RESUMO
Perfluorooctane sulfonate (PFOS) is an environmentally persistent chemical. Dietary 100 ppm PFOS fed to male mice and rats for 4 weeks caused hepatic steatosis through an unknown mechanism. Choline deficient diets can cause hepatic steatosis. A hepatic choline:PFOS ion complex was hypothesized to cause this effect in mice. This study tested whether dietary choline supplementation attenuates PFOS-induced hepatic steatosis in rats. Sprague Dawley rats (12/sex/group) were fed control, choline supplemented (CS), 100 ppm PFOS, or 100 ppm PFOS + CS diets for 3 weeks. Male rats fed both PFOS-containing diets had decreased serum cholesterol and triglycerides (TGs) on days 9, 16, and/or 23 and increased hepatic free fatty acids and TG (ie, steatosis). Female rats fed both PFOS diets had decreased serum cholesterol on days 9 and 16 and decreased hepatic free fatty acid and TG at termination (ie, no steatosis). Liver PFOS concentrations were similar for both sexes. Liver choline concentrations were increased in male rats fed PFOS (±CS), but the increase was lower in the PFOS + CS group. Female liver choline concentrations were not altered by any diet. These findings demonstrate a clear sex-related difference in PFOS-induced hepatic steatosis in the rat. Additional evaluated mechanisms (ie, nuclear receptor activation, mRNA upregulation, and choline kinase activity inhibition) did not appear to be involved in the hepatic steatosis. Dietary PFOS (100 ppm) induced hepatic steatosis in male, but not female, rats that was not attenuated by choline supplementation. The mechanism of lipid accumulation and the sex-related differences warrant further investigation.
Assuntos
Ácidos Alcanossulfônicos/toxicidade , Colina/administração & dosagem , Suplementos Nutricionais , Poluentes Ambientais/toxicidade , Fluorocarbonos/toxicidade , Fígado/efeitos dos fármacos , Hepatopatia Gordurosa não Alcoólica/induzido quimicamente , Hepatopatia Gordurosa não Alcoólica/prevenção & controle , Animais , Biomarcadores/sangue , Colesterol/sangue , Ácidos Graxos não Esterificados/metabolismo , Feminino , Regulação da Expressão Gênica , Fígado/metabolismo , Fígado/patologia , Masculino , Hepatopatia Gordurosa não Alcoólica/sangue , Hepatopatia Gordurosa não Alcoólica/genética , Tamanho do Órgão , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Ratos Sprague-Dawley , Fatores Sexuais , Fatores de Tempo , Triglicerídeos/sangueRESUMO
Choline is an essential nutrient utilized for phosphatidylcholine biosynthesis and lipoprotein packaging and secretion. Recently, choline supplementation has been used by athletes and the public for weight loss. However, the potential toxicological impact of choline dietary supplementation requires further investigation. This study examined the effects of choline dietary supplementation in Sprague Dawley rats for 4 weeks. Rats were fed diets containing basal choline levels (control) or 5-, 10-, or 15-fold (5×, 10×, or 15×) basal diet concentration. In groups fed choline-supplemented diets, there were no toxicologically relevant findings in clinical observations, food intake, clinical chemistry, liver weights, or liver histopathology. However, decreased mean body weights (8.5-10.2%) and body weight gains (24-31%) were noted for the 10× choline-supplemented (females only) and 15× choline-supplemented (both sexes) groups relative to the control groups from day 3 onward. These body weight effects were not related to a persistent reduction in average food intake. Serum cholesterol was increased in the 15× choline-supplemented male rats relative to the controls, an expected effect of choline supplementation; however, there were no changes in the serum cholesterol of female rats. Serum choline concentrations were increased in female rats relative to the male rats across all treatment groups. The maximum tolerated dose for male and female rats were the 15× and 10× choline supplements, respectively, based on decreased mean body weight and body weight gains. This study supported the conclusions of a clinical trial that showed a high choline diet can decrease body weight in humans.
Assuntos
Colina/farmacologia , Suplementos Nutricionais , Redução de Peso/efeitos dos fármacos , Animais , Colina/administração & dosagem , Colina/sangue , Ingestão de Alimentos/efeitos dos fármacos , Feminino , Fígado/efeitos dos fármacos , Masculino , Ratos , Ratos Sprague-DawleyRESUMO
Ethyl-N-(2-hydroxyethyl)-perfluorooctanesulfonamide (EtFOSE) was one of the key building blocks for many of the perfluorooctanesulfonyl-based chemistry and laboratory studies have shown that EtFOSE can metabolically degrade to perfluorooctanesulfonate (PFOS). Non-occupational contribution sources to PFOS are thought to occur in general population via diets, drinking water, air and dust. For workers, however, the exposure route was mostly airborne and the exposure source was predominantly to precursor compounds such as EtFOSE. We undertook this study to investigate how much EtFOSE was converted to PFOS in the serum for male rats after 6h of exposure to EtFOSE vapor (whole body) at ambient temperature, which simulated a work place exposure scenario. There were no abnormal clinical observations and all rats gained weight during study. Interim tail-vein blood samples, collected up to 21 days after exposure, were analyzed for Et-FOSE and PFOS concentrations by LC-MS/MS. Upon inhalation exposure, the biotransformation of EtFOSE to PFOS in serum in the male rats was rapid and very little EtFOSE was detected in the serum within 24h after EtFOSE exposure. The highest conversion to PFOS in serum after exposure to EtFOSE vapor appeared to occur between Day 8-14 post exposure. Considering the potential surface and fur adsorption of test compound in the whole-body exposure system, our data would support that at least 10% of the inhaled EtFOSE was biotransformed to PFOS in the serum based on the range of lower 95% CI (confidence interval) values. This information is valuable because it quantitatively translates EtFOSE exposure into serum PFOS concentration, which serves as a matrix for internal dosimetry (of PFOS exposure) that can be used as an anchor across species as well as between different exposure routes.
