Abstract
Di-(2-ethylhexyl)-phthalate (DEHP) is a ubiquitous environmental pollutant and is widely used in industrial plastics. Intrahepatic cholestasis of pregnancy (ICP), distinguished by maternal pruritus and elevated serum bile acid levels, is linked to unfavorable pregnancy consequences. Few studies have investigated the potential effect of gestational DEHP exposure on the cholestasis in pregnant female mice, and the underlying mechanisms remain unclear. In the present study, a mouse model of cholestasis during pregnancy was established by DEHP exposure. We found that DEHP induces elevated bile acid levels by affecting bile acid synthesis and transporter receptor expression in the maternal liver and placenta of pregnant female mice, ultimately leading to intrauterine growth restriction (IUGR). In addition, DEHP changed the bile acid composition of maternal serum and liver as well as placenta and amniotic fluid in pregnant female mice; Importantly, we found that DEHP down-regulates the expression of farnesoid X receptor (FXR), which is considered to be a bile acid receptor. FXR agonist obeticholic acid (OCA) effectively alleviated the adverse effects of DEHP on pregnant female mice. While, OCA itself had no adverse effects on normal pregnant female mice. In summary, DEHP could induces bile acid disorder and IUGR in pregnant female mice by affect FXR, which was reversed by OCA.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
Data availability
The authors confirm that the data supporting the findings of this study are available within the article.
Abbreviations
- BCRP:
-
Breast cancer resistance protein
- CA:
-
Cholic acid
- CDCA:
-
Chenodeoxycholic acid
- CYP3A11:
-
Cytochrome P450 3A11
- CYP7A1:
-
Cholesterol 7α-hydroxylase
- DEHP:
-
Di-ethyl-hexyl phthalate
- DCA:
-
Deoxycholic acid
- FXR:
-
Farnesoid X receptor
- GCDCA:
-
Glycine chenodeoxycholic acid
- GUDCA:
-
Glycine ursodeoxycholic acid
- GCA:
-
Glycine cholic acid
- GDCA:
-
Glycine deoxycholic acid
- GHDCA:
-
Glycine hyodeoxycholic acid
- GLCA:
-
Glycine cholic acid
- HDCA:
-
Hyodeoxycholic acid
- ICP:
-
Intrahepatic cholestasis of pregnancy
- LCA:
-
Lithocholic acid
- MRP2:
-
Multidrug resistant associated protein 2
- NTCP:
-
Na-taurocholate cotransporting polypeptide
- OCA:
-
Obeticholic acid
- PAEs:
-
Phthalates acid esters
- SHP:
-
Small heterodimer partner
- TDCA:
-
Taurodeoxycholic acid
- TCA:
-
Taurocholic acid
- TLCA:
-
Taurine cholic acid
- TDCA:
-
Taurodeoxycholic acid
- TUDCA:
-
Taurine ursodeoxycholic acid
- TCDCA:
-
Taurine goose deoxycholic acid
- THDCA:
-
Taurine hyodeoxycholic acid
- T-β-MCA:
-
Taurine-β-muricholic acid
- T-β-MCA:
-
Taurine-β-muricholic acid
- UDCA:
-
Ursodeoxycholic acid
- α-MCA:
-
α-Muricholic acid
- β-MCA:
-
β-Muricholic acid
References
Ali AH, Lindor KD (2016) Obeticholic acid for the treatment of primary biliary cholangitis. Expert Opin Pharmacother 17:1809–1815. https://doi.org/10.1080/14656566.2016.1218471
Arthuis C, Diguisto C, Lorphelin H et al (2020) Perinatal outcomes of intrahepatic cholestasis during pregnancy: an 8-year case-control study. PLoS One 15:e228213. https://doi.org/10.1371/journal.pone.0228213
Batool S, Batool S, Shameem S, Batool T, Batool S (2022) Effects of dibutyl phthalate and di(2-ethylhexyl) phthalate on hepatic structure and function of adult male mice. Toxicol Ind Health 38:470–480. https://doi.org/10.1177/07482337221108578
Brites D (2002) Intrahepatic cholestasis of pregnancy: changes in maternal-fetal bile acid balance and improvement by ursodeoxycholic acid. Ann Hepatol 1:20–28
