Urinary Phthalate Metabolites and Biomarkers of Oxidative Stress in Pregnant Women: A Repeated Measures Analysis

Background Phthalate exposure occurs readily in the environment and has been associated with an array of health end points, including adverse birth outcomes. Some of these may be mediated by oxidative stress, a proposed mechanism for phthalate action. Objectives In the present study, we explored the associations between phthalate metabolites and biomarkers of oxidative stress measured in urine samples from multiple time points during pregnancy. Methods Women were participants in a nested case–control study of preterm birth (n = 130 cases, n = 352 controls). Each was recruited early in pregnancy and followed until delivery, providing urine samples at up to four visits. Nine phthalate metabolites were measured to assess exposure, and 8-hydroxydeoxyguanosine and 8-isoprostane were also measured in urine as markers of oxidative stress. Associations were assessed using linear mixed models to account for intraindividual correlation, with inverse selection probability weightings based on case status to allow for greater generalizability. Results Interquartile range increases in phthalate metabolites were associated with significantly higher concentrations of both biomarkers. Estimated differences were greater in association with monobenzyl phthalate (MBzP), mono-n-butyl phthalate (MBP), and monoisobutyl phthalate (MiBP), compared with di(2-ethylhexyl) phthalate (DEHP) metabolites. Conclusions Urinary phthalate metabolites were associated with increased oxidative stress biomarkers in our study population of pregnant women. These relationships may be particularly relevant to the study of birth outcomes linked to phthalate exposure. Although replication is necessary in other populations, these results may also be of great importance for a range of other health outcomes associated with phthalates. Citation Ferguson KK, McElrath TF, Chen YH, Mukherjee B, Meeker JD. 2015. Urinary phthalate metabolites and biomarkers of oxidative stress in pregnant women: a repeated measures analysis. Environ Health Perspect 123:210–216; http://dx.doi.org/10.1289/ehp.1307996

[1]  Terri L. Moore,et al.  Regression Analysis by Example , 2001, Technometrics.

[2]  Michigan.,et al.  Toxicological profile for dichloropropenes , 2008 .

[3]  J. Meeker,et al.  Predictors of urinary bisphenol A and phthalate metabolite concentrations in Mexican children. , 2013, Chemosphere.

[4]  M. Tokuda,et al.  Role of oxidative stress in germ cell apoptosis induced by di(2-ethylhexyl)phthalate. , 2002, The Biochemical journal.

[5]  Kelly K Ferguson,et al.  Urinary phthalate metabolites in relation to biomarkers of inflammation and oxidative stress: NHANES 1999-2006. , 2011, Environmental research.

[6]  O. Kwon,et al.  EFFECTS OF DIBUTYL PHTHALATE AND MONOBUTYL PHTHALATE ON CYTOTOXICITY AND DIFFERENTIATION IN CULTURED RAT EMBRYONIC LIMB BUD CELLS; PROTECTION BY ANTIOXIDANTS , 2002, Journal of toxicology and environmental health. Part A.

[7]  B. Spur,et al.  Oxidative stress early in pregnancy and pregnancy outcome , 2008, Free radical research.

[8]  I. Rusyn,et al.  Phthalates rapidly increase production of reactive oxygen species in vivo: role of Kupffer cells. , 2001, Molecular pharmacology.

[9]  R. Hornung,et al.  Estimation of Average Concentration in the Presence of Nondetectable Values , 1990 .

[10]  Antonia M. Calafat,et al.  Variability of Urinary Phthalate Metabolite and Bisphenol A Concentrations before and during Pregnancy , 2012, Environmental health perspectives.

[11]  D. Waxman,et al.  Activation of PPARα and PPARγ by Environmental Phthalate Monoesters , 2003 .

[12]  P. Chang,et al.  Urinary 8-OHdG: a marker of oxidative stress to DNA and a risk factor for cancer, atherosclerosis and diabetics. , 2004, Clinica chimica acta; international journal of clinical chemistry.

[13]  L K Lowry,et al.  Interpretation of urine results used to assess chemical exposure with emphasis on creatinine adjustments: a review. , 1993, American Industrial Hygiene Association journal.

[14]  Y. Lim,et al.  Diethylhexyl Phthalates Is Associated with Insulin Resistance via Oxidative Stress in the Elderly: A Panel Study , 2013, PloS one.

[15]  Jane E Norman,et al.  Inflammation and Pregnancy , 2006, Reproductive sciences.

[16]  A. Berger FUNDAMENTALS OF BIOSTATISTICS , 1969 .

[17]  J. Meeker,et al.  Variability in urinary phthalate metabolite levels across pregnancy and sensitive windows of exposure for the risk of preterm birth. , 2014, Environment international.

[18]  J. Angerer,et al.  Phthalate exposure in pregnant women and their children in central Taiwan. , 2011, Chemosphere.

[19]  John D. Meeker,et al.  Exploration of oxidative stress and inflammatory markers in relation to urinary phthalate metabolites: NHANES 1999-2006. , 2012, Environmental science & technology.

[20]  Kelly K Ferguson,et al.  Environmental phthalate exposure and preterm birth. , 2014, JAMA pediatrics.