Assuntos
Ácidos Alcanossulfônicos/sangue , Fluorocarbonos/sangue , Sulfonamidas/farmacocinética , Administração por Inalação , Animais , Biotransformação , Masculino , Ratos Sprague-DawleyRESUMO
An oral dose study with perfluorooctanesulfonate (PFOS) was undertaken to identify potential associations between serum PFOS and changes in serum clinical chemistry parameters in purpose-bred young adult cynomolgus monkeys (Macaca fascicularis). In this study, control group (n = 6/sex) was sham-dosed with vehicle (0.5% Tween 20 and 5% ethanol in water), low-dose group (n = 6/sex) received 1 single K+PFOS dose (9 mg/kg), and high-dose group (n = 4-6/sex) received 3 separate K+ PFOS doses (11-17.2 mg/kg). Monkeys were given routine checkups and observed carefully for health problems on a daily basis. Scheduled blood samples were drawn from all monkeys prior to, during, and after K+PFOS administration for up to 1 year and they were analyzed for PFOS concentrations and clinical chemistry markers for coagulation, lipids, hepatic, renal, electrolytes, and thyroid-related hormones. No mortality occurred during the study. All the monkeys were healthy, gained weight, and were released back to the colony at the end of the study. The highest serum PFOS achieved was approximately 165 µg/ml. When compared with time-matched controls, administration of K+PFOS to monkeys did not result in any toxicologically meaningful or clinically relevant changes in serum clinical measurements for coagulation, lipids, hepatic, renal, electrolytes, and thyroid-related hormones. A slight reduction in serum cholesterol (primarily the high-density lipoprotein fraction), although not toxicologically significant, was observed. The corresponding lower-bound fifth percentile benchmark concentrations (BMCL1sd) were 74 and 76 µg/ml for male and female monkeys, respectively. Compared to the 2013-2014 geometric mean serum PFOS level of 4.99 ng/ml (0.00499 µg/ml) in US general population reported by CDC NHANES, this represents 4 orders of magnitude for margin of exposure.
Assuntos
Ácidos Alcanossulfônicos/sangue , Ácidos Alcanossulfônicos/toxicidade , Fluorocarbonos/sangue , Fluorocarbonos/toxicidade , Lipídeos/sangue , Fígado/efeitos dos fármacos , Hormônios Tireóideos/sangue , Animais , Coagulação Sanguínea/efeitos dos fármacos , Peso Corporal/efeitos dos fármacos , HDL-Colesterol/sangue , Relação Dose-Resposta a Droga , Feminino , Fígado/metabolismo , Macaca fascicularis , MasculinoRESUMO
Perfluoroalkyl sulfonates (PFSAs) such as perfluorohexane sulfonate (PFHxS) and perfluorooctane sulfonate (PFOS) have very long serum elimination half-lives in humans, and preferentially distribute to serum and liver. The enterohepatic circulation of PFHxS and PFOS likely contributes to their extended elimination half-lives. We previously demonstrated that perfluorobutane sulfonate (PFBS), PFHxS, and PFOS are transported into hepatocytes both in a sodium-dependent and a sodium-independent manner. We identified Na+/taurocholate cotransporting polypeptide (NTCP) as the responsible sodium-dependent transporter. Furthermore, we demonstrated that the human apical sodium-dependent bile salt transporter (ASBT) contributes to the intestinal reabsorption of PFOS. However, so far no sodium-independent uptake transporters for PFSAs have been identified in human hepatocytes or enterocytes. In addition, perfluoroalkyl carboxylates (PFCAs) with 8 and 9 carbons were shown to preferentially distribute to the liver of rodents; however, no rat or human liver uptake transporters are known to transport these PFCAs. Therefore, we tested whether PFBS, PFHxS, PFOS, and PFCAs with 7-10 carbons are substrates of organic anion transporting polypeptides (OATPs). We used CHO and HEK293 cells to demonstrate that human OATP1B1, OATP1B3, and OATP2B1 can transport PFBS, PFHxS, PFOS, and the 2 PFCAs (C8 and C9). In addition, we show that rat OATP1A1, OATP1A5, OATP1B2, and OATP2B1 transport all 3 PFSAs. In conclusion, our results suggest that besides NTCP and ASBT, OATPs also are capable of contributing to the enterohepatic circulation and extended human serum elimination half-lives of the tested perfluoroalkyl acids.
