Skip to main content
SpringerLink
Log in

Perfluorooctane sulfonate increased hepatic expression of OAPT2 and MRP2 in rats

  • Toxicogenomics
  • Published:
Archives of Toxicology Aims and scope Submit manuscript

Abstract

The toxicity of perfluorooctane sulfonate (PFOS), a persistent organic compound, is of great concern. Several studies have reported that PFOS decreases circulating thyroid hormone (TH) concentrations. However, the mechanisms involved remain to be determined. Female rats were exposed to (1) vehicle; (2) PFOS (0.2, 1.0, and 3.0 mg/kg); (3) propylthiouracil (PTU, 10 mg/kg); or (4) PTU (10 mg/kg) + PFOS (3.0 mg/kg) by gavage once a day for 5 consecutive days. Parameters including contents of total T4 (TT4) and total T3 (TT3) in both serum and bile, serum concentrations of transthyretin and thyroglobulin, as well as transcripts of transporters involved in hepatic uptake and efflux of T4 were determined in control and PFOS-exposed groups. TT4 and TT3 were also analyzed in PTU and PTU + PFOS groups in order to reflect the different hormone effects between PFOS, PTU, and PFOS + PTU. Results showed that serum TT4 and TT3 decreased, while bile TT4 and TT3 remained stable following PFOS exposure. Exposure to 3.0 mg/kg of PFOS significantly enhanced hepatic organic anion transporter OATP2 mRNA expression (1.43 times of control). Treatment with PFOS increased hepatic expression of multidrug resistance–associated protein MRP2, approximately 1.80 and 1.69 times of control in 1.0 and 3.0 mg/kg groups, respectively. Spearman’s correlation coefficients revealed that MRP2 mRNA expression correlated well with serum TT4 level (r = −0.528, P = 0.012). Serum thyroglobulin and transthyretin levels remained stable. Serum TT3, bile TT4, and bile TT3 were significantly different between PFOS and PTU groups. No significant differences of TT4 and TT3 in both serum and bile were observed between PTU and PTU + PFOS (P > 0.05). In conclusion, PFOS increased hepatic expression of OAPT2, which could possibly enhance hepatic uptake and metabolism of T4 in rats. PFOS-induced TT4 deficiency is mainly due to the extrathyroidal metabolism of T4, which is probably different from the classic goitrogen, PTU.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  • Abe T, Kakyo M, Sakagami H, Tokui T, Nishio T, Tanemoto M, Nomura H, Hebert SC, Matsuno S, Kondo H, Yawo H (1998) Molecular characterization and tissue distribution of a new organic anion transporter subtype (oatp3) that transports thyroid hormones and taurocholate and comparison with oatp2. J Biol Chem 273(35):22395–22401

    Article  PubMed  CAS  Google Scholar 

  • Beach SA, Newsted JL, Coady K, Giesy JP (2006) Ecotoxicological evaluation of perfluorooctanesulfonate (PFOS). Rev Environ Contam Toxicol 2006(186):133–174

    Article  Google Scholar 

  • Boas M, Feldt-Rasmussen U, Skakkebaek NE, Main KM (2006) Environmental chemicals and thyroid function. Eur J Endocrinol 154(5):599–611

    Article  PubMed  CAS  Google Scholar 

  • Butenhoff JL, Olsen GW, Pfahles-Hutchens A (2006) The applicability of biomonitoring data for perfluorooctanesulfonate to the environmental public health continuum. Environ Health Perspect 114(11):1776–1782

    PubMed  CAS  Google Scholar 

  • Chang SC, Thibodeaux JR, Eastvold ML, Ehresman DJ, Bjork JA, Froehlich JW, Lau C, Singh RJ, Wallace KB, Butenhoff JL (2008) Thyroid hormone status and pituitary function in adult rats given oral doses of perfluorooctanesulfonate (PFOS). Toxicology 243(3):330–339

