Sex hormone-regulated renal transport of perfluorooctanoic acid
Introduction
Perfluorooctanoic acid (PFOA) is a potent synthetic surfactant that is used in a variety of industrial processes [1]. This chemical has been identified as a major contributor to organic fluorine in human serum [2], and the subsequent studies have revealed that serum levels of organic fluorine in plant workers occupationally exposed to this chemical were 10- to 50-fold higher than that in the general public [3]. The biological half-life (t1/2) in humans has been estimated to be 18–24 months following analysis of the serum from a plant worker [3].
The effects of PFOA on biological systems have been extensively studied in rodents. PFOA causes peroxisome proliferation as well as induction of various enzymes involved in lipid metabolism [4], [5], [6], [7], [8]. Toxic effects of PFOA have been reported, such as induction of fatty liver [5] and uncoupling of the mitochondrial respiratory chain [9]. PFOA also affects the serum levels of various hormones, i.e. reducing thyroid hormone and testosterone, and increasing estradiol in rats [10], [11]. Although these findings suggest that PFOA affects hormonal states and metabolism of lipids in human, to date, no significant correlation has been observed between serum levels of PFOA and any biological parameters in plant workers [12], [13], [14].
PFOA, once absorbed by the body, is predominantly eliminated in urine and the rate of fecal elimination is far less than that of urinary elimination in rats [15], [16]. Urinary elimination, therefore, is critical for detoxification of PFOA. We and other investigators have shown that urinary elimination of PFOA is markedly faster in female rats compared with male rats [15], [16], [17], [18], [19]. There are also significant sex differences in the metabolism of some chemicals and drugs [20], [21], [22]. Since PFOA is metabolically inert [16], [23], [24], sex-related difference observed in the biological effects of PFOA is not due to a difference in metabolism of PFOA. In the previous study, we observed that perfluorocarboxylic acid (PFCA) with a shorter carbon chain length was more rapidly eliminated in urine [15]. This suggests that PFCA are recognized and transported into urine by certain biological systems, although little is known about the molecular mechanism responsible for PFOA transport. Recently, several transporters have been cloned, by which various organic anions are transported across biological membranes, in various tissues including liver, kidney, intestine and brain [25], [26], [27], [28], [29], [30], [31], [32], [33]. These transporters have broad substrate specificities and transport various drugs as well as endogenous substrates [34]. Regulation of the expression of these transporters by sex hormones, however, has not been fully investigated yet. We have hypothesized, therefore, that PFOA is transported into urine by a transporter whose expression is regulated by sex hormones. In the present study, we investigated in detail the activities of renal PFOA transport under various hormonal states in male and female rats. Furthermore, the activities were compared with renal levels of mRNA of various organic anion transporters to identify potential candidates for PFOA transporters.
Section snippets
Materials
PFOA was purchased from Sigma Aldrich Japan (Tokyo, Japan). Inulin and probenecid were purchased from Sigma Chemical Co. (St. Louis, MO). Testosterone propionate and β-estradiol-3-benzoate were purchased from Wako Pure Chemical Ind. (Osaka, Japan). All other chemicals were of analytical grade. 3-Bromoacetyl-7-methoxycoumarin (BrAMC) was synthesized as described previously [35].
Animals
Male and female Wistar rats were obtained from SLC (Hamamatsu, Japan) and subjected to experiments when 9 weeks old
Sex-related difference in PFOA clearance in rats
Fig. 1 shows plasma concentration-time profiles of PFOA after intravenous injection in male and female rats. Plasma PFOA fell rapidly in female rats whereas it one decreased gradually in male rats. Toxicokinetic analysis revealed that the total clearance of PFOA in female rats was 44 times higher than that in male rats (Table 2). In female rats, the t1/2 was calculated to be 0.08 day, 1/70 that in male rats.
Renal clearance of PFOA in rats
The CLR of PFOA in female rats was markedly higher than that in male rats (Table 3)
Discussion
Recent studies have shown that PFOA accumulates to a high degree in the human body and the t1/2 was estimated to be 18–24 months [3]. Since this chemical is widely used in industrial applications, it is plausible that long-term exposure to this chemical results in its accumulation in humans, which may lead to toxic effects in biological systems. PFOA is not metabolized in biological systems and is eliminated in urine and feces as the free carboxylic acid in experimental animals [16], [23], [24]
Acknowledgements
This research was supported in part, by a Grant-in-Aid for Scientific Research (C) from the Ministry of Education, Science, Sports and Culture, Japan and Sasagawa Scientific Research Grant.
