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PubMed1998

The estrogenicity of bisphenol A-related diphenylalkanes with various substituents at the central carbon and the hydroxy groups.

The chemical structure of hydroxylated diphenylalkanes or bisphenols consists of two phenolic rings joined together through a bridging carbon. This class of endocrine disruptors that mimic estrogens is widely used in industry, particularly in plastics. Bisphenol F, bisphenol A, fluorine-containing bisphenol A (bisphenol AF), and other diphenylalkanes were found to be estrogenic in a bioassay with MCF7 human breast cancer cells in culture (E-SCREEN assay). Bisphenols promoted cell proliferation and increased the synthesis and secretion of cell type-specific proteins. When ranked by proliferative potency, the longer the alkyl substituent at the bridging carbon, the lower the concentration needed for maximal cell yield; the most active compound contained two propyl chains at the bridging carbon. Bisphenols with two hydroxyl groups in the para position and an angular configuration are suitable for appropriate hydrogen bonding to the acceptor site of the estrogen receptor. Our data suggest that estrogenicity is influenced not only by the length of the substituents at the bridging carbon but also by their nature. Because diphenylalkane derivatives are widespread and their production and use are increasing, potential exposure of humans to estrogenic bisphenols is becoming a significant issue. The hazardous effects of inadvertent exposure to bisphenol-releasing chemicals in professional workers and the general populations therefore deserve investigation.

Benzhydryl Compounds↗

PubMed2005

Covert signal disruption: anti-ecdysteroidal activity of bisphenol A involves cross talk between signaling pathways.

Bisphenol A is a key industrial chemical used in the manufacture of polycarbonate plastics and other products. Several recent reports ascribe toxicological properties to this compound that have been attributed to the disruption of endocrine-related processes. In the present study, the toxicity of bisphenol A was definitively characterized in the water flea (Daphnia magna) in an effort to discern whether this compound may elicit endocrine toxicity in an invertebrate species and to establish the mechanism by which this toxicity is elicited. The ability of bisphenol A to interfere with two ecdysteroid-dependent physiological processes--molting and embryonic development--was evaluated. Bisphenol A elicited antiecdysteroidal activity as indicated by its prolongation of the intermolt period and interference with embryonic development. This apparent antiecdysteroidal activity was not due to reduced availability of endogenous ecdysteroid nor due to ecdysteroid-receptor antagonism. The ability of bisphenol A to elicit antiecdysteroidal activity by functioning as a juvenoid hormone was next evaluated. Bisphenol A, alone, did not elicit juvenoid activity. However, bisphenol A did enhance the activity of the crustacean juvenoid hormone methyl farnesoate. A definitive assessment of the effects of bisphenol A on the reproductive capacity of daphnids revealed a concentration-response relationship that extended at least one order of magnitude below exposure levels that were overtly toxic to the maternal organisms. These results demonstrate that bisphenol A is chronically toxic to daphnids, probably through its ability to interfere with ecdysteroid/juvenoid regulated processes. However, effects are elicited at levels that are not likely to pose environmental concern.

Animals↗

PubMed2001

Cell-transforming activity and estrogenicity of bisphenol-A and 4 of its analogs in mammalian cells.

