Abstract
Phthalates, a class of widely used endocrine-disrupting chemicals (EDCs), are toxic to various organ systems in animals and humans. Intrahepatic cholestasis of pregnancy (ICP) is a reversible liver dysfunction causing cholestasis in late pregnancy. Evidence on the associations between exposure to phthalates and ICP is still lacking. In the present study, we investigated the relationships between urinary concentrations of phthalate metabolites and the risk of ICP in a Chinese population-based birth cohort. Pregnant women participated in the Ma’anshan Birth Cohort (MABC) study in China. Seven phthalate metabolites were detected in a urine sample in early pregnancy. Chemical concentrations were grouped by quartiles, and associations with outcomes were examined using logistic regression with adjustment for urine creatinine, race, education, poverty status, smoking status, alcohol consumption, maternal age, prepregnancy body mass index (BMI), parity, twin pregnancy, and pregnancy-related liver complications. Of 3474 women recruited into the Ma’anshan Birth Cohort, 2760 met the inclusion criteria and contributed to further analysis and biomonitoring data. Elevated odds ratios (ORs) of ICP were observed in the highest quartiles of monomethyl phthalate (MMP) exposure (OR = 1.59, 95% confidence intervals (CI) = 1.01–2.51) and monobutyl phthalate (MBP) exposure (OR = 1.82, 95% CI = 1.16–2.85) in the adjusted analyses. Our findings add to the evidence that supports the role of maternal phthalate exposure in the first trimester of gestation as a risk factor for ICP.
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Abbreviations
- EDCs:
-
Endocrine-disrupting chemicals
- ICP:
-
Intrahepatic cholestasis of pregnancy
- MABC:
-
Ma’anshan Birth Cohort study
- MMP:
-
Monomethyl phthalate
- MEP:
-
Monoethyl phthalate
- MBP:
-
Mono-n-butyl phthalate
- MBzP:
-
Monobenzyl phthalate
- MEHP:
-
Mono (2-ethylhexyl) phthalate
- MEHHP:
-
Mono (2-ethyl-5-hydroxyl) phthalate
- MEOHP:
-
Mono (2-ethyl-5-oxohexyl) phthalate
- LOD:
-
Limits of detection
- BMI:
-
Body mass index
- PVC:
-
Polyvinylchloride
- DEHP:
-
Di (2-ethylhexyl) phthalate
References
Ai Y, Liu SY, Yao Q (2004) Clinical characteristics of 1241 cases of intrahepatic cholestasis of pregnancy. Zhonghua Fu Chan Ke Za Zhi 39:217–220
Bagel S, Dessaigne B, Bourdeaux D, Boyer A, Bouteloup C, Bazin JE, Chopineau J, Sautou V (2011) Influence of lipid type on bis (2-ethylhexyl)phthalate (DEHP) leaching from infusion line sets in parenteral nutrition. JPEN J Parenter Enteral Nutr 35:770–775
Birnbaum LS (2013) State of the science of endocrine disruptors. Environ Health Perspect 121:A107
Botton J, Philippat C, Calafat AM, Carles S, Charles MA, Slama R, The Eden Mother-Child Cohort Study G (2016) Phthalate pregnancy exposure and male offspring growth from the intra-uterine period to five years of age. Environ Res 151:601–609
Cabrerizo R, Castano GO, Burgueno AL, Fernandez Gianotti T, Gonzalez Lopez Ledesma MM, Flichman D, Pirola CJ, Sookoian S (2014) Promoter DNA methylation of farnesoid X receptor and pregnane X receptor modulates the intrahepatic cholestasis of pregnancy phenotype. PLoS One 9:e87697
Calafat AM, Needham LL (2009) What additional factors beyond state-of-the-art analytical methods are needed for optimal generation and interpretation of biomonitoring data? Environ Health Perspect 117:1481–1485
Chappell LC, Gurung V, Seed PT, Chambers J, Williamson C, Thornton JG, Consortium PS (2012) Ursodeoxycholic acid versus placebo, and early term delivery versus expectant management, in women with intrahepatic cholestasis of pregnancy: semifactorial randomised clinical trial. BMJ 344:e3799
Dai ZYHL, Tao WQ (1986) The importance of intrahepatic cholestasis of pregnancy. Shanghai Med 9:440–443
De Toni L, Tisato F, Seraglia R, Roverso M, Gandin V, Marzano C, Padrini R, Foresta C (2017) Phthalates and heavy metals as endocrine disruptors in food: a study on pre-packed coffee products. Toxicol Rep 4:234–239