References (49)
- et al.
Characterization of hepatic response of rat to administration of perfluorooctanoic acid, perfluorodecanoic acid at low levels
Toxicology
(1995) - et al.
Alterations by perfluorooctanoic acid of glycerolipid metabolism in rat liver
Chemico-Biol. Interact.
(1999) - et al.
Biochemical and morphological studies of ammonium perfluorooctanoate-induced hepatomegaly and peroxisome proliferation
Exp. Mol. Pathol.
(1987) - et al.
Effect of peroxisome proliferators, ammonium perfluorooctanoate (C8), on hepatic aromatase activity in adult male Crl:CD BR (CD) rats
Fund. Appl. Toxicol.
(1996) - et al.
Comparison of the elimination between perfluorinated fatty acids with different carbon chain length in rats
Chemico-Biol. Interact.
(2001) - et al.
Tokicokinetics of inhalated 2-butoxyethanol and its major metabolite, 2-butoxyacetic acid, in F344 rats and B6C3F1 mice
Toxicol. Appl. Pharm.
(1998) - et al.
Sex differences in the metabolism of hexachlorobenzene by rats and the development of porphyria in females
Biochem. Pharmacol.
(1982) - et al.
Identification of a novel gene family encoding human liver-specific organic anion transporter LST-1
J. Biol. Chem.
(1999) - et al.
Identification and functional characterization of thepromotor region of the human organic anion transporting polypeptide gene
Hepatology
(1997) - et al.
Molecular cloning and characterization of a novel multispecific organic anion transporter from rat brain
J. Biol. Chem.
(1999)
Cloning and functional characterization of a novel rat organic anion transporter mediating basolateral uptake of methotrexate in the kidney
J. Biol. Chem.
Expression cloning and characterization of a novel multispecific organic anion transporter
J. Biol. Chem.
Cellular and molecular aspects of drug transport in the kidney
Kidney Int.
Determination by high-performance liquid chromatography of perfluorinated carboxylic acids in biological samples
J. Chromatogr. B
A new spectrophotometric method for the detection and determination of keto sugars and trioses
J. Biol. Chem.
Induction by perfluorinated fatty acids with different carbon chain length of peroxisomal β-oxidation in the liver of rats
Chemico-Biol. Interact.
Evidence for the active renal secretion of S-pentachlorophenyl-N-acetyl-l-cysteine by female rats
Biochem. Pharmacol.
Sex- and species-related nephropathy of 6-(1-aminocyclohexanecarboxamino)penicillamic acid (cyclacillin) and its relationship to the metabolic disposition
Toxicol. Appl. Pahrm.
Organic fluorocompounds in human plasma: prevalence and characterization
Surface active materials from perfluorocarboxylic acid
Ind. Eng. Chem. Proc. Res. Dev.
Health status of plant workers exposed to fluorochemicals—a preliminary report
Am. Ind. Hyg. Assoc. J.
Fish oil-feeding prevents perfluorooctanoic acid-induced fatty liver in mice
Toxicol. Appl. Pharm.
Effects of perfluoro fatty acids on xenobiotic-metabolizing enzymes which detoxify reactive form of oxygen and lipid peroxidation in mouse liver
Biochem. Pharmacol.
Effects of perfluoro-n-decanoic acid on the respiratory activity of isolated rat liver mitochondria
J. Toxicol. Environ. Health
Cited by (232)
Environmental occurrence, bioaccumulation and human risks of emerging fluoroalkylether substances: Insight into security of alternatives
2024, Science of the Total EnvironmentEffect of dietary antioxidants on excretion of perfluorooctanoic acid (PFOA) via regulating uptake transporters expression and intestinal permeability in mice
2023, Ecotoxicology and Environmental SafetyPrenatal exposure to legacy PFAS and neurodevelopment in preschool-aged Canadian children: The MIREC cohort
2023, Neurotoxicology and TeratologyCan blood proteome diversity among fish species help explain perfluoroalkyl acid trophodynamics in aquatic food webs?
2023, Science of the Total Environment