Chen W, Gao XX, Ma L et al (2019) Obeticholic Acid Protects against Gestational Cholestasis-Induced Fetal Intrauterine Growth Restriction in Mice. Oxid Med Cell Longev 15:7419249. https://doi.org/10.1155/2019/7419249
Coleman JP, Hudson LL (1995) Cloning and characterization of a conjugated bile acid hydrolase gene from Clostridium perfringens. Appl Environ Microbiol 61(7):2514–2520. https://doi.org/10.1128/aem.61.7.2514-2520.1995
Denson LA, Sturm E, Echevarria W et al (2001) The orphan nuclear receptor, shp, mediates bile acid-induced inhibition of the rat bile acid transporter, ntcp. Gastroenterology 121:140–147. https://doi.org/10.1053/gast.2001.25503
Earls AO, Axford IP, Braybrook JH (2003) Gas chromatography-mass spectrometry determination of the migration of phthalate plasticisers from polyvinyl chloride toys and childcare articles. J Chromatogr a 983:237–246. https://doi.org/10.1016/s0021-9673(02)01736-3
Erythropel HC, Maric M, Nicell JA, Leask RL, Yargeau V (2014) Leaching of the plasticizer di(2-ethylhexyl)phthalate (DEHP) from plastic containers and the question of human exposure. Appl Microbiol Biotechnol 98:9967–9981. https://doi.org/10.1007/s00253-014-6183-8
Fiorucci S, Clerici C, Antonelli E et al (2005) Protective effects of 6-ethyl chenodeoxycholic acid, a farnesoid x receptor ligand, in estrogen-induced cholestasis. J Pharmacol Exp Ther 313:604–612. https://doi.org/10.1124/jpet.104.079665
Gaitantzi H, Hakenberg P, Theobald J et al (2018) Di (2-ethylhexyl) phthalate and its role in developing cholestasis: an in vitro study on different liver cell types. J Pediatr Gastroenterol Nutr 66:e28–e35. https://doi.org/10.1097/MPG.0000000000001813
Gao JJ, Lang XX, Yu QQ, Li HY, Wang HJ, Wang MQ (2021) Amphiphilic bodipy-based nanoparticles as “light-up” fluorescent probe for paes detection by an aggregation/disaggregation approach. Spectrochim Acta A Mol Biomol Spectrosc 252:119492. https://doi.org/10.1016/j.saa.2021.119492
Gartung C, Ananthanarayanan M, Rahman MA et al (1996) Down-regulation of expression and function of the rat liver na+/bile acid cotransporter in extrahepatic cholestasis. Gastroenterology 110:199–209. https://doi.org/10.1053/gast.1996.v110.pm8536857
Glantz A, Marschall HU, Mattsson LA (2004) Intrahepatic cholestasis of pregnancy: relationships between bile acid levels and fetal complication rates. Hepatology 40:467–474. https://doi.org/10.1002/hep.20336
Hagenbuch B, Meier PJ (1994) Molecular cloning, chromosomal localization, and functional characterization of a human liver na+/bile acid cotransporter. J Clin Invest 93:1326–1331. https://doi.org/10.1172/JCI117091
Hirschfield GM, Mason A, Luketic V et al (2015) Efficacy of obeticholic acid in patients with primary biliary cirrhosis and inadequate response to ursodeoxycholic acid. Gastroenterology 148:751–761. https://doi.org/10.1053/j.gastro.2014.12.005
Huang PC, Tien CJ, Sun YM, Hsieh CY, Lee CC (2008) Occurrence of phthalates in sediment and biota: relationship to aquatic factors and the biota-sediment accumulation factor. Chemosphere 73:539–544. https://doi.org/10.1016/j.chemosphere.2008.06.019
Huang YQ, Tang YX, Qiu BH, Talukder M, Li XN, Li JL (2022) Di-2-ethylhexyl phthalate (dehp) induced lipid metabolism disorder in liver via activating the lxr/srebp-1c/pparalpha/gamma and nf-kappab signaling pathway. Food Chem Toxicol 165:113119. https://doi.org/10.1016/j.fct.2022.113119
Huang L, Zhu X, Zhou S et al (2021) Phthalic acid esters: natural sources and biological activities. Toxins (Basel) 13. https://doi.org/10.3390/toxins13070495
Jung D, Mangelsdorf DJ, Meyer UA (2006) Pregnane x receptor is a target of farnesoid x receptor. J Biol Chem 281:19081–19091. https://doi.org/10.1074/jbc.M600116200
