>ex vivo<\/jats:italic>\n                      model, with a potency ranking of BPF &amp;gt; TDF &amp;gt; BPS &amp;gt; BPA &amp;gt; BPAF. These findings were reinforced by the results from other studies in which human platelets were exposed\n                      <jats:italic>ex vivo<\/jats:italic>\n                      to bisphenols. The\n                      <jats:italic>in silico<\/jats:italic>\n                      analyses revealed that bisphenols exhibit favourable binding affinities for TP, which may explain the\n                      <jats:italic>ex vivo<\/jats:italic>\n                      findings. Bisphenols also showed binding affinity for P2Y\n                      <jats:sub>12<\/jats:sub>\n                      , PAR1, and PAR4.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>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.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fphar.2026.1840963","type":"journal-article","created":{"date-parts":[[2026,6,22]],"date-time":"2026-06-22T04:34:02Z","timestamp":1782102842000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["Bisphenols-enhanced platelet aggregation via TP, P2Y12, PAR1 and PAR4 receptors: a thrombotic legacy in a plastic-ubiquitous world"],"prefix":"10.3389","volume":"17","author":[{"given":"Opata Edward","family":"Kwame","sequence":"first","affiliation":[{"name":"Departamento de Toxicolog\u00eda, Centro de Investigaci\u00f3n y de Estudios Avanzados del Instituto Polit\u00e9cnico Nacional","place":["Ciudad de M\u00e9xico, M\u00e9xico"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aurora","family":"de la Pe\u00f1a-D\u00edaz","sequence":"additional","affiliation":[{"name":"Departamento de Farmacolog\u00eda, Laboratorio de Trombosis y Fibrin\u00f3lisis, Facultad de Medicina, Unidad de Investigaci\u00f3n UNAM-INC, UNAM, Unidad For\u00e1nea, Instituto Nacional de Cardiolog\u00eda \u201cIgnacio Ch\u00e1vez\u201d","place":["Ciudad de M\u00e9xico, M\u00e9xico"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yesenia I.","family":"Mart\u00ednez-Jim\u00e9nez","sequence":"additional","affiliation":[{"name":"Departamento de Toxicolog\u00eda, Centro de Investigaci\u00f3n y de Estudios Avanzados del Instituto Polit\u00e9cnico Nacional","place":["Ciudad de M\u00e9xico, M\u00e9xico"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mirthala","family":"Flores-Garc\u00eda","sequence":"additional","affiliation":[{"name":"Departamento de Biolog\u00eda Molecular, Instituto Nacional de Cardiolog\u00eda \u201cIgnacio Ch\u00e1vez\u201d","place":["Ciudad de M\u00e9xico, M\u00e9xico"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emma S.","family":"Calder\u00f3n-Aranda","sequence":"additional","affiliation":[{"name":"Departamento de Toxicolog\u00eda, Centro de Investigaci\u00f3n y de Estudios Avanzados del Instituto Polit\u00e9cnico Nacional","place":["Ciudad de M\u00e9xico, M\u00e9xico"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Irene","family":"Lee-Rivera","sequence":"additional","affiliation":[{"name":"Departamento de Neuropatolog\u00eda Molecular, Instituto de Fisiolog\u00eda Celular, Universidad Nacional Aut\u00f3noma de M\u00e9xico","place":["Ciudad de M\u00e9xico, M\u00e9xico"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roc\u00edo","family":"G\u00f3mez","sequence":"additional","affiliation":[{"name":"Departamento de Toxicolog\u00eda, Centro de Investigaci\u00f3n y de Estudios Avanzados del Instituto Polit\u00e9cnico Nacional","place":["Ciudad de M\u00e9xico, M\u00e9xico"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,6,22]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"222","DOI":"10.2174\/1871530322666220607124757","article-title":"Hematotoxicity of Co-Administration of bisphenol A and acetaminophen in rats and its amelioration by melatonin","volume":"23","author":"Akhter","year":"2023","journal-title":"Endocr. 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