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<p>Understanding the renal mechanisms underlying per- and polyfluoroalkyl substances (PFASs) elimination is critical to explain species- and structure-dependent toxicokinetic (TK) differences. This study investigated the in vitro uptake of ten PFASs, including perfluoroalkyl carboxylic acids (PFCAs) and sulfonic acids (PFSAs) with carbon chain lengths ranging from 4 to 10, as well as emerging PFASs (GenX, PFO2OA), by eight human and four rat homologous renal transporters using in vitro cell-based assays. Results showed that Organic Anion Transporter 1 (OAT1) specifically mediated PFHxA uptake and identified PFCAs up to nine carbons (PFHxA, PFOA, PFNA) and PFSAs up to six carbons (PFBS and PFHxS) as likely substrates of human OAT3 and OAT4. In rats, Oat1 and Oatp1a1 mediated the transport of these short- and medium-chain PFASs. In addition, the emerging PFASs, GenX and PFO2OA, were identified as likely substrates for human OAT3, rat Oat1, and rat Oatp1a1. In contrast, long-chain PFASs (PFDA, PFOS, PFDS) were not substrates for any tested transporter in either species. Uptake of short- and medium-chain PFASs by human OAT1, OAT3, and rat Oat1, located on the basolateral membrane, supports their roles in active secretion, whereas their interaction with human OAT4 and rat Oatp1a1, in the apical membranes of proximal tubular cells, indicates a potential contribution to tubular reabsorption. The comparable PFAS chain-length threshold for the uptake of PFASs by homologous human and rat renal transporters suggests that additional mechanisms may account for interspecies differences in PFAS renal clearance.</p>

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Comparative in vitro study of structure related uptake of ten perfluoroalkyl substances by human and rat renal transporters

  • 期刊论文

  • 发表日期：

    2026年7月14日

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  • Chloé M. L. Argoul,
  • Pierre-Louis Toutain,
  • Nicole Picard-Hagen,
  • Anna Klukovits,
  • Gábor Koncsos,
  • Véronique Gayrard,
  • Marlène Z. Lacroix

摘要

Understanding the renal mechanisms underlying per- and polyfluoroalkyl substances (PFASs) elimination is critical to explain species- and structure-dependent toxicokinetic (TK) differences. This study investigated the in vitro uptake of ten PFASs, including perfluoroalkyl carboxylic acids (PFCAs) and sulfonic acids (PFSAs) with carbon chain lengths ranging from 4 to 10, as well as emerging PFASs (GenX, PFO2OA), by eight human and four rat homologous renal transporters using in vitro cell-based assays. Results showed that Organic Anion Transporter 1 (OAT1) specifically mediated PFHxA uptake and identified PFCAs up to nine carbons (PFHxA, PFOA, PFNA) and PFSAs up to six carbons (PFBS and PFHxS) as likely substrates of human OAT3 and OAT4. In rats, Oat1 and Oatp1a1 mediated the transport of these short- and medium-chain PFASs. In addition, the emerging PFASs, GenX and PFO2OA, were identified as likely substrates for human OAT3, rat Oat1, and rat Oatp1a1. In contrast, long-chain PFASs (PFDA, PFOS, PFDS) were not substrates for any tested transporter in either species. Uptake of short- and medium-chain PFASs by human OAT1, OAT3, and rat Oat1, located on the basolateral membrane, supports their roles in active secretion, whereas their interaction with human OAT4 and rat Oatp1a1, in the apical membranes of proximal tubular cells, indicates a potential contribution to tubular reabsorption. The comparable PFAS chain-length threshold for the uptake of PFASs by homologous human and rat renal transporters suggests that additional mechanisms may account for interspecies differences in PFAS renal clearance.