Estrogenicity is an important mechanism in hormonal carcinogenesis but not sufficient to explain the carcinogenic activity of all estrogens. Additional mechanisms, related to genetic alterations, in conjunction with estrogenicity mediated through the estrogen receptor, have been suggested. An environmental estrogen bisphenol-A (BP-A) and its analogs are widespread in our living environment. Because of the potential for human exposure, the possible relationship between carcinogenicity and estrogenicity of these bisphenols was studied using mammalian cells. We quantitatively compared the cell-transforming activity of BP-A and 4 of its analogs (BP-2, BP-3, BP-4 and BP-5) in Syrian hamster embryo (SHE) cells lacking estrogen-receptor expression. The transforming activity determined by the morphological transformation frequencies in SHE cells treated with the bisphenols ranked: BP-4 > BP-5 > BP-3 > BP-A > BP-2. We also compared the estrogenicity of the 5 bisphenols in MCF7 human breast cancer cells as determined by cell proliferation or progesterone receptor (PgR) expression assayed by RT-PCR. When MCF7 cells were treated with the bisphenols, the proliferative potency ranked: BP-A > BP-5 > BP-4 > BP-3 = BP-2. The level of mRNA for PgR in cells treated with the bisphenols was BP-A > BP-5 > BP-4 > BP-3 > BP-2. These indicate that the transforming activity does not correlate with the estrogenicity of the bisphenols, except for BP-2 that has the weakest activity at the both endpoints. In addition, our results suggest that bisphenols with few, if any, transforming and estrogenic activities could be altered by a modification of the chemical structure. Published 2001 Wiley-Liss, Inc.

Animals↗

PubMed2000

Down-regulation of murine Cyp1a-1 in mouse hepatoma Hepa-1c1c7 cells by bisphenol A.

Cultured mouse hepatoma Hepa-1c1c7 cells were treated with either bisphenol A or 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) or in combination to assess the role of bisphenol A in the process of Cyp1a-1 induction. Treatment of Hepa-1c1c7 cultures with 2,3,7, 8-tetrachlorodibenzo-p-dioxin (TCDD) induced Cyp1a-1, as determined by analysis of 7-ethoxyresorufin O-deethylase (EROD) activities. Bisphenol A alone did not affect the activity of Cyp1a-1-specific EROD; in contrast, TCDD-induced EROD activities were markedly reduced in the concomitant treatment of TCDD and bisphenol A in a dose-dependent manner. Treatment with tamoxifen, an antiestrogen that acts through the estrogen receptor, did not affect the suppressive effects of bisphenol A on TCDD-induced EROD activity. TCDD-induced Cyp1a-1 mRNA levels were markedly suppressed in the concomitant treatment of TCDD and bisphenol A consistent with their effects on EROD activity. Transient transfection assay using dioxin-response element (DRE)-linked luciferase revealed that bisphenol A reduced transformation of the aryl hydrocarbons (Ah) receptor to a form capable of specifically binding to the DRE sequence in the promoter of the Cyp1a-1 gene. These results suggest the down-regulation of the Cyp1a-1 gene expression by bisphenol A in Hepa-1c1c7 cells might be antagonism of the DRE binding potential of nuclear Ah receptor but not mediated through estradiol receptor.

Animals↗

PubMed2000

Preparation of 4,4'-(1-[(2)H6]methylethylidene)bis-[2,3,5,6-(2)H4]phenol and its application to the measurement of bisphenol A in beverages by stable isotope dilution mass spectrometry.

The preparation of 4,4'-(1-[(2)H6]methylethylidene)bis-[2,3,5,6-(2)H4]phenol, bisphenol A-d14, was achieved in excellent yield by reaction of [2H6]acetone with [2H6]phenol in the presence of deuterium chloride. The product thus obtained was shown by mass spectroscopy to be a mixture of the 2H14, 2H13 and 2H12 isotopomers in the relative proportions of 82.3:16.2:1.5, respectively. An isotope dilution gas chromatography-mass spectrometric method using bisphenol A-d14 as an internal standard was developed to measure the level of bisphenol A in beverages. The procedure involves extracting bisphenol A into dichloromethane, and then purifying the analyte by back extraction into dilute aqueous sodium hydroxide. Conversion of bisphenol A and its internal standard, bisphenol A-d14, to their corresponding O-bis(trifluoroacetyl) derivatives by treatment with trifluoroacetic anhydride gave compounds with good chromatographic properties and whose mass fragmentometry is such that loss of M-CH3 and M-C2H3 are the base peaks in the mass spectra of the analyte and internal standard, respectively. Quantification of bisphenol A was achieved by comparing the area of the M-15 ion to that of the corresponding ion of bisphenol A-d14. The characteristics of our assay are: an analyte recovery of better than 95%, a root mean square signal-to-noise ratio of 79:1 for 1.7 pg on column and an inter-assay RSD of better than 4% (n=5).