Assuntos
Ácidos Alcanossulfônicos/metabolismo , Poluentes Ambientais/metabolismo , Fluorocarbonos/metabolismo , Hepatócitos/metabolismo , Transportador 1 de Ânion Orgânico Específico do Fígado/metabolismo , Transportadores de Ânions Orgânicos/metabolismo , Membro 1B3 da Família de Transportadores de Ânion Orgânico Carreador de Soluto/metabolismo , Animais , Transporte Biológico , Células CHO , Caprilatos/metabolismo , Cricetulus , Células HEK293 , Humanos , Transportador 1 de Ânion Orgânico Específico do Fígado/genética , Transportadores de Ânions Orgânicos/genética , Transportadores de Ânions Orgânicos Sódio-Independentes/genética , Transportadores de Ânions Orgânicos Sódio-Independentes/metabolismo , Ratos , Proteínas Recombinantes de Fusão/metabolismo , Membro 1B3 da Família de Transportadores de Ânion Orgânico Carreador de Soluto/genética , Ácidos Sulfônicos/metabolismoRESUMO
The mechanisms underlying perfluorooctane sulfonate (PFOS)-induced steatosis remain unclear. The hypothesis that PFOS causes steatosis and other hepatic effects by forming an ion pair with choline was examined. C57BL/6 mice were fed either a control diet or a marginal methionine/choline-deficient (mMCD) diet, with and without 0.003, 0.006, or 0.012% potassium PFOS. Dietary PFOS caused a dose-dependent decrease in body weight, and increases in the relative liver weight, hepatic triglyceride concentration and serum markers of liver toxicity and oxidative stress. Some of these effects were exacerbated in mice fed the mMCD diet supplemented with 0.012% PFOS compared with those fed the control diet supplemented with 0.012% PFOS. Surprisingly, serum PFOS concentrations were higher while liver PFOS concentrations were lower in mMCD-fed mice compared with corresponding control-fed mice. To determine if supplemental dietary choline could prevent PFOS-induced hepatic effects, C57BL/6 mice were fed a control diet, or a choline supplemental diet (1.2%) with or without 0.003% PFOS. Lipidomic analysis demonstrated that PFOS caused alterations in hepatic lipid metabolism in the PFOS-fed mice compared with controls, and supplemental dietary choline prevented these PFOS-induced changes. Interestingly, dietary choline supplementation also prevented PFOS-induced oxidative damage. These studies are the first to suggest that PFOS may cause hepatic steatosis and oxidative stress by effectively reducing the choline required for hepatic VLDL production and export by forming an ion pair with choline, and suggest that choline supplementation may prevent and/or treat PFOS-induced hepatic steatosis and oxidative stress.
Assuntos
Ácidos Alcanossulfônicos/metabolismo , Colina/metabolismo , Fígado Gorduroso/induzido quimicamente , Fluorocarbonos/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Ácidos Alcanossulfônicos/toxicidade , Animais , Colina/toxicidade , Relação Dose-Resposta a Droga , Fluorocarbonos/toxicidade , Masculino , Camundongos , Camundongos Endogâmicos C57BLRESUMO
Among the perfluoroalkyl sulfonates (PFASs), perfluorohexane sulfonate (PFHxS), and perfluorooctane sulfonate (PFOS) have half-lives of several years in humans, mainly due to slow renal clearance and potential hepatic accumulation. Both compounds undergo enterohepatic circulation. To determine whether transporters involved in the enterohepatic circulation of bile acids are also involved in the disposition of PFASs, uptake of perfluorobutane sulfonate (PFBS), PFHxS, and PFOS was measured using freshly isolated human and rat hepatocytes in the absence or presence of sodium. The results demonstrated sodium-dependent uptake for all 3 PFASs. Given that the Na(+)/taurocholate cotransporting polypeptide (NTCP) and the apical sodium-dependent bile salt transporter (ASBT) are essential for the enterohepatic circulation of bile acids, transport of PFASs was investigated in stable CHO Flp-In cells for human NTCP or HEK293 cells transiently expressing rat NTCP, human ASBT, and rat ASBT. The results demonstrated that both human and rat NTCP can transport PFBS, PFHxS, and PFOS. Kinetics with human NTCP revealed Km values of 39.6, 112, and 130 µM for PFBS, PFHxS, and PFOS, respectively. For rat NTCP Km values were 76.2 and 294 µM for PFBS and PFHxS, respectively. Only PFOS was transported by human ASBT whereas rat ASBT did not transport any of the tested PFASs. Human OSTα/ß was also able to transport all 3 PFASs. In conclusion, these results suggest that the long half-live and the hepatic accumulation of PFOS in humans are at least, in part, due to transport by NTCP and ASBT.
Assuntos
Ácidos Alcanossulfônicos/farmacocinética , Fluorocarbonos/farmacocinética , Transportadores de Ânions Orgânicos Dependentes de Sódio/fisiologia , Ácidos Sulfônicos/farmacocinética , Simportadores/fisiologia , Animais , Hepatócitos/metabolismo , Humanos , RatosRESUMO
Previous studies suggested that perfluorooctanoate (PFOA) could activate the estrogen receptor (ER). The present study examined the hypothesis that PFOA can activate ER using an in vivo uterotrophic assay in CD-1 mice and an in vitro reporter assay. Pre-pubertal female CD-1 mice fed an estrogen-free diet from postnatal day (PND)14 through weaning on PND18 were administered 0, 0.005, 0.01, 0.02, 0.05, 0.1, or 1mg/kg PFOA or 17ß-estradiol (E2, 0.5mg/kg) from PND18-20. In contrast to E2, PFOA caused no changes in the relative uterine weight, the expression of ER target genes, or the morphology of the uterus/cervix and/or vagina on PND21. Treatment of a stable human cell line containing an ER-dependent luciferase reporter construct with a broad concentration range of PFOA caused no change in ER-dependent luciferase activity; whereas E2 caused a marked increase of ER-dependent luciferase activity. These data indicate that PFOA does not activate mouse or human ER.
