Roles of Rat Renal Organic Anion Transporters in Transporting Perfluorinated Carboxylates with Different Chain Lengths

Abstract

Perfluorinated carboxylates (PFCAs) are generally stable to metabolic and environmental degradation and have been found at low concentrations in environmental and biological samples. Renal clearance of PFCAs depends on chain length, species, and, in some cases, gender within species. While perfluoroheptanoate (C7) is almost completely eliminated renally in both male and female rats, renal clearance of perfluorooctanoate (C8) and perfluorononanoate (C9) is much higher in female rats. Perfluorodecanoate (C10) mainly accumulates in the liver for both genders. Therefore, we tested whether PFCAs with different chain lengths are substrates of rat renal transporters with gender-specific expression patterns. Inhibition of uptake of model substrates was measured for the basolateral organic anion transporter (Oat)1 and Oat3 and the apical Oat2, organic anion transporting polypeptide (Oatp)1a1, and Urat1 with 10microM PFCAs with chain lengths from 2 to 18 (C2-C18) carbons. Perfluorohexanoate (C6), C7, and C8 inhibited Oat1-mediated p-aminohippurate transport, with C7 being the strongest inhibitor. C8 and C9 were the strongest inhibitors for Oat3-mediated estrone-3-sulfate transport, while Oatp1a1-mediated estradiol-17beta-glucuronide uptake was inhibited by C9, C10, and perflouroundecanoate (C11), with C10 giving the strongest inhibition. No strong inhibitors were found for Oat2 or Urat1. Kinetic analysis was performed for the strongest inhibitors. Oat1 transported C7 and C8 with K(m) values of 50.5 and 43.2microM, respectively. Oat3 transported C8 and C9 with K(m) values of 65.7 and 174.5microM, respectively. Oatp1a1-mediated transport yielded K(m) values of 126.4 (C8), 20.5 (C9), and 28.5microM (C10). These results suggest that Oat1 and Oat3 are involved in renal secretion of C7-C9, while Oatp1a1 can contribute to the reabsorption of C8 through C10, with highest affinities for C9 and C10.

Uptake and elimination of perfluorinated phosphonic acids in the rat

“…Renal excretion of the longer chain PFCAs (!C10) is low in both genders (<5% [34]), and so movement into the renal filtrate may control renal excretion and serum half-lives. In the rat, OAT1 and OAT3 are both involved with the secretion of organic anions into the renal filtrate [28,32]; these transport proteins have a demonstrated affinity for the C7-C9 PFCAs [32]. Whether OAT1 or OAT3 can explain the longer serum half-lives in female rats as compared to male rats for PFDA [16] is not clear, because Kudo et al [28] did not observe any gender differences in their expression.…”

“…Oral absorption of organic anions is not well characterized, but likely involves organic anion transport (OAT) proteins [27]. The PFCAs and PFSAs have demonstrated affinity with a variety of OAT proteins [28][29][30][31][32], and this interaction has been implicated in gender and species differences observed in PFOA renal excretion [28,31]. Organic anion transport proteins are present in intestinal epithelial cells [27] as well as liver hepatocytes [33], both of which are involved in the movement of chemicals from the gut contents into the bloodstream.…”

“…Changes in PFCA renal excretion with gender and chain length may be explained by the increased expression in male rats of the resorptive OAT protein OATp1a1 [28]. In vitro studies have found that OATp1a1 has a low affinity for perfluorobutanoic acid and perfluoropentanoic acid, with increasing PFCA affinity as the chain length increases from C6 to C10 [31,32]. This observation is consistent with the short serum half-lives and high renal excretion observed for the smaller PFCAs ( C6) in both genders [16,34,36], and the longer serum half-lives and lower renal excretion of PFOA and PFNA in male rats as compared to female rats [16].…”

Per- and polyfluorinated substances (PFASs): Environmental challenges

“…The renal organic anion transporter system that mediates renal excretion and resorption [345] may differ depending on PFCA chain length, animal species and gender [212,346]. The immune response to PFOA and PFOS are also different: while the former reduced the number of B and T cells, the latter suppressed antigen specific antibody response independently from reduction in B and T cell numbers [224].…”

Transfer of Perfluorooctanoic Acid (PFOA) and Perfluorooctane Sulfonate (PFOS) From Contaminated Feed Into Milk and Meat of Sheep: Pilot Study

“…Studies on the elimination of PFOA by way of urine in rats showed a sex-dependent elimination effect. Vanden Heuvel et al (1991) reported that female rats eliminated 91 % of the intravenously administered dose by way of urine within 24 h. Due to the high excretion rate in female rats, the ability to express specific transporter systems in the kidney has been discussed (Weaver et al 2010). PFOS was excreted only in small proportions by way of urine and ranged near the LOD of 0.1 lg/L.…”