    Article  PubMed  CAS  Google Scholar 

  • Chang SC, Ehresman DJ, Bjork JA, Wallace KB, Parker GA, Stump DG, Butenhoff JL (2009) Gestational and lactational exposure to potassium perfluorooctanesulfonate (K+PFOS) in rats: toxicokinetics, thyroid hormone status, and related gene expression. Reprod Toxicol 27(3–4):387–399

    Article  PubMed  CAS  Google Scholar 

  • Cheek AO, Kow K, Chen J, McLachlan JA (1999) Potential mechanisms of thyroid disruption in humans: interaction of organochlorine compounds with thyroid receptor, transthyretin, and thyroid-binding globulin. Environ Health Perspect 107(4):273–278

    Article  PubMed  CAS  Google Scholar 

  • Cho SD, Kim JH, Kim DY, Lee YS, Kang KS (2003) Pre-validation study for OECD enhanced test guideline 407 protocol by gavage for 4 weeks using propylthiouracil and tamoxifen. Toxicol Lett 144(2):195–204

    Article  PubMed  CAS  Google Scholar 

  • Czarnywojtek A, Krysinska I, Lacka K, Stawny B, Rolski M, Jarzab B, Wloch J, Gembicki M (2002) A study of thyroglobulin concentration in the thyroid and serum of patients with different thyroid disorders. Arch Immunol Ther Exp (Warsz) 50(2):143–148

    CAS  Google Scholar 

  • Fromme H, Tittlemier SA, Volkel W, Wilhelm M, Twardella D (2009) Perfluorinated compounds-exposure assessment for the general population in western countries. Int J Hyg Environ Health 212(3):239–270

    Article  PubMed  CAS  Google Scholar 

  • Hamers T, Kamstra JH, Sonneveld E, Murk AJ, Kester MH, Andersson PL, Legler J, Brouwer A (2006) In vitro profiling of the endocrine-disrupting potency of brominated flame retardants. Toxicol Sci 92(1):157–173

    Article  PubMed  CAS  Google Scholar 

  • Han X, Snow TA, Kemper RA, Jepson GW (2003) Binding of perfluorooctanoic acid to rat and human plasma proteins. Chem Res Toxicol 16(6):775–781

    Article  PubMed  CAS  Google Scholar 

  • Kato Y, Suzuki H, Ikushiro S, Yamada S, Degawa M (2005) Decrease in serum thyroxine level by phenobarbital in rats is not necessarily dependent on increase in hepatic UDP-glucuronosyltransferase. Drug Metab Dispos 33(11):1608–1612

    Article  PubMed  CAS  Google Scholar 

  • Lando A, Holm K, Nysom K, Krogh Rasmussen A, Hoier Madsen M, Feldt-Rasmussen U, Muller J (2003) Serum thyroglobulin as a marker of thyroid neoplasms after childhood cancer. Acta Paediatr 92(11):1284–1290

    Article  PubMed  CAS  Google Scholar 

  • Lau C, Thibodeaux JR, Hanson RG, Rogers JM, Grey BE, Stanton ME, Butenhoff JL, Stevenson LA (2003) Exposure to perfluorooctane sulfonate during pregnancy in rat and mouse. II: postnatal evaluation. Toxicol Sci 74(2):382–392

    Article  PubMed  CAS  Google Scholar 

  • Lau C, Anitole K, Hodes C, Lai D, Pfahles-Hutchens A, Seed J (2007) Perfluoroalkyl acids: a review of monitoring and toxicological findings. Toxicol Sci 99(2):366–394

    Article  PubMed  CAS  Google Scholar 

  • Livak KJ, Schmittgen TD (2001) Analysis of relative gene expression data using real-time quantitative PCR and the 2−ΔΔCT method. Methods 25(4):402–408

    Article  PubMed  CAS  Google Scholar 

  • Luebker DJ, Case MT, York RG, Moore JA, Hansen KJ, Butenhoff JL (2005) Two-generation reproduction and cross-foster studies of perfluorooctanesulfonate (PFOS) in rats. Toxicology 215(1–2):126–148