Assuntos
Caprilatos/toxicidade , Poluentes Ambientais/toxicidade , Fluorocarbonos/toxicidade , Receptores de Estrogênio/efeitos dos fármacos , Útero/efeitos dos fármacos , Vagina/efeitos dos fármacos , Animais , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Estradiol/farmacologia , Receptor alfa de Estrogênio/efeitos dos fármacos , Receptor alfa de Estrogênio/genética , Receptor alfa de Estrogênio/metabolismo , Estrogênios/farmacologia , Feminino , Regulação da Expressão Gênica , Genes Reporter , Humanos , Camundongos , Tamanho do Órgão , Receptores de Estrogênio/genética , Receptores de Estrogênio/metabolismo , Elementos de Resposta , Transfecção , Útero/metabolismo , Útero/patologia , Vagina/metabolismo , Vagina/patologiaRESUMO
This study examined the effect of prenatal perfluorooctanoic acid (PFOA) administration on pre- and postnatal development using peroxisome proliferator-activated receptor α (PPARα)-humanized mice to determine if species differences in receptor activity might influence the developmental effects induced by PFOA. Pregnant mice were treated daily with water or PFOA (3mg/kg) by po gavage from gestation day 1 (GD1) until GD17 and then either euthanized on GD18 or allowed to give birth and then euthanized on postnatal day 20 (PND20). No changes in average fetal weight, crown-to-rump length, or placental weight were observed on GD18. Expression of mRNA encoding the PPARα target genes acyl CoA oxidase (Acox1) and cytochrome P450 4a10 (Cyp4a10) in maternal and fetal liver was increased on GD18 in wild-type and PPARα-humanized mice but not in Pparα-null mice. On PND20, relative liver weight was higher in wild-type mice but not in Pparα-null mice or PPARα-humanized mice. Hepatic expression of Acox1 and Cyp4a10 mRNA was higher in wild-type mice but not in Pparα-null mice or PPARα-humanized mice on PND20. The percentage of mice surviving postnatally was lower in wild-type litters but not in litters from Pparα-null mice or PPARα-humanized mice. No changes in pup weight gain, onset of eye opening, or mammary gland development were found in any genotype. Results from these studies demonstrate that the developmental/postnatal effects resulting from prenatal PFOA exposure in mice are differentially mediated by mouse and human PPARα.
Assuntos
Caprilatos/toxicidade , Fluorocarbonos/toxicidade , PPAR alfa/metabolismo , Animais , Feminino , Humanos , Camundongos , Camundongos Knockout , Gravidez , Reação em Cadeia da Polimerase em Tempo Real , Especificidade da EspécieRESUMO
OBJECTIVE: To examine in a longitudinal occupational assessment whether changes in serum concentrations of perfluorooctanoic acid (PFOA) and perfluorooctanesulfonate (PFOS) are associated with changes in non-high-density lipoprotein (HDL) cholesterol. METHODS: Baseline and end-of-project PFOA, PFOS, lipid, and hepatic clinical chemistries were measured in 204 workers involved with the demolition of former perfluoroalkyl manufacturing facilities. Analyses were restricted to the 179 workers who did not take lipid-lowering medications. Two thirds had baseline PFOA and PFOS levels similar to the general population. RESULTS: The change in non-HDL cholesterol was not associated with the changes in PFOA or PFOS. An increase in HDL was associated with an increase in PFOA, although the magnitude was small. This increase in HDL resulted in a decrease in the total cholesterol/HDL ratio. CONCLUSION: Adverse associations were not observed between changes in PFOA, PFOS, non-HDL cholesterol, HDL, and hepatic clinical chemistries.
Assuntos
Ácidos Alcanossulfônicos/sangue , Caprilatos/sangue , VLDL-Colesterol/sangue , Fluorocarbonos/sangue , Lipídeos/sangue , Lipoproteínas HDL/sangue , Exposição Ocupacional , Adulto , Indústria Química , LDL-Colesterol/sangue , Feminino , Humanos , Fígado/metabolismo , Estudos Longitudinais , Masculino , Pessoa de Meia-IdadeRESUMO
Some cross-sectional epidemiological studies have reported positive associations of serum concentrations of non-high density lipoprotein cholesterol with serum perfluorooctanesulfonate (PFOS) and perfluorooctanoate (PFOA). However, the strength of the reported associations is inconsistent for exposure-response across three orders of magnitude of serum PFOS and/or PFOA concentrations. These positive associations are unexpected based on toxicological/mechanistic studies, suggesting that the associations may have a biological, rather than a causal, basis. This study tested the hypothesis that PFOS and PFOA distribute into serum lipoprotein fractions such that increases in serum lipoproteins would result in corresponding increases in serum concentrations of PFOS and PFOA. Based on observed binding of PFOS and PFOA to isolated ß-lipoproteins in physiological saline (96% and 40% bound, respectively) in preliminary experiments using ultrafiltration and LC-MS/MS methods, binding to human donor plasma lipoprotein fractions was investigated by two density gradient methods. The majority of PFOS and PFOA recovered masses were found in lipoprotein-depleted plasma. Plasma density gradient fractionation data suggested that maximally 9% of PFOS distributes to lipoprotein-containing fractions, yet only 1% or less of PFOA is so distributed. These data do not support a strong role for plasma lipoprotein fractions in explaining the inconsistent dose-response associations reported in cross-sectional epidemiological studies.