Kaestner F, Seiler F, Rapp D et al (2020) Exposure of patients to di(2-ethylhexy)phthalate (DEHP) and its metabolite mehp during extracorporeal membrane oxygenation (ecmo) therapy. Plos One 15:e224931. https://doi.org/10.1371/journal.pone.0224931
Kim KH, Choi S, Zhou Y et al (2017) Hepatic fxr/shp axis modulates systemic glucose and fatty acid homeostasis in aged mice. Hepatology 66:498–509. https://doi.org/10.1002/hep.29199
Kjaergaard K, Frisch K, Sorensen M et al (2021) Obeticholic acid improves hepatic bile acid excretion in patients with primary biliary cholangitis. J Hepatol 74:58–65. https://doi.org/10.1016/j.jhep.2020.07.028
Kruh GD, Belinsky MG, Gallo JM, Lee K (2007) Physiological and pharmacological functions of mrp2, mrp3 and mrp4 as determined from recent studies on gene-disrupted mice. Cancer Metastasis Rev 26:5–14. https://doi.org/10.1007/s10555-007-9039-1
Li TG, Chiang JY (2014) Bile acid signaling in metabolic disease and drug therapy. Pharmacol Rev 66(4):948–983. https://doi.org/10.1124/pr.113.008201
Liu C, Gao J, Liu J et al (2020) Intrahepatic cholestasis of pregnancy is associated with an increased risk of gestational diabetes and preeclampsia. Ann Transl Med 8:1574. https://doi.org/10.21037/atm-20-4879
Liu RJ, He YJ, Liu H, Zheng DD, Huang SW, Liu CH (2021) Protective effect of lycium barbarum polysaccharide on di-(2-ethylhexyl) phthalate-induced toxicity in rat liver. Environ Sci Pollut Res Int 28:23501–23509. https://doi.org/10.1007/s11356-020-11990-8
Makishima M, Okamoto AY, Repa JJ et al (1999) Identification of a nuclear receptor for bile acids. Science 284:1362–1365. https://doi.org/10.1126/science.284.5418.1362
Maranghi F, Lorenzetti S, Tassinari R et al (2010) In utero exposure to di-(2-ethylhexyl) phthalate affects liver morphology and metabolism in post-natal cd-1 mice. Reprod Toxicol 29:427–432. https://doi.org/10.1016/j.reprotox.2010.03.002
Marin JJ, Macias RI, Briz O et al (2008) Molecular bases of the fetal liver-placenta-maternal liver excretory pathway for cholephilic compounds. Liver Int 28:435–454. https://doi.org/10.1111/j.1478-3231.2008.01680.x
Marschall HU (2019) Ursodeoxycholic acid for intrahepatic cholestasis in pregnancy. Lancet 394:810–812. https://doi.org/10.1016/S0140-6736(19)31607-1
Neuschwander-Tetri BA, Loomba R, Sanyal AJ et al (2015) Farnesoid x nuclear receptor ligand obeticholic acid for non-cirrhotic, non-alcoholic steatohepatitis (flint): a multicentre, randomised, placebo-controlled trial. Lancet 385:956–965. https://doi.org/10.1016/S0140-6736(14)61933-4
Nies AT, Keppler D (2007) The apical conjugate efflux pump abcc2 (mrp2). Pflugers Arch 453:643–659. https://doi.org/10.1007/s00424-006-0109-y
Pataia V, Dixon PH, Williamson C (2017) Pregnancy and bile acid disorders. Am J Physiol Gastrointest Liver Physiol 313:G1–G6. https://doi.org/10.1152/ajpgi.00028.2017
Pataia V, Mcilvride S, Papacleovoulou G et al (2020) Obeticholic acid improves fetal bile acid profile in a mouse model of gestational hypercholanemia. Am J Physiol Gastrointest Liver Physiol 319:G197–G211. https://doi.org/10.1152/ajpgi.00126.2020
Piechota J, Jelski W (2020) Intrahepatic cholestasis in pregnancy: review of the literature. J Clin Med 9. https://doi.org/10.3390/jcm9051361
Pournejati R, Gust R, Sagasser J et al (2021) In vitro evaluation of cytotoxic effects of di(2-ethylhexyl)phthalate (DEHP) produced by bacillus velezensis strain rp137 isolated from persian gulf. Toxicol in Vitro 73:105148. https://doi.org/10.1016/j.tiv.2021.105148
Qin X, Wang X (2019) Role of vitamin d receptor in the regulation of cyp3a gene expression. Acta Pharm Sin B 9:1087–1098. https://doi.org/10.1016/j.apsb.2019.03.005