    Article  PubMed  CAS  Google Scholar 

  • Martin MT, Brennan RJ, Hu W, Ayanoglu E, Lau C, Ren H, Wood CR, Corton JC, Kavlock RJ, Dix DJ (2007) Toxicogenomic study of triazole fungicides and perfluoroalkyl acids in rat livers predicts toxicity and categorizes chemicals based on mechanisms of toxicity. Toxicol Sci 97(2):595–613

    Article  PubMed  CAS  Google Scholar 

  • Meerts IA, van Zanden JJ, Luijks EA, van Leeuwen-Bol I, Marsh G, Jakobsson E, Bergman A, Brouwer A (2000) Potent competitive interactions of some brominated flame retardants and related compounds with human transthyretin in vitro. Toxicol Sci 56(1):95–104

    Article  PubMed  CAS  Google Scholar 

  • Mitchell AM, Tom M, Mortimer RH (2005) Thyroid hormone export from cells: contribution of P-glycoprotein. J Endocrinol 185(1):93–98

    Article  PubMed  CAS  Google Scholar 

  • Morgado I, Campinho MA, Costa R, Jacinto R, Power DM (2009) Disruption of the thyroid system by diethylstilbestrol and ioxynil in the sea bream (Sparus aurata). Aquat Toxicol 92(4):271–280

    Article  PubMed  CAS  Google Scholar 

  • Renner R (2001) Growing concern over perfluorinated chemicals. Environ Sci Technol 35(7):154–160

    Article  Google Scholar 

  • Richardson VM, Staskal DF, Ross DG, Diliberto JJ, DeVito MJ, Birnbaum LS (2008) Possible mechanisms of thyroid hormone disruption in mice by BDE 47, a major polybrominated diphenyl ether congener. Toxicol Appl Pharmacol 226(3):244–250

    Article  PubMed  CAS  Google Scholar 

  • Saghir SA, Charles GD, Bartels MJ, Kan LH, Dryzga MD, Brzak KA, Clark AJ (2008) Mechanism of trifluralin-induced thyroid tumors in rats. Toxicol Lett 180(1):38–45

    Article  PubMed  CAS  Google Scholar 

  • Schmutzler C, Gotthardt I, Hofmann PJ, Radovic B, Kovacs G, Stemmler L, Nobis I, Bacinski A, Mentrup B, Ambrugger P, Gruters A, Malendowicz LK, Christoffel J, Jarry H, Seidlova-Wuttke D, Wuttke W, Kohrle J (2007) Endocrine disruptors and the thyroid gland-a combined in vitro and in vivo analysis of potential new biomarkers. Environ Health Perspect 115(1):77–83

    Article  PubMed  Google Scholar 

  • Schuur AG, Boekhorst FM, Brouwer A, Visser TJ (1997) Extrathyroidal effects of 2, 3, 7, 8-tetrachlorodibenzo-p-dioxin on thyroid hormone turnover in male Sprague-Dawley rats. Endocrinology 138(9):3727–3734

    Article  PubMed  CAS  Google Scholar 

  • Seacat AM, Thomford PJ, Hansen KJ, Olsen GW, Case MT, Butenhoff JL (2002) Subchronic toxicity studies on perfluorooctanesulfonate potassium salt in cynomolgus monkeys. Toxicol Sci 68(1):249–264

    Article  PubMed  CAS  Google Scholar 

  • Shi X, Du Y, Lam PK, Wu RS, Zhou B (2008) Developmental toxicity and alteration of gene expression in zebrafish embryos exposed to PFOS. Toxicol Appl Pharmacol 230(1):23–32

    Article  PubMed  CAS  Google Scholar 

  • Shivaraj G, Prakash BD, Sonal V, Shruthi K, Vinayak H, Avinash M (2009) Thyroid function tests: a review. Eur Rev Med Pharmacol Sci 13(5):341–349

    PubMed  CAS  Google Scholar 

  • Takayama S, Aihara K, Onodera T, Akimoto T (1986) Antithyroid effects of propylthiouracil and sulfamonomethoxine in rats and monkeys. Toxicol Appl Pharmacol 82(2):191–199