Assuntos
Ácidos Alcanossulfônicos/sangue , Caprilatos/sangue , Fluorocarbonos/sangue , Lipoproteínas/sangue , Centrifugação com Gradiente de Concentração , Estudos Transversais , Relação Dose-Resposta a Droga , Humanos , Ligação ProteicaRESUMO
The present study investigated the potential role for activation of PPARα and CAR/PXR by potassium PFOS (K⺠PFOS) with respect to the etiology of hepatic hypertrophy and hepatocellular adenoma in rats. Male Sprague-Dawley rats were fed K⺠PFOS (20 or 100 ppm) for either 1, 7, or 28 days. Wyeth 14,643 (Wy 14,643, 50 ppm) and phenobarbital (PB, 500 ppm) were the controls for PPARα and CAR/PXR activation, respectively. Measurements included: plasma ALT, AST, cholesterol, triglycerides, and glucose; liver protein and DNA content; liver activities of palmitoyl CoA oxidase (ACOX), Cyp4A, CYP2B, and CYP3A; induction of liver CYP4A1, CYP2E1, CYP2B1/2, and CYP3A1 proteins (SDS-PAGE and Western blots); liver and thyroid microscopic histopathology, apoptotic index, and cell proliferation index. Terminal body weight was decreased by K⺠PFOS (100 ppm) and Wy 14,643. All test-compound treatments increased liver weight. Plasma lipids were decreased by both PFOS and Wy 14,643. After treatment for 1 day, K⺠PFOS (100 ppm), PB, and Wy 14,643 increased mean hepatic DNA concentration and total hepatic DNA, and total DNA remained elevated after treatment for 7 days and 28 days (PB and Wy 14,643 only). Hepatic P450 concentration was elevated after 7 and 28 days by K⺠PFOS and by PB. K⺠PFOS and Wy 14,643 increased liver activities of ACOX and CYP4A as well as increased liver CYP4A1 protein. By 28 days of treatment, K⺠PFOS and PB increased liver activities of CYP2B and CYP3A as well as increased liver CYP2B1/2 and CYP3A1 proteins, and Wy 14,643 increased CYP2B enzyme activity to a slight extent. All test compounds increased the liver cell proliferative index and decreased the liver apoptotic index. No histological changes of the thyroid were noted; however, PB and WY increased thyroid follicular cell proliferation index (seven-day treatment only), while K⺠PFOS did not. The thyroid follicular cell apoptotic index did not differ between groups. The hepatomegaly and hepatocellular adenoma observed after dietary exposure of Sprague-Dawley rats to K⺠PFOS likely are due to the increased expression of xenosensor nuclear receptors PPARα and CAR/PXR. Given the markedly lower or absent response of human hepatocytes to the proliferative stimulus from activation of PPARα and CAR/PXR, the hepatocellular proliferative response from activation of these receptors by PFOS observed in rats is not expected to be of human relevance.
Assuntos
Adenoma de Células Hepáticas/induzido quimicamente , Ácidos Alcanossulfônicos/toxicidade , Proliferação de Células/efeitos dos fármacos , Fluorocarbonos/toxicidade , Neoplasias Hepáticas/induzido quimicamente , PPAR alfa/metabolismo , Receptores Citoplasmáticos e Nucleares/metabolismo , Receptores de Esteroides/metabolismo , Adenoma de Células Hepáticas/química , Adenoma de Células Hepáticas/metabolismo , Adenoma de Células Hepáticas/patologia , Ácidos Alcanossulfônicos/administração & dosagem , Ácidos Alcanossulfônicos/análise , Ácidos Alcanossulfônicos/farmacocinética , Animais , Apoptose/efeitos dos fármacos , Carcinógenos/administração & dosagem , Carcinógenos/análise , Carcinógenos/farmacocinética , Carcinógenos/toxicidade , Receptor Constitutivo de Androstano , Sistema Enzimático do Citocromo P-450/metabolismo , Relação Dose-Resposta a Droga , Poluentes Ambientais/administração & dosagem , Poluentes Ambientais/análise , Poluentes Ambientais/farmacocinética , Poluentes Ambientais/toxicidade , Fluorocarbonos/administração & dosagem , Fluorocarbonos/análise , Fluorocarbonos/farmacocinética , Hepatomegalia/induzido quimicamente , Fígado/química , Fígado/efeitos dos fármacos , Fígado/metabolismo , Fígado/patologia , Neoplasias Hepáticas/química , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , Masculino , Proteínas de Neoplasias/metabolismo , Receptor de Pregnano X , Distribuição Aleatória , Ratos , Ratos Sprague-Dawley , Glândula Tireoide/efeitos dos fármacos , Glândula Tireoide/patologia , Testes de Toxicidade SubagudaRESUMO