Benzhydryl Compounds↗

PubMed2003

Induction of oxidative stress by bisphenol A in the epididymal sperm of rats.

Bisphenol A has been shown to affect the reproduction of male rats and mice. However, the mechanism of action of bisphenol A on the epididymal sperm is not elucidated. The present study was undertaken to evaluate the effect of bisphenol A on the antioxidant system of rat epididymal sperm. Bisphenol A was administered orally to male rats at the dose levels of 0.2, 2 and 20 microg/Kg body weight per day for 45 days. After 24 h of the last treatment, rats were weighed and killed using anesthetic ether. The body weight of treated rats did not show significant change as compared with the corresponding control groups. In bisphenol A-treated rats there was a significant decrease in the weight of the testis and epididymis; the weight of ventral prostate increased significantly whereas there was no significant change in the weight of seminal vesicles as compared with the corresponding group of control animals. Sperm collected from the epididymis were used for sperm count and biochemical estimations. Administration of bisphenol A caused a reduction in the epididymal sperm motility and sperm count in a dose-dependent manner. The activities of superoxide dismutase, catalase, glutathione reductase and glutathione peroxidase were decreased while the levels of H(2)O(2) and lipid peroxidation increased significantly in the treated rats as compared with the corresponding group of control animals. The results suggested that graded doses of bisphenol A elicit depletion of antioxidant defence system and induce oxidative stress in epididymal sperm of rats. In conclusion, the adverse effect of bisphenol A on male reproduction may be due to induction of oxidative stress in sperm.

Administration, Oral↗

PubMed2003

Bisphenol A induces reactive oxygen species generation in the liver of male rats.

Bisphenol A, an environmental contaminant, widely used as a monomer in polycarbonate plastics, has been shown to cause abnormalities in liver of rats and mice. The nature and mechanism of action of bisphenol A on liver is not clear. The aim of the present study was to investigate if bisphenol A induces oxidative stress in the liver of rats and if co-administration of vitamin C, an antioxidant, can prevent oxidative stress. Bisphenol A (0.2, 2.0 and 20 micro g/kg body weight per day) and bisphenol A+vitamin C (0.2, 2.0, 20 micro g+40 mg/kg body weight per day) was orally administered to rats for 30 days. After 24 h of the last treatment, rats were killed using overdose of anesthetic ether. Body weights of the animals and the weights of liver showed no significant changes. The activities of antioxidant enzymes, superoxide dismutase, catalase, glutathione reductase and glutathione peroxidase were decreased in mitochondrial and microsome-rich fractions of liver. The levels of hydrogen peroxide and lipid peroxidation increased in the treated rats when compared with the corresponding group of control animals. Activity of alanine transaminase, a marker enzyme of hepatic injury remained unchanged in the treated rats as compared with the corresponding control rats. Co-administration of bisphenol A and vitamin C showed no changes in the activities of superoxide dismutase, catalase, glutathione reductase and glutathione peroxidase and in the levels of hydrogen peroxide and lipid peroxidation as compared with the corresponding control groups. The results indicated that bisphenol A induces oxidative stress in the liver of rats by decreasing the antioxidant enzymes. Co-administration of vitamin C reversed the effects of bisphenol A-induced oxidative stress in the liver of rats.

Air Pollutants↗

PubMed2002

Development of an enzyme-linked immunosorbent assay for bisphenol a using chicken immunoglobulins.