Erkekoglu P, Zeybek ND, Giray B, Asan E, Hincal F (2012) The effects of di(2-ethylhexyl)phthalate exposure and selenium nutrition on sertoli cell vimentin structure and germ-cell apoptosis in rat testis. Arch Environ Contam Toxicol 62:539–547
Eveillard A, Lasserre F, de Tayrac M, Polizzi A, Claus S, Canlet C, Mselli-Lakhal L, Gotardi G, Paris A, Guillou H, Martin PG, Pineau T (2009) Identification of potential mechanisms of toxicity after di-(2-ethylhexyl)-phthalate (DEHP) adult exposure in the liver using a systems biology approach. Toxicol Appl Pharmacol 236:282–292
Ferguson KK, McElrath TF, Ko YA, Mukherjee B, Meeker JD (2014a) Variability in urinary phthalate metabolite levels across pregnancy and sensitive windows of exposure for the risk of preterm birth. Environ Int 70:118–124
Ferguson KK, McElrath TF, Meeker JD (2014b) Environmental phthalate exposure and preterm birth. JAMA Pediatr 168:61–67
Fischer CJ, Bickle Graz M, Muehlethaler V, Palmero D, Tolsa JF (2013) Phthalates in the NICU: is it safe? J Paediatr Child Health 49:E413–E419
Gao H, Xu Y, Sun L, Jin Z, Hu H, Sheng J, Ren L, Tao F (2015) Determination of seven phthalate metabolites in human urine by high performance liquid chromatography-tandem mass spectrometry. Se Pu 33:622–627
Ge X, Tao F, Huang K, Mao L, Huang S, Niu Y, Hao J, Sun Y, Rutayisire E (2016) Maternal snoring may predict adverse pregnancy outcomes: a cohort study in China. PLoS One 11:e0148732
Geenes V, Williamson C (2009) Intrahepatic cholestasis of pregnancy. World J Gastroenterol 15:2049–2066
Geenes V, Chappell LC, Seed PT, Steer PJ, Knight M, Williamson C (2014) Association of severe intrahepatic cholestasis of pregnancy with adverse pregnancy outcomes: a prospective population-based case-control study. Hepatology 59:1482–1491
Glantz A, Marschall HU, Mattsson LA (2004) Intrahepatic cholestasis of pregnancy: relationships between bile acid levels and fetal complication rates. Hepatology 40:467–474
Guo Y, Zhang Z, Liu L, Li Y, Ren N, Kannan K (2012) Occurrence and profiles of phthalates in foodstuffs from China and their implications for human exposure. J Agric Food Chem 60:6913–6919
Hirvioja ML, Kivinen S (1993) Inheritance of intrahepatic cholestasis of pregnancy in one kindred. Clin Genet 43:315–317
Hsieh CJ, Chang YH, Hu A, Chen ML, Sun CW, Situmorang RF, Wu MT, Wang SL, group Ts (2019) Personal care products use and phthalate exposure levels among pregnant women. Sci Total Environ 648:135–143
Huang HB, Pan WH, Chang JW, Chiang HC, Guo YL, Jaakkola JJ, Huang PC (2017) Does exposure to phthalates influence thyroid function and growth hormone homeostasis? The Taiwan Environmental Survey for Toxicants (TEST) 2013. Environ Res 153:63–72
Huang HB, Kuo PL, Chang JW, Jaakkola JJK, Liao KW, Huang PC (2018) Longitudinal assessment of prenatal phthalate exposure on serum and cord thyroid hormones homeostasis during pregnancy - Tainan birth cohort study (TBCS). Sci Total Environ 619-620:1058–1065
Joshi D, James A, Quaglia A, Westbrook RH, Heneghan MA (2010) Liver disease in pregnancy. Lancet 375:594–605
Jung D, Mangelsdorf DJ, Meyer UA (2006) Pregnane X receptor is a target of farnesoid X receptor. J Biol Chem 281:19081–19091
Katsikantami I, Sifakis S, Tzatzarakis MN, Vakonaki E, Kalantzi OI, Tsatsakis AM, Rizos AK (2016) A global assessment of phthalates burden and related links to health effects. Environ Int 97:212–236
Kim Y, Ha EH, Kim EJ, Park H, Ha M, Kim JH, Hong YC, Chang N, Kim BN (2011) Prenatal exposure to phthalates and infant development at 6 months: prospective Mothers and Children’s Environmental Health (MOCEH) study. Environ Health Perspect 119:1495–1500
Kim S, Lee J, Park J, Kim HJ, Cho G, Kim GH, Eun SH, Lee JJ, Choi G, Suh E, Choi S, Kim S, Kim YD, Kim SK, Kim SY, Kim S, Eom S, Moon HB, Kim S, Choi K (2015) Concentrations of phthalate metabolites in breast milk in Korea: estimating exposure to phthalates and potential risks among breast-fed infants. Sci Total Environ 508:13–19