Qin X, Zhang Y, Lu J, Huang S, Liu Z, Wang X (2021) Cyp3a deficiency alters bile acid homeostasis and leads to changes in hepatic susceptibility in rats. Toxicol Appl Pharmacol 429:115703. https://doi.org/10.1016/j.taap.2021.115703
Rolo AP, Oliveira PJ, Moreno AJ, Palmeira CM (2000) Bile acids affect liver mitochondrial bioenergetics: possible relevance for cholestasis therapy. Toxicol Sci 57:177–185. https://doi.org/10.1093/toxsci/57.1.177
Rowdhwal S, Chen J (2018) Toxic effects of di-2-ethylhexyl phthalate: an overview. Biomed Res Int 2018:1750368. https://doi.org/10.1155/2018/1750368
Salhab A, Amer J, Lu Y, Safadi R (2022) Sodium(+)/taurocholate cotransporting polypeptide as target therapy for liver fibrosis. Gut 71:1373–1385. https://doi.org/10.1136/gutjnl-2020-323345
Shen R, Zhao LL, Yu Z et al (2017) Maternal di-(2-ethylhexyl) phthalate exposure during pregnancy causes fetal growth restriction in a stage-specific but gender-independent manner. Reprod Toxicol 67:117–124. https://doi.org/10.1016/j.reprotox.2016.12.003
Sinal CJ, Tohkin M, Miyata M, Ward JM, Lambert G, Gonzalez FJ (2000) Targeted disruption of the nuclear receptor fxr/bar impairs bile acid and lipid homeostasis. Cell 102:731–744. https://doi.org/10.1016/s0092-8674(00)00062-3
Singh M, Singh A, Kundu S, Bansal S, Bajaj A (2013) Deciphering the role of charge, hydration, and hydrophobicity for cytotoxic activities and membrane interactions of bile acid based facial amphiphiles. Biochim Biophys Acta 1828:1926–1937. https://doi.org/10.1016/j.bbamem.2013.04.003
Song F, Chen Y, Chen L, Li H, Cheng X, Wu W (2021) Association of elevated maternal serum total bile acids with low birth weight and intrauterine fetal growth restriction. JAMA Netw Open 4:e2117409. https://doi.org/10.1001/jamanetworkopen.2021.17409
Sun L, Cai J, Gonzalez FJ (2021) The role of farnesoid x receptor in metabolic diseases, and gastrointestinal and liver cancer. Nat Rev Gastroenterol Hepatol 18:335–347. https://doi.org/10.1038/s41575-020-00404-2
Tanaka H, Hashiba H, Kok J, Mierau I (2000) Bile salt hydrolase of Bifidobacterium longum: biochemical and genetic characterization. Appl Environ Microbiol 66(6):2502–2512. https://doi.org/10.1128/AEM.66.6.2502-2512.2000
Wang L, Lee YK, Bundman D et al (2002) Redundant pathways for negative feedback regulation of bile acid production. Dev Cell 2:721–731. https://doi.org/10.1016/s1534-5807(02)00187-9
Wang JQ, Gao H, Sheng J et al (2020) Urinary concentrations of phthalate metabolites during gestation and intrahepatic cholestasis of pregnancy: a population-based birth cohort study. Environ Sci Pollut Res Int 27:11714–11723. https://doi.org/10.1007/s11356-020-07675-x
Williamson C, Geenes V (2014) Intrahepatic cholestasis of pregnancy. Obstet Gynecol 124:120–133. https://doi.org/10.1097/AOG.0000000000000346
Yu Z, Han Y et al (2018) Gestational di-(2-ethylhexyl) phthalate exposure causes fetal intrauterine growth restriction through disturbing placental thyroid hormone receptor signaling. Toxicol Lett 294:1–10. https://doi.org/10.1016/j.toxlet.2018.05.013
Yu L, Yang M, Cheng M et al (2021a) Associations between urinary phthalate metabolite concentrations and markers of liver injury in the us adult population. Environ Int 155:106608. https://doi.org/10.1016/j.envint.2021.106608
Yu Z, Shi ZH, Zheng ZY et al (2021b) DEHP induce cholesterol imbalance via disturbing bile acid metabolism by altering the composition of gut microbiota in mouse. Chemosphere 263:127959. https://doi.org/10.1016/j.chemosphere.2020.127959