Bisphenol A was coupled, after derivatization into a suitable hapten, to bovine serum albumin and ovalbumin in order to produce immunizing and coating antigens. The immunizing antigens were injected into chickens, which allowed the isolation of specific bisphenol A immunoglobulins from the egg yolk. These antibodies were used in an indirect competitive enzyme-linked immunosorbent assay for the determination of bisphenol A in aqueous solutions. Various parameters, influencing the assay sensitivity, were evaluated. The applicability of the assay for the determination of bisphenol A in milk was also studied. The assay was not as sensitive as other analytical techniques used in bisphenol A analysis, since typical I(50) levels of 2.5 microM were reached in aqueous solutions. This study nevertheless illustrates the usefulness and the potency of chicken antibodies in the analysis of migration residues from packaging materials using immunochemical techniques. In addition, the assay showed to be quite specific for bisphenol A as well. Only for bisphenol A analogues, cross reactivities of about 40% were reached, enabling the use of the antibodies for the screening of bisphenol A and alike compounds.

Animals↗

PubMed2001

Bioavailability and mammary excretion of bisphenol a in Sprague-Dawley rats.

This study reports the absolute oral bioavailability and mammary excretion of bisphenol A in rats. The oral bioavailability was determined after administration of relatively low iv (0.1 mg/kg) and oral (10 mg/kg) doses of bisphenol A to rats. After iv injection, serum levels of bisphenol A declined biexponentially, with the mean initial distribution and terminal elimination half-lives being 6.1 +/- 1.3 min and 52.5 +/- 2.4 min, respectively. The systemic clearance (Cls) and the steady-state volume of distribution (Vss) averaged 107.9 +/- 28.7 m/min/kg and 5.6 +/- 2.4 L/kg, respectively. Upon oral administration, the maximum serum concentration (Cmax) and the time to reach the maximum concentration (Tmax) were 14.7 +/- 10.9 ng/ml and 0.2 +/- 0.2 h, respectively. The apparent terminal elimination half-life of bisphenol A (21.3 +/- 7.4 h) after oral administration was significantly longer than that after iv injection, indicating the flip-flop of the absorption and elimination rates. The absolute oral bioavailability of bisphenol A was low (5.3 +/- 2.1%). To determine the extent of mammary excretion, bisphenol A was given by simultaneous iv bolus injection plus infusion to steady state at low, medium, and high doses. The steady-state serum levels of bisphenol A were linearly increased with higher dosing rates. The systemic clearance (mean range, 119.2-154.1 ml/min/kg) remained unaltered over the dosing rate studied. The levels of bisphenol A in milk exceeded those in serum, with the steady-state milk to serum concentration ratio being 2.4-2.7.

Administration, Oral↗

PubMed2004

Chemical analysis of monomers in epoxy resins based on bisphenols F and A.

Diglycidyl ether of bisphenol A (DGEBA) is the monomer and most important contact allergen in epoxy resin(s) based on bisphenol A (DGEBA-R). Both thin-layer chromatography (TLC) and high-pressure liquid chromatography (HPLC) methods are available for the analysis of products containing DGEBA-R. With respect to detection and quantification, epoxy resins of the bisphenol F-type, i.e. epoxy resins containing the isomers of diglycidyl ethers of bisphenol F (DGEBF), are not as well investigated as DGEBA-R. The isomers of DGEBF are p,p'-DGEBF, o,p'-DGEBF and o,o'-DGEBF. Both p,p'-DGEBF and o,p'-DGEBF have been shown to be contact allergens in humans, and all 3 isomers are sensitizers in the guinea pig maximization test. We aimed (i). to develop HPLC methods for separation and purification of the individual DGEBF isomers, (ii). to detect and quantify the DGEBF isomers in epoxy resins of the bisphenol F-type and (iii). to evaluate and develop the TLC as a method for the detection of the DGEBF monomers. We found the total content of the DGEBF isomers in the investigated epoxy resins of the bisphenol F-type to vary from 17.0 to 81.7% w/w. Some of them also contained 0.1-2.4% w/w DGEBA. The HPLC method showed a sensitivity that was 2000-20 000x higher than that obtained with the TLC method for the DGEBF monomers. We concluded that the range of the DGEBF isomer content in epoxy resins of the bisphenol F-type is approximately the same as the monomer content in liquid compared to solid DGEBA-R. The relevance of contact allergy to DGEBA-R can remain unrecognized if the suspected product is an epoxy resin of the bisphenol F-type, which is analysed with the TLC method.