In a prior 28-day dietary study in rats with 20 and 100 ppm K⺠PFOS, activation of PPARα and CAR/PXR were concluded to be etiological factors in K⺠PFOS-induced hepatomegaly and hepatic tumorigenesis. The objective of this study was to evaluate persistence/resolution of K⺠PFOS-induced, liver-related effects in male Sprague Dawley rats following a 7-day dietary exposure to K⺠PFOS at 20 or 100 ppm. Groups of 10 rats per treatment were observed on recovery Day(s) 1, 28, 56, and 84 following treatment. Changes consistent with hepatic PPARα and CAR/PXR activation noted on recovery Day 1 included: increased liver weight; decreased plasma cholesterol, alanine aminotransferase, and triglycerides; decreased liver DNA concentration and increased hepatocellular cytosolic CYP450 concentration; increased liver activity of acyl CoA oxidase, CYP4A, CYP2B, and CYP3A; increased liver proliferative index and decreased liver apoptotic index; decreased hepatocellular glycogen-induced vacuoles; increased centrilobular hepatocellular hypertrophy. Most effects resolved to control levels during recovery. Effects on plasma cholesterol, hepatocellular cytosolic CYP450 concentrations, liver apoptotic index, CYP3A, and centrilobular hepatocellular hypertrophy persisted through the end of the recovery period. Thyroid parameters (histology, apoptosis, and proliferation) were unaffected at all time points. Mean serum PFOS concentrations on recovery Day 1 were 39 and 140 µg/mL (20 ppm and 100 ppm K⺠PFOS, respectively), decreasing to 4 and 26 µg/mL by recovery Day 84. Thus, hepatic effects in male rats resulting from K⺠PFOS-induced activation of PPARα and CAR/PXR resolved slowly or were still present after 84-days following a 7-day dietary treatment, consistent with the slow elimination rate of PFOS.
Assuntos
Ácidos Alcanossulfônicos/farmacocinética , Ácidos Alcanossulfônicos/toxicidade , Carcinógenos/farmacocinética , Carcinógenos/toxicidade , Fluorocarbonos/farmacocinética , Fluorocarbonos/toxicidade , Hepatomegalia/induzido quimicamente , Fígado/efeitos dos fármacos , Glândula Tireoide/efeitos dos fármacos , Ácidos Alcanossulfônicos/administração & dosagem , Ácidos Alcanossulfônicos/metabolismo , Animais , Apoptose/efeitos dos fármacos , Carcinógenos/administração & dosagem , Carcinógenos/metabolismo , Proliferação de Células/efeitos dos fármacos , Receptor Constitutivo de Androstano , Sistema Enzimático do Citocromo P-450/metabolismo , Relação Dose-Resposta a Droga , Poluentes Ambientais/administração & dosagem , Poluentes Ambientais/metabolismo , Poluentes Ambientais/farmacocinética , Poluentes Ambientais/toxicidade , Fluorocarbonos/administração & dosagem , Fluorocarbonos/metabolismo , Meia-Vida , Hepatomegalia/sangue , Hepatomegalia/metabolismo , Hepatomegalia/patologia , Fígado/metabolismo , Fígado/patologia , Masculino , PPAR alfa/metabolismo , Receptor de Pregnano X , Distribuição Aleatória , Ratos , Ratos Sprague-Dawley , Receptores Citoplasmáticos e Nucleares/metabolismo , Receptores de Esteroides/metabolismo , Glândula Tireoide/patologia , Testes de Toxicidade SubagudaRESUMO
Perfluorooctanesulfonate (PFOS) has been found in biological samples in wildlife and humans. The geometric mean half-life of serum elimination of PFOS in humans has been estimated to be 4.8 years (95% CI, 4.0-5.8). A series of studies was undertaken to establish pharmacokinetic parameters for PFOS in rats, mice, and monkeys after single oral and/or IV administration of K(+)PFOS. Animals were followed for up to 23 weeks, and pharmacokinetic parameters were determined by WinNonlin® software. Rats and mice appeared to be more effective at eliminating PFOS than monkeys. The serum elimination half-lives in the rodent species were on the order of 1-2 months; whereas, in monkeys, the serum elimination half lives approximated 4 months. Collectively, these studies provide valuable insight for human health risk assessment regarding the potential for accumulation of body burden in humans on repeated exposure to PFOS and PFOS-generating materials.
