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This study combined in vitro, ex vivo, and in vivo experiments with computational modeling to evaluate the effects of legacy PFAS (PFOS and PFOA) and their alternatives (6:2 Cl-PFESA, HFPO-DA, HFPO-TA, and HFPO-TeA) on FXII and downstream contact activation. In vitro and ex vivo screening showed that 6:2 Cl-PFESA had a greater capacity to activate FXII than PFOS, whereas HFPO-TA induced more pronounced FXII cleavage and a larger, albeit modest, increase in activated FXII (FXIIa) activity relative to PFOA. Both alternatives also triggered plasma prekallikrein activation. Intravenous exposure to 6:2 Cl-PFESA significantly increased plasma FXIIa activity in mice, suggesting that this PFAS alternative may perturb the contact system in vivo. Structure-activity analysis showed that, unlike linear PFAS, FXII activation induced by HFPO alternatives did not follow a simple carbon chain-length dependence. Molecular dynamics simulations and virtual alanine scanning analysis using FXII crystal and AlphaFold structures suggested a domain-selective mechanism, with the carboxylic PFAS favoring the fibronectin type-II domain (Fib-II) and the sulfonic PFAS favoring both the Fib-II and the proline-rich (PR) domain. These findings uncover new activators of the contact system, informing the potential hematological effects of PFAS alternatives, and provide computational support for a possible domain-selective mechanism for PFAS\u2013FXII interactions.<\/jats:p>","DOI":"10.1021\/acs.est.6c05707","type":"journal-article","created":{"date-parts":[[2026,9,12]],"date-time":"2026-09-12T16:02:09Z","timestamp":1789228929000},"source":"Crossref","is-referenced-by-count":0,"title":["Novel\nPFAS Alternatives 6:2 Cl-PFESA and HFPO-TA as\nPlasma FXII Activators: Experimental Evidence and Computational Mechanistic\nInsights"],"prefix":"10.1021","author":[{"given":"Yurou","family":"Gao","sequence":"first","affiliation":[{"name":"Chinese Academy of Sciences , , ,","place":["Beijing, China, 100085"]},{"name":"University of Chinese Academy of Sciences , , ,","place":["Beijing, China, 100049"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuxin","family":"Wan","sequence":"additional","affiliation":[{"name":"Jiangxi Normal University , , ,","place":["Nanchang, China, 330022"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiahui","family":"Su","sequence":"additional","affiliation":[{"name":"Chinese Academy of Sciences , , ,","place":["Beijing, China, 100085"]},{"name":"Peking University , , ,","place":["Beijing, China, 100871"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuzhu","family":"Zhang","sequence":"additional","affiliation":[{"name":"Chinese Academy of Sciences , , ,","place":["Beijing, China, 100085"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7007-4417","authenticated-orcid":true,"given":"Xuejiao J.","family":"Gao","sequence":"additional","affiliation":[{"name":"Jiangxi Normal University , , ,","place":["Nanchang, China, 330022"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4759-5016","authenticated-orcid":true,"given":"Qian S.","family":"Liu","sequence":"additional","affiliation":[{"name":"Chinese Academy of Sciences , , ,","place":["Beijing, China, 100085"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2521-100X","authenticated-orcid":true,"given":"Qunfang","family":"Zhou","sequence":"additional","affiliation":[{"name":"Chinese Academy of Sciences , , ,","place":["Beijing, China, 100085"]},{"name":"University of Chinese Academy of Sciences , , ,","place":["Beijing, China, 100049"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6335-3917","authenticated-orcid":true,"given":"Guibin","family":"Jiang","sequence":"additional","affiliation":[{"name":"Chinese Academy of Sciences , , ,","place":["Beijing, China, 100085"]},{"name":"University of Chinese Academy of Sciences , , ,","place":["Beijing, China, 100049"]},{"name":"University of Chinese Academy of Sciences , , ,","place":["Beijing, China, 100049"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2026,9,12]]},"reference":[{"issue":"1","key":"2026091212020075500_cit1","doi-asserted-by":"publisher","first-page":"17","DOI":"10.1186\/s12959-015-0048-y","article-title":"Contact Pathway\nof Coagulation and Inflammation","volume":"13","author":"Wu","year":"2015","journal-title":"Thromb. 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