Kim JH, Park H, Lee J, Cho G, Choi S, Choi G, Kim SY, Eun SH, Suh E, Kim SK, Kim HJ, Kim GH, Lee JJ, Kim YD, Eom S, Kim S, Moon HB, Park J, Choi K, Kim S, Kim S (2016) Association of diethylhexyl phthalate with obesity-related markers and body mass change from birth to 3 months of age. J Epidemiol Community Health 70:466–472
Koniecki D, Wang R, Moody RP, Zhu J (2011) Phthalates in cosmetic and personal care products: concentrations and possible dermal exposure. Environ Res 111:329–336
Lammert F, Marschall HU, Glantz A, Matern S (2000) Intrahepatic cholestasis of pregnancy: molecular pathogenesis, diagnosis and management. J Hepatol 33:1012–1021
Laurenzana EM, Coslo DM, Vigilar MV, Roman AM, Omiecinski CJ (2016) Activation of the constitutive androstane receptor by monophthalates. Chem Res Toxicol 29:1651–1661
Loff PD, Subotic U, Oulmi-Kagermann J, Kranzlin B, Reinecke MF, Staude C (2007) Diethylhexylphthalate extracted by typical newborn lipid emulsions from polyvinylchloride infusion systems causes significant changes in histology of rabbit liver. JPEN J Parenter Enteral Nutr 31:188–193
Marschall HU (2015) Management of intrahepatic cholestasis of pregnancy. Expert Rev Gastroenterol Hepatol 9:1273–1279
Martineau M, Raker C, Powrie R, Williamson C (2014) Intrahepatic cholestasis of pregnancy is associated with an increased risk of gestational diabetes. Eur J Obstet Gynecol Reprod Biol 176:80–85
Martinez-Ibarra A, Martinez-Razo LD, Vazquez-Martinez ER, Martinez-Cruz N, Flores-Ramirez R, Garcia-Gomez E, Lopez-Lopez M, Ortega-Gonzalez C, Camacho-Arroyo I, Cerbon M (2019) Unhealthy Levels of Phthalates and Bisphenol A in Mexican Pregnant Women with Gestational Diabetes and Its Association to Altered Expression of miRNAs Involved with Metabolic Disease. Int J Mol Sci:20
Martino-Andrade AJ, Chahoud I (2010) Reproductive toxicity of phthalate esters. Mol Nutr Food Res 54:148–157
McIlvride S, Dixon PH, Williamson C (2017) Bile acids and gestation. Mol Asp Med 56:90–100
Menzyk T, Bator M, Derra A, Kierach R, Kukla M (2018) The role of metabolic disorders in the pathogenesis of intrahepatic cholestasis of pregnancy. Clin Exp Hepatol 4:217–223
Papacleovoulou G, Abu-Hayyeh S, Williamson C (2011) Nuclear receptor-driven alterations in bile acid and lipid metabolic pathways during gestation. Biochim Biophys Acta 1812:879–887
Papacleovoulou G, Abu-Hayyeh S, Nikolopoulou E, Briz O, Owen BM, Nikolova V, Ovadia C, Huang X, Vaarasmaki M, Baumann M, Jansen E, Albrecht C, Jarvelin MR, Marin JJ, Knisely AS, Williamson C (2013) Maternal cholestasis during pregnancy programs metabolic disease in offspring. J Clin Invest 123:3172–3181
Philips EM, Kahn LG, Jaddoe VWV, Shao Y, Asimakopoulos AG, Kannan K, Steegers EAP, Trasande L (2018) First trimester urinary bisphenol and phthalate concentrations and time to pregnancy: a population-based cohort analysis. J Clin Endocrinol Metab 103:3540–3547
Plonait SL, Nau H, Maier RF, Wittfoht W, Obladen M (1993) Exposure of newborn infants to di-(2-ethylhexyl)-phthalate and 2-ethylhexanoic acid following exchange transfusion with polyvinylchloride catheters. Transfusion 33:598–605
Reyes H, Baez ME, Gonzalez MC, Hernandez I, Palma J, Ribalta J, Sandoval L, Zapata R (2000) Selenium, zinc and copper plasma levels in intrahepatic cholestasis of pregnancy, in normal pregnancies and in healthy individuals, in Chile. J Hepatol 32:542–549
Ropponen A, Sund R, Riikonen S, Ylikorkala O, Aittomaki K (2006) Intrahepatic cholestasis of pregnancy as an indicator of liver and biliary diseases: a population-based study. Hepatology 43:723–728
Saadeldin IM, Hussein MA, Suleiman AH, Abohassan MG, Ahmed MM, Moustafa AA, Moumen AF, Abdel-Aziz Swelum A (2018) Ameliorative effect of ginseng extract on phthalate and bisphenol A reprotoxicity during pregnancy in rats. Environ Sci Pollut Res Int 25:21205–21215