Allergens↗

PubMed2003

Leaching of bisphenol A from new and old babies' bottles, and new babies' feeding teats.

Bisphenol A is the monomer used in the manufacture of polycarbonate. Bisphenol A is also known to mimic the female hormone estrogen. In this study, the possibility of the leaching of bisphenol A from polycarbonate babies' bottles and feeding teats was investigated. Bisphenol A was extracted from water samples exposed to the bottles and teats using liquid-liquid extraction. Bisphenol A was analysed by gas chromatograph-mass spectrometer with quadrapole detector in selected ion monitoring mode. Mean leaching of bisphenol A from 100 used babies' bottles when filled with water at 25 degrees C and 80 degrees C were 0.71 +/- 1.65 ng/cm2 (mean +/- standard deviation) and 3.37 +/- 5.68 ng/cm2 respectively. Mean leaching of bisphenol A from 30 new babies' bottles when filled with water at 25 degrees C and 80 degrees C were 0.03 +/- 0.02 ng/cm2 and 0.18 degrees 0.30 ng/cm2 respectively. Bisphenol A was observed to have leached from babies' feeding teats into 37 degrees C water ranged from non-detectable to 22.86 ng/g. The technique employed in this study is fast, reliable and economical.

Benzhydryl Compounds↗

PubMed1997

Relative binding affinity-serum modified access (RBA-SMA) assay predicts the relative in vivo bioactivity of the xenoestrogens bisphenol A and octylphenol.

We have developed a relative binding affinity-serum modified access (RBA-SMA) assay to determine the effect of serum on the access of xenoestrogens to estrogen receptors within intact cultured MCF-7 human breast cancer cells. We used this assay to predict low dose activity of two xenoestrogens in mice. In serum-free medium, bisphenol A, a component of polycarbonates and of resins used to line metal food cans, showed a lower relative binding affinity (RBA; 0.006%) than octylphenol (0.072%) and nonylphenol (0.026%), which are used as surfactants in many commercial products (all RBAs are relative to estradiol, which is equal to 100%). In 100% serum from adult men, bisphenol A showed a higher RBA (0.01%) than in serum-free medium and thus enhanced access to estrogen receptors relative to estradiol. In contrast, octylphenol showed a 22-fold decrease in RBA (0.0029%) and nonylphenol showed a 5-fold decrease in RBA (0.0039%) when measured in adult serum. This indicates that, relative to estradiol, serum had less of an inhibitory effect on the cell uptake and binding in MCF-7 cells of bisphenol A, while serum had a greater inhibitory effect on octylphenol and nonylphenol relative to estradiol. Extrapolation of these relative activities in adult serum predicted that the estrogenic bioactivity of bisphenol A would be over 500-fold greater than that of octylphenol in fetal mouse serum. Bisphenol A and octylphenol were fed to pregnant mice at 2 and 20 micrograms/kg/day. Exposure of male mouse fetuses to either dose of bisphenol A, but to neither dose of octylphenol, significantly increased their adult prostate weight relative to control males, which is consistent with the higher predicted bioactivity of bisphenol A than octylphenol in the RBA-SMA assay. In addition, our findings show for the first time that fetal exposure to environmentally relevant parts-per-billion (ppb) doses of bisphenol A, in the range currently being consumed by people, can alter the adult reproductive system in mice.

Animals↗

PubMed2005

[Exposure to bisphenol-A affects the rewarding system in mice].