    Article  PubMed  CAS  Google Scholar 

  • Thibodeaux JR, Hanson RG, Rogers JM, Grey BE, Barbee BD, Richards JH, Butenhoff JL, Stevenson LA, Lau C (2003) Exposure to perfluorooctane sulfonate during pregnancy in rat and mouse. I: maternal and prenatal evaluations. Toxicol Sci 74(2):369–381

    Article  PubMed  CAS  Google Scholar 

  • Vansell NR, Klaassen CD (2001) Increased biliary excretion of thyroxine by microsomal enzyme inducers. Toxicol Appl Pharmacol 176(3):187–194

    Article  PubMed  CAS  Google Scholar 

  • Visser TJ (1996) Pathways of thyroid hormone metabolism. Acta Med Austriaca 23(1–2):10–16

    PubMed  CAS  Google Scholar 

  • Weiss JM, Andersson PL, Lamoree MH, Leonards PE, van Leeuwen SP, Hamers T (2009) Competitive binding of poly- and perfluorinated compounds to the thyroid hormone transport protein transthyretin. Toxicol Sci 109(2):206–216

    Article  PubMed  CAS  Google Scholar 

  • Wong H, Lehman-McKeeman LD, Grubb MF, Grossman SJ, Bhaskaran VM, Solon EG, Shen HS, Gerson RJ, Car BD, Zhao B, Gemzik B (2005) Increased hepatobiliary clearance of unconjugated thyroxine determines DMP 904-induced alterations in thyroid hormone homeostasis in rats. Toxicol Sci 84(2):232–242

    Article  PubMed  CAS  Google Scholar 

  • Yu WG, Liu W, Jin YH (2009a) Effects of perfluorooctane sulfonate on rat thyroid hormone biosynthesis and metabolism. Environ Toxicol Chem 28(5):990–996

    Article  PubMed  CAS  Google Scholar 

  • Yu WG, Liu W, Jin YH, Liu XH, Wang FQ, Liu L, Nakayama SF (2009b) Prenatal and postnatal impact of perfluorooctane sulfonate (PFOS) on rat development: a cross-foster study on chemical burden and thyroid hormone system. Environ Sci Technol 43(21):8416–8422

    Article  PubMed  CAS  Google Scholar 

  • Zhou T, Ross DG, DeVito MJ, Crofton KM (2001) Effects of short-term in vivo exposure to polybrominated diphenyl ethers on thyroid hormones and hepatic enzyme activities in weanling rats. Toxicol Sci 61(1):76–82

    Article  PubMed  CAS  Google Scholar 

  • Zoeller TR, Dowling AL, Herzig CT, Iannacone EA, Gauger KJ, Bansal R (2002) Thyroid hormone, brain development, and the environment. Environ Health Perspect 110(3):355–361

    PubMed  CAS  Google Scholar 

Download references

Acknowledgments

This work is supported by the National Nature Science Foundation of China (No. 20837004 and No. 20877016), Scientific Research Fund of Liaoning Provincial Education Department (No. 2008S058), and the Program for Changjiang Scholars and Innovative Research Team in University (IRT0813).

Author information

Authors and Affiliations

  1. Key Laboratory of Industrial Ecology and Environmental Engineering (Ministry of Education), School of Environmental Science and Technology, Dalian University of Technology, Linggong Road 2, 116024, Dalian, People’s Republic of China

    Wen-Guang Yu, Wei Liu & Yi-He Jin

  2. Division of Hygienic Toxicology, School of Public Health, China Medical University, North 2 Road 92, 110001, Shenyang, Liaoning, China

    Li Liu

Authors
  1. Wen-Guang Yu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Wei Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Li Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Yi-He Jin
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Yi-He Jin.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (DOC 36 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Yu, WG., Liu, W., Liu, L. et al. Perfluorooctane sulfonate increased hepatic expression of OAPT2 and MRP2 in rats. Arch Toxicol 85, 613–621 (2011). https://doi.org/10.1007/s00204-010-0613-x

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00204-010-0613-x

Keywords

Search

Navigation