The relative bioavailability and metabolism of bisphenol A in rats is dependent upon the route of administration.
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Bisphenol A (BPA) is used to produce polymers for food contact applications, thus there is potential for oral exposure of humans to trace amounts via the diet. BPA was weakly estrogenic in screening assays measuring uterine weight/response, although much higher oral doses of BPA were required to elicit a uterotropic response as compared to other routes of administration. The objective of this study was to determine if a route dependency exists in the pharmacokinetics and metabolism of 14C-labeled BPA following single oral (po), intraperitoneal (ip), or subcutaneous (sc) doses of either 10 or 100 mg/kg to Fischer 344 rats. Results indicated a marked route dependency in the pharmacokinetics of BPA. The relative bioavailability of BPA and plasma radioactivity was markedly lower following oral administration as compared to sc or ip administration. The major fraction of plasma radioactivity following oral dosing was the monoglucuronide conjugate of BPA (68-100% of plasma radioactivity). BPA was the major component in plasma at Cmax following sc or ip administration exceeded only by BPA-monoglucuronide in females dosed ip. Up to four additional unidentified metabolites were present only in the plasma of animals dosed ip or sc. One of these, found only following ip administration, was tentatively identified as the monosulfate conjugate of BPA. The monoglucuronide conjugate was the major urinary metabolite; unchanged BPA was the principal component excreted in feces. These results demonstrated a route dependency of BPA bioavailability in rats, with oral administration resulting in the lowest bioavailability, and offer an explanation for the apparent route differences in estrogenic potency observed for BPA. (+info)
Estrogenic activity of octylphenol, nonylphenol, bisphenol A and methoxychlor in rats.
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Considerable attention has recently been focused on environmental chemicals that disrupt the reproductive system by altering steroid receptor function. Although numerous in vitro and in vivo methods have been shown to be useful approaches for identifying chemicals that can disrupt reproduction through a direct interaction with the estrogen receptor, it is imperative that the protocols selected be capable of detecting chemicals with a broad range of estrogenic activity. Here we evaluate the reliability of the 3-day uterotrophic assay for detecting chemicals with strong or weak estrogenic activity in both prepubertal and ovariectomized adult Long Evans rats. These data were compared to additional measures of estrogenic activity, which included the age of vaginal opening, the induction of cornified vaginal epithelial cells in ovariectomized adult rats, and estrous cyclicity in intact adult rats. Test chemicals selected for these studies included 17-beta-estradiol, ethynyl estradiol, methoxychlor, 4-tert-octylphenol, 4-nonylphenol and bisphenol A. Data from in vitro receptor binding assays compared the ability of the test chemicals to compete with [3H]-estradiol or [3H]-promegestone for binding to estrogen or progesterone receptors. As expected, the binding affinities for the estrogen receptor ranged from high to low, as reflected by Ki concentrations of 0.4 nM for 17-beta-estradiol and ethynyl estradiol, and 0.05-65 microM for 4-tert-octyphenol, 4-nonylphenol, and methoxychlor. Although none of the test chemicals demonstrated a high affinity for binding to the progesterone receptor, 4-tert-octylphenol and 4-nonylphenol exhibited a weak affinity, with Ki concentrations ranging from 1.2 to 3.8 microM. In vivo studies indicated that the 3-day uterotrophic assay in prepubertal rats was the best method for detecting estrogenic activity when compared with all other end points, based upon the dose-response data for ethynyl estradiol (0.01-0.1 mg/kg), 4-tert-octylphenol (50-200 mg/kg, oral), and 4-nonylphenol (25-100 mg/kg, oral). Although oral doses of ethynyl estradiol (0.01 mg/kg) and 4-nonylphenol (50 mg/kg) induced a significant increase in uterine weight in the prepubertal rats, these doses were ineffective for stimulating a similar response in ovariectomized adult rats. The age of vaginal opening was advanced following oral exposure from postnatal days 21-35 to ethynyl estradiol (0.01 mg/kg), methoxychlor (50 mg/kg), 4-tert-octylphenol (200 mg/kg), and 4-nonylphenol (50 mg/kg). Although bisphenol A (200 mg/kg, oral) induced a significant uterotrophic response within 3 days in prepubertal rats, doses up to 400 mg/kg failed to advance the age of vaginal opening. Monitoring changes in the vaginal epithelium of ovariectomized adult rats was the least effective method for detecting estrogenic activity for 4-tert-octylphenol and bisphenol A. The number of 4-5 day estrous cycles was reduced during a 25-day exposure to ethynyl estradiol (0.01 mg/kg), methoxychlor (50 mg/ kg), 4-tert-octylphenol (200 mg/kg), 4-nonylphenol (100 mg/kg), and bisphenol A (100 mg/kg) by oral gavage. Although long periods of extended diestrus (7-14 days) were generally correlated with exposure to ethynyl estradiol and 4-tert-octylphenol, the cycling patterns following exposure to methoxychlor, 4-nonylphenol and bisphenol A were not as clearly defined, with shorter periods of extended diestrus (4-7 days) and/or estrus (3-5 days) intermittently observed throughout the exposure period. Together these data provide a comparison of the 3-day uterotrophic assay with alternative measures of estrogenic activity for a group of test chemicals with a broad range of affinities for the estrogen receptor. These data can be useful during the assessment and validation of methods for screening environmental chemicals for endocrine disrupting activity. (+info)
In vitro inhibition and induction of human hepatic cytochrome P450 enzymes by modafinil.