Bisphenol-A has been extensively evaluated for toxicity in a variety of tests as the most common environmental endocrine disruptor. In the present study, we found that prenatal and neonatal exposure to bisphenol-A affects the development of the central dopaminergic system in the mouse limbic area. Additionally, this treatment with bisphenol-A produced a down-regulation of dopamine D3 receptor and an up-regulation of dopamine D1 receptor function to activate G-protein in the mouse limbic forebrain, which is thought to play a critical role for rewarding effects by drugs of abuse. We next investigated the relationship between the neurobehavioral toxicity and its exposure period. The exposure to bisphenol-A during either organogenesis or lactation, but not implantation and parturition, significantly enhanced the morphine-induced hyperlocomotion and rewarding effect. Furthermore, the exposure to bisphenol-A during either organogenesis or lactation also produced an up-regulation of dopamine D1 receptor function to activate G-protein in the mouse limbic forebrain. These results indicate that either organogenesis or lactation is more sensitive to the bisphenol-A-induced neuronal toxicity than any other periods. In conclusion, we found here that prenatal and neonatal exposure to bisphenol-A can potentiate the central dopaminergic systems, resulting in the supersensitivity of the drugs of abuse-induced rewarding effects and hyperlocomotion in the mouse. Furthermore, the organogenesis and lactation are the most important period to cause the alteration of dopaminergic system by bisphenol-A exposure in the mouse.

Animals↗

PubMed2003

Inhibition of the norepinephrine transporter function in cultured bovine adrenal medullary cells by bisphenol A.

We report here the effects of an environmental estrogen, bisphenol A, on norepinephrine (NE) transporter function in cultured bovine adrenal medullary cells. The effects of bisphenol A were compared to those of 17beta-estradiol. Bisphenol A significantly inhibited [3H]NE uptake by the cells in a concentration-dependent manner (1-100 microM). Kinetic analysis revealed that bisphenol A, as well as 17beta-estradiol, noncompetitively inhibited [3H]NE uptake. Bisphenol A and 17beta-estradiol inhibited the specific binding of [3H]desipramine to plasma membranes isolated from bovine adrenal medulla. As shown by Scatchard analysis of [3H]desipramine binding, bisphenol A increased the dissociation constant (K(d)) and decreased the maximal binding (B(max)), indicating a mixed type of inhibition. 17beta-Estradiol increased the K(d) without altering the B(max), thereby indicating competitive inhibition. The present findings suggest that bisphenol A inhibits the function of the NE transporter by acting on a site different from that of 17beta-estradiol in the adrenal medulla and probably in the brain noradrenergic neurons.

Adrenal Medulla↗

PubMed2001

Bisphenol A in hazardous waste landfill leachates.

The levels of bisphenol A in hazardous waste landfill leachates collected in Japan in 1996 were determined by gas chromatograph/mass spectrometer (GC/MS). Bisphenol A was found in seven of 10 sites investigated. All the hazardous waste landfills with leachates contaminated by bisphenol A were controlled. The concentrations of bisphenol A ranged from 1.3 to 17,200 microg/l with a median concentration of 269 microg/l. The source of bisphenol A in landfill leachates may be the waste plastics in waste landfill. The concentrations of bisphenol A in some samples exceeded the EC50 or LC50 levels for aquatic biota. Landfill leachates may be a significant source of bisphenol A found in the environment.

Air Pollutants, Occupational↗

PubMed2002

Oxygenation of bisphenol A to quinones by polyphenol oxidase in vegetables.

To understand conversion of bisphenol A and its related compounds under some chemical and biological environments, oxidation of these compounds was performed. Bisphenol A was oxidized to monoquinone and bisquinone derivatives by Fremy's salt, a radical oxidant; but salcomine and alkali did not catalyze the oxidation by molecular oxygen. Bisphenol A, bisphenol B, and 3,4'-(1-methylethylidene)bisphenol were converted to their monoquinone derivatives in the presence of oxygen and polyphenol oxidase from mushroom at 25 degrees C at pH 6.5. Among crude enzyme solutions of fruits and vegetables, potato, mushroom, eggplant, edible burdock, and yacon showed remarkable oxidative activity on bisphenol A. The highest activity was observed in potato, and the main product obtained by the enzymatic oxygenation was the monoquinone derivative of bisphenol A, accompanied by a small amount of the bisquinone derivative. The oxidation reactions found here will be useful for developing techniques for elimination of phenolic endocrine disrupters from the environment.