Assuntos
Ácidos Alcanossulfônicos/farmacocinética , Poluentes Ambientais/farmacocinética , Fluorocarbonos/farmacocinética , Administração Oral , Ácidos Alcanossulfônicos/sangue , Ácidos Alcanossulfônicos/urina , Animais , Poluentes Ambientais/sangue , Poluentes Ambientais/urina , Fezes/química , Feminino , Fluorocarbonos/sangue , Fluorocarbonos/urina , Meia-Vida , Injeções Intravenosas , Fígado/metabolismo , Macaca fascicularis , Masculino , Taxa de Depuração Metabólica , Camundongos , Camundongos Endogâmicos , Ratos , Ratos Sprague-Dawley , Especificidade da Espécie , Distribuição TecidualRESUMO
Sequential 28-day and 90-day oral toxicity studies were performed in male and female rats with ammonium perfluorobutyrate (NH(4)(+)PFBA) at doses up to 150 and 30mg/kg-d, respectively. Ammonium perfluorooctanoate was used as a comparator at a dose of 30mg/kg-d in the 28-day study. Female rats were unaffected by NH(4)(+)PFBA. Effects in males included: increased liver weight, slight to minimal hepatocellular hypertrophy; decreased serum total cholesterol; and reduced serum thyroxin with no change in serum thyrotropin. During recovery, liver weight, histological, and cholesterol effects were resolved. Results of RT-qPCR were consistent with increased transcriptional expression of the xenosensor nuclear receptors PPARα and CAR as well as the thyroid receptor, and decreased expression of Cyp1A1 (Ah receptor-regulated). No observable adverse effect levels (NOAELs) were 6 and >150mg/kg-d for male and female rats in the 28-day study and 6 and >30mg/kg-d in the 90-dat study, respectively.
Assuntos
Fluorocarbonos/toxicidade , Testes de Toxicidade Subcrônica/métodos , Poluentes Químicos da Água/toxicidade , Administração Oral , Animais , Peso Corporal/efeitos dos fármacos , Colesterol/sangue , Relação Dose-Resposta a Droga , Feminino , Fluorocarbonos/sangue , Fluorocarbonos/farmacocinética , Expressão Gênica/efeitos dos fármacos , Fígado/efeitos dos fármacos , Fígado/metabolismo , Fígado/patologia , Masculino , Tamanho do Órgão/efeitos dos fármacos , RNA Mensageiro/genética , Ratos , Ratos Sprague-Dawley , Glândula Tireoide/efeitos dos fármacos , Glândula Tireoide/metabolismo , Glândula Tireoide/patologia , Hormônios Tireóideos/sangue , Poluentes Químicos da Água/sangue , Poluentes Químicos da Água/farmacocinéticaRESUMO
Perfluorohexanesulfonate (PFHxS) has been found in biological samples from wildlife and humans. The human geometric mean serum PFHxS elimination half-life has been estimated to be 2665days. A series of studies was undertaken to establish pharmacokinetic parameters for PFHxS in rats, mice, and monkeys after single administration with pharmacokinetic parameters determined by WinNonlin(®) software. Rats and mice appeared to be more effective at eliminating PFHxS than monkeys. With the exception of female rats, which had serum PFHxS elimination half-life of approximately 2 days, the serum elimination half-lives in the rodent species and monkeys approximated 1month and 4months, respectively, when followed over extended time periods (10-24weeks). Collectively, these studies provide valuable insight for human health risk assessment regarding the potential for accumulation of PFHxS in humans.
Assuntos
Poluentes Ambientais/farmacocinética , Ácidos Sulfônicos/farmacocinética , Administração Oral , Animais , Relação Dose-Resposta a Droga , Poluentes Ambientais/sangue , Poluentes Ambientais/urina , Fezes/química , Feminino , Fluorocarbonos , Meia-Vida , Injeções Intravenosas , Fígado/metabolismo , Macaca fascicularis , Masculino , Taxa de Depuração Metabólica , Camundongos , Camundongos Endogâmicos , Ratos , Ratos Sprague-Dawley , Fatores Sexuais , Especificidade da Espécie , Ácidos Sulfônicos/sangue , Ácidos Sulfônicos/urina , Distribuição TecidualRESUMO
Perfluorobutane sulfonate (PFBS), perfluorohexane sulfonate (PFHxS), and perfluorooctane sulfonate (PFOS) are stable perfluoroalkyl sulfonate (PFAS) surfactants, and PFHxS and PFOS are frequently detected in human biomonitoring studies. Some epidemiological studies have shown modest positive correlations of serum PFOS with non-high-density lipoprotein (HDL)-cholesterol (C). This study investigated the mechanism underlying the effect of PFAS surfactants on lipoprotein metabolism. APOE*3-Leiden.CETP mice were fed a Western-type diet with PFBS, PFHxS, or PFOS (30, 6, and 3 mg/kg/day, respectively) for 4-6 weeks. Whereas PFBS modestly reduced only plasma triglycerides (TG), PFHxS and PFOS markedly reduced TG, non-HDL-C, and HDL-C. The decrease in very low-density lipoprotein (VLDL) was caused by enhanced lipoprotein lipase-mediated VLDL-TG clearance and by decreased production of VLDL-TG and VLDL-apolipoprotein B. Reduced HDL production, related to decreased apolipoprotein AI synthesis, resulted in decreased HDL. PFHxS and PFOS increased liver weight and hepatic TG content. Hepatic gene expression profiling data indicated that these effects were the combined result of peroxisome proliferator-activated receptor alpha and pregnane X receptor activation. In conclusion, the potency of PFAS to affect lipoprotein metabolism increased with increasing alkyl chain length. PFHxS and PFOS reduce plasma TG and total cholesterol mainly by impairing lipoprotein production, implying that the reported positive correlations of serum PFOS and non-HDL-C are associative rather than causal.