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The ability of modafinil to affect human hepatic cytochrome P450 (CYP) activities was examined in vitro. The potential for inhibition of CYP1A2, CYP2A6, CYP2B6, CYP2C9, CYP2C19, CYP2D6, CYP2E1, CYP3A4/5, and CYP4A9/11 by modafinil (5-250 microM) was evaluated with pooled human liver microsomes. Modafinil exhibited minimal capacity to inhibit any CYP enzyme, except CYP2C19. Modafinil inhibited the 4'-hydroxylation of S-mephenytoin, a marker substrate for CYP2C19, reversibly and competitively with a K(i) value of 39 microM, which approximates the steady-state C(max) value of modafinil in human plasma at a dosage of 400 mg/day. No irreversible inhibition of any CYP enzyme was observed, and there was no evidence of metabolism-dependent inhibition. The potential for induction of CYP activity was evaluated by exposing primary cultures of human hepatocytes to modafinil (10-300 microM). Microsomes were then prepared and assayed for CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP3A4/5 activities. The mean activities of microsomal CYP1A2, CYP2B6, and CYP3A4/5 from modafinil-treated hepatocytes were higher (up to 2-fold) than those in the solvent-treated controls but were less than those produced by reference inducers of these enzymes. At high concentrations of modafinil (>/=100 microM), the mean activity of CYP2C9 was decreased (up to 60%) relative to that in the solvent controls. Overall, modafinil was shown to have effects on human hepatic CYP1A2, CYP2B6, CYP2C9, CYP2C19, and CYP3A4/5 activities in vitro. Although effects obtained in vitro are not always predictive of effects in vivo, such results provide a rational basis for understanding drug-drug interactions that are observed clinically and for planning subsequent investigations. (+info)
Pubertal development and reproductive functions of Crl:CD BR Sprague-Dawley rats exposed to bisphenol A during prenatal and postnatal development.
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Bisphenol A (BPA) is used on a large scale in the manufacture of polycarbonate plastics. BPA has been shown to bind weakly to both estrogen receptor (ER)alpha and ERbeta, and to transactivate reporter genes in vitro. The purpose of the present study was to determine whether exposure of rats to BPA during pre- and postnatal development affects estrogen-mediated end points related to pubertal development and reproductive functions. BPA was administered to pregnant Crl:CD BR Sprague-Dawley rats by gavage at 0, 3.2, 32, or 320 mg/kg/day from gestation day (GD) 11 through postnatal day (PND) 20. Diethylstilbestrol (DES) at 15 microg/kg/day was used as a reference chemical with known estrogenic effects. Female pubertal development was not affected by indirect BPA exposure of the offspring at any of the dose levels. Treatment with this chemical also did not produce detectable effects on the volume of the sexually dimorphic nucleus of the preoptic area (SDN-POA), estrous cyclicity, sexual behavior, or male reproductive organ weights of F(1) offspring. However, DES at 15 microg/kg/day increased the volume of the SDN-POA of female offspring and affected their normal estrous cyclicity following puberty. In this study, pre- and postnatal exposure of rats to BPA at 3.2, 32, or 320 mg/kg/day from GD 11 through PND 20 did not have any apparent adverse effects on female rat pubertal development and reproductive functions. (+info)
Anaerobic-aerobic process for microbial degradation of tetrabromobisphenol A.