Agaricales↗

PubMed2002

Male-specific suppression of hepatic microsomal UDP-glucuronosyl transferase activities toward sex hormones in the adult male rat administered bisphenol A.

Various adverse effects of endocrine disruptors on the reproductive organs of male animals have been reported. We found that UDP-glucuronosyltransferase (UGT) activities towards bisphenol A, testosterone and oestradiol were significantly decreased in liver microsomes prepared from adult male Wistar rats administered with the endocrine disruptor bisphenol A (1 mg/2 days for 2 or 4 weeks). However, suppression of the transferase activities was not observed in female rats, even after bisphenol A treatment for 4 weeks. Diethylstilbestrol, which is well known as an endocrine disruptor, had the same effects, but p -cumylphenol had no effect on UGT activities towards sex hormones. Co-administration of an anti-oestrogen, tamoxifen, inhibited the suppression of the transferase activities by bisphenol A. Western blotting analysis showed that the amount of UGT2B1, an isoform of UGT which glucuronidates bisphenol A, was decreased in the rat liver microsomes by the treatment. Northern blotting analysis also indicated that UGT2B1 mRNA in the liver was decreased by bisphenol A treatment. The suppression of UGT activities, UGT2B1 protein and UGT2B1 mRNA expression did not occur in female rats. The results indicate that bisphenol A treatment reduces the mRNA expression of UGT2B1 and other UGT isoforms that mediate the glucuronidation of sex hormones in adult male rats, and this suggests that the endocrine balance may be disrupted by suppression of glucuronidation.

Animals↗

PubMed1989

Hydrolysis of bisphenol A diglycidylether by epoxide hydrolases in cytosolic and microsomal fractions of mouse liver and skin: inhibition by bis epoxycyclopentylether and the effects upon the covalent binding to mouse skin DNA.

Synergistic interactions have been reported in the carcinogenicity of two epoxy resin components to mouse skin. A mixture of bisphenol A diglycidylether and bis epoxycyclopentylether was highly carcinogenic, despite the fact that neither compound gave positive results when applied individually. To elucidate the mechanism of this synergistic interaction we have investigated the effects of bis epoxycyclopentylether upon the hydrolysis and DNA-binding of bisphenol A diglycidylether. This glycidylether was rapidly hydrolysed by microsomal and cytosolic fractions of mouse liver and skin. In three different mouse strains the specific epoxide hydrolase activities were 28.3-48.5; 33.0-38.8; 7.9-10.2 and 0.85-0.98 nmol/mg protein/min for liver microsomal and cytosolic and skin microsomal and cytosolic fractions respectively. This is the first demonstration of an epoxide hydrolase activity in skin cytosolic fractions. Bis epoxycyclopentylether inhibited the microsomal activities. This inhibition appeared to be slightly more effective with microsomal fractions from liver. The effect of this inhibition upon the binding of bisphenol A diglycidylether to mouse skin DNA was investigated using bisphenol A diglycidylether radiolabelled at two different positions. When high doses of bisphenol A diglycidylether were applied to the mouse skin one major DNA adduct was observed which was identified as a glycidaldehyde adduct. This adduct was not detectable at the lowest bisphenol A diglycidylether dose tested, unless bis epoxycyclopentylether was applied simultaneously. These findings suggest that glycidaldehyde may be formed from bisphenol A diglycidylether. At low doses, however, the epoxide groups are hydrolysed before glycidaldehyde can be formed, unless the epoxide hydrolase is inhibited. Such inhibition and the associated increased production of glycidaldehyde may account for the potentiation of the carcinogenic response in the epoxide mixture.

Animals↗