Schettler T (2006) Human exposure to phthalates via consumer products. Int J Androl 29:134–139 discussion 181-5
Shneider B, Cronin J, Van Marter L, Maller E, Truog R, Jacobson M, Kevy S (1991) A prospective analysis of cholestasis in infants supported with extracorporeal membrane oxygenation. J Pediatr Gastroenterol Nutr 13:285–289
Silva MJ, Barr DB, Reidy JA, Malek NA, Hodge CC, Caudill SP, Brock JW, Needham LL, Calafat AM (2004) Urinary levels of seven phthalate metabolites in the U.S. population from the National Health and Nutrition Examination Survey (NHANES) 1999-2000. Environ Health Perspect 112:331–338
von Rettberg H, Hannman T, Subotic U, Brade J, Schaible T, Waag KL, Loff S (2009) Use of di(2-ethylhexyl)phthalate-containing infusion systems increases the risk for cholestasis. Pediatrics 124:710–716
Wang HX, Wang B, Zhou Y, Jiang QW (2013) Rapid and sensitive analysis of phthalate metabolites, bisphenol A, and endogenous steroid hormones in human urine by mixed-mode solid-phase extraction, dansylation, and ultra-performance liquid chromatography coupled with triple quadrupole mass spectrometry. Anal Bioanal Chem 405:4313–4319
Wang W, Leung AOW, Chu LH, Wong MH (2018) Phthalates contamination in China: status, trends and human exposure-with an emphasis on oral intake. Environ Pollut 238:771–782
Wenzel AG, Bloom MS, Butts CD, Wineland RJ, Brock JW, Cruze L, Unal ER, Kucklick JR, Somerville SE, Newman RB (2018) Influence of race on prenatal phthalate exposure and anogenital measurements among boys and girls. Environ Int 110:61–70
Wikstrom Shemer E, Marschall HU, Ludvigsson JF, Stephansson O (2013) Intrahepatic cholestasis of pregnancy and associated adverse pregnancy and fetal outcomes: a 12-year population-based cohort study. BJOG 120:717–723
Wikstrom Shemer EA, Stephansson O, Thuresson M, Thorsell M, Ludvigsson JF, Marschall HU (2015) Intrahepatic cholestasis of pregnancy and cancer, immune-mediated and cardiovascular diseases: a population-based cohort study. J Hepatol 63:456–461
Yao HY, Han Y, Gao H, Huang K, Ge X, Xu YY, Xu YQ, Jin ZX, Sheng J, Yan SQ, Zhu P, Hao JH, Tao FB (2016) Maternal phthalate exposure during the first trimester and serum thyroid hormones in pregnant women and their newborns. Chemosphere 157:42–48
Zhu Y, Wan Y, Li Y, Zhang B, Zhou A, Cai Z, Qian Z, Zhang C, Huo W, Huang K, Hu J, Cheng L, Chang H, Huang Z, Xu B, Xia W, Xu S (2016) Free and total urinary phthalate metabolite concentrations among pregnant women from the Healthy Baby Cohort (HBC), China. Environ Int 88:67–73
Zoeller RT, Brown TR, Doan LL, Gore AC, Skakkebaek NE, Soto AM, Woodruff TJ, Vom Saal FS (2012) Endocrine-disrupting chemicals and public health protection: a statement of principles from The Endocrine Society. Endocrinology 153:4097–4110
Acknowledgments
The work was supported by the National Natural Science Foundation of China (No. 81330068), the China Postdoctoral Science Foundation funded project (2016M592041), and the Postdoctoral Science Foundation funded project of Anhui Province (2016B114). The authors would like to thank the pregnant women who participated in the study, as well as the doctors, nurses and other staff who supported the study.
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All participants were fully informed prior to participating in the study, and the study was ethically approved by the Anhui Medical University (number: 20131195) based on the institution’s ethical standards and the ethical standards of the Declaration of Helsinki.
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Wang, JQ., Gao, H., Sheng, J. et al. Urinary concentrations of phthalate metabolites during gestation and intrahepatic cholestasis of pregnancy: a population-based birth cohort study. Environ Sci Pollut Res 27, 11714–11723 (2020). https://doi.org/10.1007/s11356-020-07675-x
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DOI: https://doi.org/10.1007/s11356-020-07675-x