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Tetrabromobisphenol A (TBBPA) is a flame retardant that is used as an additive during manufacturing of plastic polymers and electronic circuit boards. Little is known about the fate of this compound in the environment. In the current study we investigated biodegradation of TBBPA, as well as 2,4,6-tribromophenol (TBP), in slurry of anaerobic sediment from a wet ephemeral desert stream bed contaminated with chemical industry waste. Anaerobic incubation of the sediment with TBBPA and peptone-tryptone-glucose-yeast extract medium resulted in a 80% decrease in the TBBPA concentration and accumulation of a single metabolite. This metabolite was identified by gas chromatography-mass spectrometry (GC-MS) as nonbrominated bisphenol A (BPA). On the other hand, TBP was reductively dehalogenated to phenol, which was further metabolized under anaerobic conditions. BPA persisted in the anaerobic slurry but was degraded aerobically. A gram-negative bacterium (strain WH1) was isolated from the contaminated soil, and under aerobic conditions this organism could use BPA as a sole carbon and energy source. During degradation of BPA two metabolites were detected in the culture medium, and these metabolites were identified by GC-MS and high-performance liquid chromatography as 4-hydroxybenzoic acid and 4-hydroxyacetophenone. Both of those compounds were utilized by WH1 as carbon and energy sources. Our findings demonstrate that it may be possible to use a sequential anaerobic-aerobic process to completely degrade TBBPA in contaminated soils. (+info)
Benzylidene lactam compound, KNK437, a novel inhibitor of acquisition of thermotolerance and heat shock protein induction in human colon carcinoma cells.
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Cells exposed to heat or other types of stressors transiently synthesize a group of proteins known as heat shock proteins (HSPs). A nonlethal heat treatment can elicit in the cells an ability to resist subsequent lethal heat treatments. We report here that a novel benzylidene lactam compound, KNK437, dose-dependently inhibited the acquisition of thermotolerance and the induction of various HSPs including HSP105, HSP70, and HSP40 in COLO 320DM (human colon carcinoma) cells. The induction of heat-inducible HSP70, which is reported to be involved in the development of thermotolerance, was inhibited at mRNA levels by treatment with KNK437. This compound also inhibited the acquisition of thermotolerance as developed by sodium arsenite. However, it did not increase thermosensitivity in nontolerant cells. The effect of KNK437 was much greater than that of quercetin, a bioflavonoid that was previously reported to inhibit the acquisition of thermotolerance as well as the induction of HSPs. We conclude that this drug is a novel inhibitor of the acquisition of thermotolerance caused by the induction of HSPs. (+info)
Bisphenol A and related endocrine disruptors.
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The article highlighted in this issue is "Bisphenol A-Induced Increase in Uterine Weight and Alterations in Uterine Morphology in Ovariectomized B6C3F1 Mice: Role of the Estrogen Receptor" by Andriana D. Papaconstantinou, Thomas H. Umbreit, Benjamin R. Fisher, Peter L. Goering, Nicholas T. Lappas, and Ken M. Brown (pp. 332-339). (+info)
Bisphenol A-induced increase in uterine weight and alterations in uterine morphology in ovariectomized B6C3F1 mice: role of the estrogen receptor.
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The ability of the environmental xenoestrogen bisphenol A (BPA) to increase uterine wet weight in the rodent remains controversial, and few studies have previously examined the effects of BPA on uterine morphology. Furthermore, it is not known whether BPA-induced uterotrophic effects are, similarly to beta-estradiol (E(2)), mediated through the estrogen receptor (ER). In this study, we compared the effects of BPA on uterine wet weight and morphology to those of E(2) in the B6C3F1 ovariectomized mouse. To examine whether these effects were mediated through the ER, the antiestrogen ICI 182, 780 (ICI) was co-administered with BPA or E(2). We report that subcutaneous administration of BPA at doses between 0.8 and 8 mg/day over 4 days significantly increased mean uterine wet weights above those of vehicle (corn oil)-treated mice. The uterine weight data suggest that BPA acts as a partial agonist with an EC(50) of 0.72 mg/day compared to 19.4 ng/day for E(2). BPA (2 mg/day) and E(2) (40 ng/day) induced a significant increase in luminal epithelial height and in the thickness of both the stromal and myometrial layers of the uterus. The effects of 40 ng E(2)/day on all endpoints studied were reversed by 20 microg ICI/day. ICI at 200, but not 20 microg/day, was able to reverse the BPA (2 mg/day)-induced increase in both uterine wet weight and luminal epithelial height. ICI alone at 200 microg/day stimulated an increase in thickness of both the stroma and myometrium and did not reverse the effects of BPA (2 mg/day) on these layers. These results suggest that the BPA-induced increase in uterine wet weight and in luminal epithelial height in the ovariectomized B6C3F1 mouse are mediated by the ER. (+info)