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
ABSTRACT 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.
- SourceAvailable from: Roberto Marci[Show abstract] [Hide abstract]
ABSTRACT: The potential hazardous effects that estrogen- and androgen-like chemicals may have both on wildlife and human health have attracted much attention from the scientific community. Endocrine disruptors (EDCs) are chemicals that have the capacity to interfere with normal signalling systems. EDCs may mimic, block or modulate the synthesis, release, transport, metabolism and binding or elimination of natural hormones. Even though potential EDCs may be present in the environment at only very low levels, they may still cause harmful effects, especially when several different compounds act on one target. EDCs include persistent pollutants, agrochemicals and widespread industrial compounds. Not all EDCs are man-made compounds; many plants produce substances (phytoestrogens) that can have different endocrine effects either adverse or beneficial in certain circumstances. Natural substances such as sex hormones from urban or farm wastes can become concentrated in industrial, agricultural and urban areas; thus, such wastes may be considered potential 'EDCs' for humans and/or wildlife. Much attention has focussed on changing trends in male reproductive parameters in relation to EDC exposure; however, studies on the female reproductive system have been less comprehensive. We have focussed this article on four major aspects of female reproductive health: fertility and fecundability, endometriosis, precocious puberty and breast and endometrial cancer.Human Reproduction Update 12/2007; 14(1):59-72. DOI:10.1093/humupd/dmm025 · 8.66 Impact Factor
- [Show abstract] [Hide abstract]
ABSTRACT: Nonylphenol (NP) and its parent compounds, the nonylphenol ethoxylates are some of the most prevalent chemicals found in U.S. waterways. NP is also resistant to biodegradation and is a known environmental estrogen, which makes NP a chemical of concern. Our data show that NP also activates the constitutive androstane receptor (CAR), an orphan nuclear receptor important in the induction of detoxification enzymes, including the P450s. Transactivation assays demonstrate that NP increases murine CAR (mCAR) transcriptional activity, and NP treatment can overcome the inhibitory effects of the inverse agonist, androstanol, on mCAR activation. Treatment of wild-type (CAR +/+) mice with NP at 50 or 75 mg/kg/day increases Cyp2b protein expression in a dose-dependent manner as demonstrated by Western blotting, and was confirmed by quantitative reverse transcription-PCR of Cyp2b10 transcript levels. CAR-null (CAR -/-) mice show no increased expression of Cyp2b following NP treatment, indicating that CAR is required for NP-mediated Cyp2b induction. In addition, NP increases the translocation of CAR into the nucleus, which is the key step in the commencement of CAR's transcriptional activity. NP also induced CYP2B6 in primary human hepatocytes, and increased Cyp2b10 messenger RNA and protein expression in humanized CAR mice, indicating that NP is an activator of human CAR as well. In conclusion, NP is a CAR activator, and this was demonstrated in vitro with transactivation assays and in vivo with transgenic CAR mouse models.Toxicological Sciences 09/2007; 98(2):416-26. DOI:10.1093/toxsci/kfm107 · 4.48 Impact Factor
Chapter: Endocrine Disruption in Mammals[Show abstract] [Hide abstract]
ABSTRACT: The United States presently uses more than 80 000 chemicals, a number that is estimated to grow by 2000 chemicals each year. Although generally not considered toxic at current exposure levels, many of these chemicals interfere with the endocrine system and may have profound effects on reproduction. Exposure to endocrine-disrupting chemicals (EDCs) is associated with an earlier onset of puberty, decreased fecundity and fertility, altered sexual behavior, and increased incidence of abnormalities and cancers of the reproductive tract in humans and in laboratory animals. Importantly, it appears that developing organisms may be particularly sensitive to slight variations in the hormonal milieu that occurs after exposure to some chemicals. In this chapter we review the sources and mechanisms of several well-studied EDCs and the evidence that exposure to these chemicals affects many aspects of mammalian reproduction.Hormones and Reproduction of Vertebrates, Mammals edited by David O. Norris, Kristin H. Lopez, 01/2010: chapter 14: pages 329-371; Elsevier Publishing., ISBN: 978-0-12-374928-4