Assuntos
Proteínas de Transferência de Ésteres de Colesterol/genética , Fígado Gorduroso/induzido quimicamente , Fluorocarbonos/toxicidade , Metabolismo dos Lipídeos/efeitos dos fármacos , Tensoativos/toxicidade , Ácidos Alcanossulfônicos/química , Ácidos Alcanossulfônicos/toxicidade , Animais , Fígado Gorduroso/metabolismo , Fluorocarbonos/química , Humanos , Fígado/efeitos dos fármacos , Fígado/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Relação Quantitativa Estrutura-Atividade , Ácidos Sulfônicos/química , Ácidos Sulfônicos/toxicidade , Tensoativos/químicaRESUMO
The objectives of this study were to determine the structural characteristics of perfluoroalkyl acids (PFAAs) that confer estrogen-like activity in vivo using juvenile rainbow trout (Oncorhynchus mykiss) as an animal model and to determine whether these chemicals interact directly with the estrogen receptor (ER) using in vitro and in silico species comparison approaches. Perfluorooctanoic (PFOA), perfluorononanoic (PFNA), perfluorodecanoic (PFDA), and perfluoroundecanoic (PFUnDA) acids were all potent inducers of the estrogen-responsive biomarker protein vitellogenin (Vtg) in vivo, although at fairly high dietary exposures. A structure-activity relationship for PFAAs was observed, where eight to ten fluorinated carbons and a carboxylic acid end group were optimal for maximal Vtg induction. These in vivo findings were corroborated by in vitro mechanistic assays for trout and human ER. All PFAAs tested weakly bound to trout liver ER with half maximal inhibitory concentration (IC(50)) values of 15.2-289 µM. Additionally, PFOA, PFNA, PFDA, PFUnDA, and perlfuorooctane sulfonate (PFOS) significantly enhanced human ERα-dependent transcriptional activation at concentrations ranging from 10-1000 nM. Finally, we employed an in silico computational model based upon the crystal structure for the human ERα ligand-binding domain complexed with E2 to structurally investigate binding of these putative ligands to human, mouse, and trout ERα. PFOA, PFNA, PFDA, and PFOS all efficiently docked with ERα from different species and formed a hydrogen bond at residue Arg394/398/407 (human/mouse/trout) in a manner similar to the environmental estrogens bisphenol A and nonylphenol. Overall, these data support the contention that several PFAAs are weak environmental xenoestrogens of potential concern.
Assuntos
Ácidos Acíclicos/toxicidade , Poluentes Ambientais/toxicidade , Estrogênios não Esteroides/toxicidade , Fluorocarbonos/toxicidade , Oncorhynchus mykiss/metabolismo , Receptores de Estrogênio/metabolismo , Ácidos Acíclicos/química , Animais , Ligação Competitiva , Biomarcadores/sangue , Relação Dose-Resposta a Droga , Poluentes Ambientais/química , Ensaio de Imunoadsorção Enzimática , Receptor alfa de Estrogênio/metabolismo , Estrogênios não Esteroides/química , Fluorocarbonos/química , Humanos , Fígado/metabolismo , Estrutura Molecular , Ligação Proteica , Especificidade da Espécie , Relação Estrutura-Atividade , Vitelogeninas/sangueRESUMO
The widespread presence of perfluorooctanesulfonate (PFOS), perfluorooctanoate (PFOA), and perfluorohexanesulfonate (PFHxS) in human general populations and their slow elimination profiles have led to renewed interest in understanding the potential human neonatal exposures of perfluoroalkyls (PFAs) from consumption of human milk. The objective of this study was to evaluate the concentrations of PFOS, PFHxS, and PFOA in pooled human milk samples obtained in Sweden between 1972 and 2008 (a period representing the most significant period of PFA production) and to see whether the time trend of these analytes parallels that indicated in human serum. Chemical analysis of PFOS, PFHxS, and PFOA was performed on pooled Swedish human milk samples from 1972 to 2008 after methodological refinements. The 20 samples which formed the 2007 pool were also analyzed individually to evaluate sample variations. Analyses were performed by HPLC-MS/MS. Due to the complexities of the human milk matrix and the requirement to accurately quantitate low pg/mL concentrations, meticulous attention must be paid to background contamination if accurate results are to be obtained. PFOS was the predominant analyte present in the pools and all three analytes showed statistically significant increasing trends from 1972 to 2000, with concentrations reaching a plateau in the 1990s. PFOA and PFOS showed statistically significant decreasing trends during 2001-2008. At the end of the study, in 2008, the measured concentrations of PFOS, PFHxS, and PFOA in pooled human milk were 75 pg/mL, 14 pg/mL, and 74 pg/mL, respectively. The temporal concentration trends of PFOS, PFHxS, and PFOA observed in human milk are parallel to those reported in the general population serum concentrations.
Assuntos
Ácidos Alcanossulfônicos/metabolismo , Caprilatos/metabolismo , Monitoramento Ambiental , Poluentes Ambientais/metabolismo , Fluorocarbonos/metabolismo , Leite Humano/metabolismo , Ácidos Sulfônicos/metabolismo , Adulto , Cidades , Poluição Ambiental/estatística & dados numéricos , Feminino , Humanos , Estudos Longitudinais , Exposição Materna/estatística & dados numéricos , SuéciaRESUMO
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.