Zeng H, Jiang Y, Chen P et al (2017) Schisandrol b protects against cholestatic liver injury through pregnane x receptors. Br J Pharmacol 174:672–688. https://doi.org/10.1111/bph.13729
Zhang C, Gan Y, Lv JW et al (2020) The protective effect of obeticholic acid on lipopolysaccharide-induced disorder of maternal bile acid metabolism in pregnant mice. Int Immunopharmacol 83:106442. https://doi.org/10.1016/j.intimp.2020.106442
Zhang Y, Jiao Y, Li Z, Tao Y, Yang Y (2021) Hazards of phthalates (paes) exposure: a review of aquatic animal toxicology studies. Sci Total Environ 771:145418. https://doi.org/10.1016/j.scitotenv.2021.145418
Zhang F, Zhen HL et al (2022) Di-(2-ethylhexyl) phthalate exposure induces liver injury by promoting ferroptosis via downregulation of GPX4 in pregnant mice. Front Cell Dev Biol 10:1014243. https://doi.org/10.3389/fcell.2022.1014243
Acknowledgements
We are grateful to the First Affiliated Hospital of Anhui Medical University and Anhui Public Health Clinical Center Laboratory Experimental Platform. We are grateful for the sponsorship of the National Natural Science Foundation of China (82073566), Anhui Provincial Natural Science Foundation (2008085MH280), the Anhui Medical University Clinical Pharmacology and Pharmacology Co-construction Project (2020), and Anhui public health clinical center, the first affiliated hospital of anhui medical university north area scientific research cultivation fund project (2023YKJ11, 2023YKJ106, 2023YKJ14).
Funding
We are grateful to the First Affiliated Hospital of Anhui Medical University and Anhui Public Health Clinical Center Laboratory Experimental Platform. We are grateful for the sponsorship of the National Natural Science Foundation of China (82073566), Anhui Provincial Natural Science Foundation (2008085MH280), the Anhui Medical University Clinical Pharmacology and Pharmacology Co-construction Project (2020), and Anhui public health clinical center, the first affiliated hospital of anhui medical university north area scientific research cultivation fund project (2023YKJ11, 2023YKJ106, 2023YKJ14).
Author information
Authors and Affiliations
Contributions
Fan Zhao: Conceptualization, Writing–original draft, Validation, Formal analysis, Investigation. Lun Zhang: Conceptualization, Writing – original draft, Validation, Formal analysis, Investigation. Mingchao Qu: Methodology, Resources. Lu Ye: Methodology, Resources. Jiayi Zhang: Methodology, Resources. Yun Yu: Investigation, Data curation. Qianqian Huang: Investigation, Data curation. Cheng Zhang and Jianqing Wang: Conceptualization, Writing – review & editing, Funding acquisition.
Corresponding author
Ethics declarations
Ethical approval
The experiment was conducted according to the guidelines of the National Institutes of Health (NIH publication No. 85–23, revised in 2011) and approved by the Research Ethics Committee of Anhui Medical University (Approval No.: 20200523).
Consent to participate
Not applicable.
Consent to publish
Not applicable.
Competing interests
None.
Additional information
Responsible Editor: Ludek Blaha
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Supplementary Information
Below is the link to the electronic supplementary material.
Rights and permissions
Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.
About this article
Cite this article
Zhao, F., Zhang, L., Qu, M. et al. Obeticholic acid alleviates intrauterine growth restriction induced by di-ethyl-hexyl phthalate in pregnant female mice by improving bile acid disorder. Environ Sci Pollut Res 30, 110956–110969 (2023). https://doi.org/10.1007/s11356-023-30149-9
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s11356-023-30149-9