Di-n-Butyl Phthalate Activates Constitutive Androstane Receptor and Pregnane X Receptor and Enhances the Expression of Steroid-Metabolizing Enzymes in the Liver of Rat Fetuses

University of Rhode Island, Кингстон, Rhode Island, United States
Toxicological Sciences (Impact Factor: 3.85). 09/2005; 86(2):281-90. DOI: 10.1093/toxsci/kfi204
Source: PubMed


The plasticizer di-n-butyl phthalate (DBP) is a reproductive toxicant in rodents. Exposure to DBP in utero at high doses alters early reproductive development in male rats. Di-n-butyl phthalate also affects hepatic and extrahepatic enzymes. The objectives of this study were to determine the responsiveness of steroid-metabolizing enzymes in fetal liver to DBP and to investigate the potential of DBP to activate nuclear receptors that regulate the expression of liver enzymes. Pregnant Sprague-Dawley rats were orally dosed with DBP at levels of 10, 50, or 500 mg/kg/day from gestation days 12 to 19; maternal and fetal liver samples were collected on day 19 for analyses. Increased protein and mRNA levels of CYP 2B1, CYP 3A1, and CYP 4A1 were found in both maternal and fetal liver in the 500-mg dose group. Di-n-butyl phthalate at high doses also caused an increase in the mRNA of hepatic estrogen sulfotransferase and UDP-glucuronosyltransferase 2B1 in the dams but not in the fetuses. Xenobiotic induction of CYP3A1 and 2B1 is known to be mediated by the nuclear hormone receptors pregnane X receptor (PXR) and constitutive androstane receptor (CAR). In vitro transcriptional activation assays showed that DBP activates both PXR and CAR. The main DBP metabolite, mono-butyl-phthalate (MBP) did not interact strongly with either CAR or PXR. These data indicate that hepatic steroid- and xenobiotic-metabolizing enzymes are susceptible to DBP induction at the fetal stage; such effects on enzyme expression are likely mediated by xenobiotic-responsive transcriptional factors, including CAR and PXR. Our study shows that DBP is broadly reactive with multiple pathways involved in maintaining steroid and lipid homeostasis.

Full-text preview

Available from:
  • Source
    • "PXR expression emerges as a potential biomarker related to EDC exposure and infertility, since it is enhanced in infertile women in association to either BPA and PFOS exposure. The upregulation of PXR is biologically plausible, since this " sensor " NR is involved in the metabolism of xenobiotics and endogenous compounds, including steroids [29]. It may be noteworthy that PFOA behaved differently than PFOS, as its internal levels are negatively correlated with PXR in fertile women and with AhR in infertile patients. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Significant evidence supports that many endocrine disrupting chemicals could affect female reproductive health. Aim of this study was to compare the internal exposure to bisphenol A (BPA), perfluorooctane sulphonate (PFOS), perfluorooctanoic acid (PFOA), monoethylhexyl phthalate (MEHP), and di(2-ethylhexyl) phthalate (DEHP) in serum samples of 111 infertile women and 44 fertile women. Levels of gene expression of nuclear receptors (ER α , ER β , AR, AhR, PXR, and PPAR γ ) were also analyzed as biomarkers of effective dose. The percentage of women with BPA concentrations above the limit of detection was significantly higher in infertile women than in controls. No statistically significant difference was found with regard to PFOS, PFOA, MEHP and DEHP. Infertile patients showed gene expression levels of ER α , ER β , AR, and PXR significantly higher than controls. In infertile women, a positive association was found between BPA and MEHP levels and ER α , ER β , AR, AhR, and PXR expression. PFOS concentration positively correlated with AR and PXR expression. PFOA levels negatively correlated with AhR expression. No correlation was found between DEHP levels and all evaluated nuclear receptors. This study underlines the need to provide special attention to substances that are still widely present in the environment and to integrate exposure measurements with relevant indicators of biological effects.
    Full-text · Article · Apr 2013 · International Journal of Endocrinology
  • Source
    • "Although differences were observed in the ratio of free to conjugated MBP in human serum as compared to the rat, these data are insufficient for quantitative interspecies extrapolation, because in order to replace administered dose as a dose metric, it is necessary to determine the absolute, not the relative, level of free MBP in serum as a function of exposure. The Wyde et al. (2005) study suggests that DBP-induced enzyme induction occurred. Specifically , this study reported that exposure to 50 and 500 mg/kg-d DBP leads to an increase in rat liver UDP glucuronosyltransferase 2B1 (Ugt2b1) mRNA levels. "
    [Show abstract] [Hide abstract]
    ABSTRACT: An approach for evaluating and integrating genomic data in chemical risk assessment was developed based on the lessons learned fromperforming a case study for the chemical dibutyl phthalate. Acase study prototype approach was first developed in accordance with EPA guidance and recommendations of the scientific community. Dibutyl phthalate (DBP) was selected for the case study exercise. The scoping phase of the dibutyl phthalate case studywas conducted by considering the available DBPgenomic data, taken together with the entire data set, for whether they could inform various risk assessment aspects, such as toxicodynamics, toxicokinetics, and dose-response. A description of weighing the available dibutyl phthalate data set for utility in risk assessment provides an example for consideringgenomic data for future chemical assessments. As a result of conducting the scoping process, two questions - Do the DBP toxicogenomic data inform 1) the mechanisms or modes of action?, and 2) the interspecies differences in toxicodynamics? - were selected to focus the case study exercise. Principles of the general approach include considering the genomics data in conjunction with all other data to determine their ability to inform the various quantitative and/or qualitative aspects of risk assessment, and evaluating the relationship between the available genomic and toxicity outcome data with respect to study comparability and phenotypic anchoring. Based on experience fromthe DBP case study, recommendations and ageneral approach for integrating genomic data in chemical assessment were developed to advance the broader effort to utilize 21st century data in risk assessment.
    Full-text · Article · Mar 2013 · Toxicology and Applied Pharmacology
  • Source
    • "antly , their metabolites , are toxic endocrine disruptors . More interestingly , a growing body of research has re - cently identified them as intricate environmental pollutants that may interfere with the development and functioning of human and wildlife reproductive systems ( Coí on et al . , 2000 ; Hauser et al . , 2004 ; Main et al . , 2006 ; Wyde et al . , 2005 ) ."
    [Show abstract] [Hide abstract]
    ABSTRACT: Abstract Concerns over the threats posed by a large number of molecules, collectively termed as endocrine disrupting compounds (EDCs) and generally known to alter and disrupt hormone systems and physiological functions, have often been expressed in academic and scholarly debates. From the perspective of classical toxicology, EDCs have genomic mechanisms of actions and exert agonistic or antagonistic effects on steroid receptors. They are also able to alter reproductive function by binding to estrogen or androgen receptors, and the neuroendocrine system by binding to the thyroid receptor. Recently, EDCs have been shown to have equally complex nongenomic mechanisms, altering steroid synthesis or steroid metabolism. As environmental contaminants, these molecules proved disruptively harmful for many wildlife species, particularly those from or depending on the aquatic ecosystem. An increasingly growing body of research has voiced further concerns that human populations are not immune from the dangers of ED
    Full-text · Article · Nov 2012 · Critical Reviews in Environmental Science and Technology
Show more