[21]  Ivan Spasojevic,et al.  Urinary biomarkers of oxidative status. , 2012, Clinica chimica acta; international journal of clinical chemistry.

[22]  T. Woodruff,et al.  Environmental Chemicals in Pregnant Women in the United States: NHANES 2003–2004 , 2011, Environmental health perspectives.

[23]  E. Kilpatrick,et al.  A comparison of methods for the measurement of 8-isoPGF2α : a marker of oxidative stress , 2011, Annals of clinical biochemistry.

[24]  Sajal Gupta,et al.  The effects of oxidative stress on female reproduction: a review , 2012, Reproductive Biology and Endocrinology.

[25]  A. Favier,et al.  Evaluation of cytotoxicity and oxidative DNA damaging effects of di(2-ethylhexyl)-phthalate (DEHP) and mono(2-ethylhexyl)-phthalate (MEHP) on MA-10 Leydig cells and protection by selenium. , 2010, Toxicology and applied pharmacology.

[26]  Rajinder Singh,et al.  First‐trimester increase in oxidative stress and risk of small‐for‐gestational‐age fetus , 2009, BJOG : an international journal of obstetrics and gynaecology.

[27]  Toxicological Profile for Di ( 2-Ethylhexyl ) Phthalate ( DEHP ) Draft for Public Comment December 2019 , 2009 .

[28]  S. Vandentorren,et al.  Exposure assessment of phthalates in French pregnant women: results of the ELFE pilot study. , 2010, International journal of hygiene and environmental health.

[29]  D. V. van Thiel,et al.  Biomarkers of oxidative stress study V: ozone exposure of rats and its effect on lipids, proteins, and DNA in plasma and urine. , 2013, Free radical biology & medicine.

[30]  Jessilynn Taylor,et al.  Toxicological profile for di-n-butyl phthalate , 1997 .

[31]  Se-Young Oh,et al.  Community level exposure to chemicals and oxidative stress in adult population. , 2009, Toxicology Letters.

[32]  J. Meeker,et al.  Mono-2-ethylhexyl phthalate induces oxidative stress responses in human placental cells in vitro. , 2013, Toxicology and applied pharmacology.

[33]  C. Vélez,et al.  Mitochondrial permeability and toxicity of diethylhexyl and monoethylhexyl phthalates on TK6 human lymphoblasts cells. , 2011, Toxicology in vitro : an international journal published in association with BIBRA.

[34]  B. Ames,et al.  Biomarkers of oxidative stress study III. Effects of the nonsteroidal anti-inflammatory agents indomethacin and meclofenamic acid on measurements of oxidative products of lipids in CCl4 poisoning. , 2005, Free radical biology & medicine.

[35]  Dangxia Zhou,et al.  Di-n-Butyl Phthalate (DBP) Exposure Induces Oxidative Damage in Testes of Adult Rats , 2010, Systems biology in reproductive medicine.

[36]  A. Calafat,et al.  Quantification of 22 phthalate metabolites in human urine. , 2007, Journal of chromatography. B, Analytical technologies in the biomedical and life sciences.

[37]  I. Crocker,et al.  Erratum to “Formation of Syncytial Knots is Increased by Hyperoxia, Hypoxia and Reactive Oxygen Species” [Placenta 28, Supplement A, Trophoblast Research, Volume 21 (2007) S33–S40] , 2007 .

[38]  Yannan Jiang,et al.  Secondary analysis of case‐control data , 2006, Statistics in medicine.

[39]  V. Papadopoulos,et al.  Oxidative stress and phthalate-induced down-regulation of steroidogenesis in MA-10 Leydig cells. , 2013, Reproductive toxicology.

[40]  I. Padilla,et al.  Urinary phthalate metabolite concentrations among pregnant women in Northern Puerto Rico: distribution, temporal variability, and predictors. , 2014, Environment international.

[41]  M. Cunningham,et al.  Effects of peroxisome proliferators on glutathione and glutathione-related enzymes in rats and hamsters. , 2001, Toxicology and applied pharmacology.

[42]  Frederica P. Perera,et al.  Characterization of Phthalate Exposure among Pregnant Women Assessed by Repeat Air and Urine Samples , 2008, Environmental health perspectives.

[43]  I. Crocker,et al.  Formation of syncytial knots is increased by hyperoxia, hypoxia and reactive oxygen species. , 2007, Placenta.

[44]  R. Ge,et al.  Mono-(2-ethylhexyl) phthalate affects the steroidogenesis in rat Leydig cells through provoking ROS perturbation. , 2012, Toxicology in vitro : an international journal published in association with BIBRA.

[45]  A. Calafat,et al.  Urinary Phthalate Metabolites in Relation to Preterm Birth in Mexico City , 2009, Environmental health perspectives.

[46]  J. Morrow,et al.  Measurement of F(2)-isoprostanes as an index of oxidative stress in vivo. , 2000, Free radical biology & medicine.

[47]  T. Shono,et al.  Short-time exposure to mono-n-butyl phthalate (MBP)-induced oxidative stress associated with DNA damage and the atrophy of the testis in pubertal rats , 2014, Environmental Science and Pollution Research.