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J Dent Res 82(5): 367-371, 2003
© 2003 International and American Associations for Dental Research

RESEARCH REPORT
Biomaterials & Bioengineering

Biocompatibility of Hydroxylated Metabolites of BISGMA and BFDGE

E.L. Kostoryz1,*, J.D. Eick1, A.G. Glaros1, B.M. Judy2, W.V. Welshons2, S. Burmaster1, and D.M. Yourtee1

1 Schools of Pharmacy and Dentistry, University of Missouri, 2411 Holmes Street, Kansas City, MO 64108-2792; and
2 Dept. of Veterinary Biomedical Sciences, University of Missouri, Columbia, MO, USA;

* corresponding author, kostoryze{at}umkc.edu


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 MATERIALS & METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Unpolymerized dental monomers can leach out into the oral biophase and are bioavailable for metabolism. We hypothesize that metabolites would be less toxic than parent monomers. We first identified the formation of metabolites from bisphenol F diglycidyl ether (BFDGE) and Bisphenol A glycidyl methacrylate (BISGMA) after their exposure to liver S9 fractions. Then, the metabolites and parent compounds were subjected to in vitro cytotoxicity, mutagenicity, and estrogenicity studies. Bisphenol A bis(2,3-dihydroxypropyl) ether and bisphenol F bis(2,3-dihydroxypropyl) ether were the hydroxylated metabolites of BISGMA and BFDGE, respectively. Cytotoxicity against L929 cells showed that the metabolites were significantly (p < 0.05) less cytotoxic than the parent monomers. Only BFDGE was mutagenic in the Ames assay with strain TA100 of Salmonella typhimurium. Parent and metabolite compounds did not stimulate estrogen-dependent MCF-7 cell proliferation above solvent controls. These results indicated that the hydroxylated metabolites were non-mutagenic, non-estrogenic, and less cytotoxic than their parent monomers.

KEY WORDS: BISGMA • bisphenol F diglycidyl ether • hydroxylated metabolites • cytotoxicity • mutagenicity • biocompatibility


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
MATERIALS & METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Current dental resin/composite systems are polymers of methacrylates such as bisphenol A glycidyl methacrylate (BISGMA). However, BISGMA polymerization is never complete, and unpolymerized monomers are known to remain in the polymer after the curing process. Residual unpolymerized monomers are known to leach out (Gerzina and Hume, 1996) into the oral biophase and are bioavailable for metabolism by esterases (Yourtee et al., 2001) and other enzymes.

BISGMA is known to undergo hydrolysis of its ester group to form the tetrahydroxylated metabolite bisphenol A bis(2,3-dihydroxypropyl) ether (BADPE-4OH). This metabolite was reported to be a degradation product from the hydrolysis of BISGMA-cured polymer resin model in the presence of cholesterol esterase (Santerre et al., 2001). In this reaction, BADPE-4OH is formed by the loss of two molecules of methacrylic acid from BISGMA. BADPE-4OH was also identified as a metabolite from bisphenol A diglycidyl ether (BADGE). In this case, however, BADPE-4OH was formed by the ring opening of the epoxy groups in BADGE (Climie et al., 1981), and was identified as an activity of epoxide hydrolase (Bentley et al., 1989). The toxicity of BADPE-4OH is unclear. Previously, it was reported that BADPE-4OH produced micronuclei formation in cultured human lymphocytes (Suarez et al., 2000). However, residual BADGE in the hydrolyzed fractions may have biased the net response exhibited by BADPE-4OH, as BADGE produced micronuclei formation. Therefore, evaluating the toxicity of the hydroxylated metabolite will clarify our understanding of the in vivo fate of BISGMA and BADGE.

Recently, BADGE and its congener, bisphenol F diglyicidyl ether (BFDGE), have been proposed for development of oxirane-based dental composites (Eick et al., 2002). Structurally, these oxirane compounds are similar. The difference is that the bisphenol core of BFDGE has two hydrogen atoms in the quaternary carbon instead of the two methyl groups in BADGE. We theorized that the metabolism of BFDGE may produce its tetrahydroxylated metabolite.

Studies for identifying the formation of hydroxylated metabolites of BFDGE and BISGMA as well as evaluating their toxicity are needed for a full understanding of the adverse effects of each monomer and its resins. Thus, the objectives of this study were two-fold: (a) identify the formation of the tetrahydroxylated metabolites of BFDGE and BISGMA after exposure of each monomer to liver S9 fractions in vitro, and (b) evaluate the biocompatibility of the hydroxylated metabolites in relation to their parent compounds. Biocompatibility evaluations were carried out by in vitro cytotoxicity and mutagenicity measurements in the MTT assay and the Ames assay, respectively. Concerns for estrogenicity were also addressed because BISGMA and BFDGE as well as their potential metabolites are bisphenol A and F derivatives. Bisphenol A and F are known endocrine disruptor chemicals (Welshons et al., 1999).

In general, metabolism is a mechanism for rendering xenobiotics into harmless substances (Parkinson, 1996). Therefore, our hypothesis was that the metabolite compounds would be less toxic than the parent compounds.


   MATERIALS & METHODS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS & METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Test Chemicals
BISGMA was obtained from 3M-ESPE (Dental Products Division, St. Paul, MN, USA). BFDGE, BADPE-4OH, and BFDPE-4OH were obtained from Fluka Chemical Company (Milwaukee, WI, USA) and were of 97% purity. BISGMA and BFDGE were purified to 94 and 92%, respectively, as described previously (Smith et al., 2001).

Identification of Metabolites
BISGMA and BFDGE were separately incubated with 5 mg/mL rat or human hepatic S9 fraction (Xenotech, Kansas City, KS, USA) containing, in a final volume of 2 mL, the following co-factors: 3.9 mM glucose-6-phosphate, 2 mM MgCl2, and 1.85 mM NADP. A dose of 10 µM of each monomer was added, and the solution was incubated for 1 hr in triplicate at 37°C. BADPE-4OH and BFDGE-4OH were also incubated in separate but identical incubation experiments. A 250-µL aliquot was removed at times 0, 10, 20, 30, and 60 min. The reaction was stopped with 2 mL of acetonitrile containing the internal standard and 5 mL of methyl-t-butyl ether. Each sample was centrifuged for 10 min at ~ 3500 rpm. The upper organic layer was separated and evaporated to dryness under a stream of nitrogen at 45°C. The samples were reconstituted with 50 µL of acetonitrile, followed by 75 µL of mobile phase (95% water/5% acetonitrile). After 5 min, the samples were transferred to an injection vial. A 5-µL aliquot was analyzed by high-performance liquid chromatography/mass spectra (LC/MS) for the parent monomer and commercially available metabolite. Each standard curve was prepared separately by the addition of 25 µL of working standards to 225 µL 0.1 M potassium phosphate buffer and processed in a manner identical to that used for the samples. Midazolam and Dextromethorphan (10 µM) were used as positive controls and analyzed in a manner identical to that used for the samples. Standard curves of each positive control were prepared with use of the same acetonitrile containing the internal standard and analyzed by LC/MS, monitoring for both the disappearance of parent (midazolam and dextromethorphan) and the appearance of the metabolite (1'-hydroxymidazolam and dextrophan).

Biological Assays
Cytotoxicity was evaluated against mouse fibroblast cells (American Type Culture Collection CCL I fibroblast, NCTC clone 929, Manassas, VA, USA). Cells were grown in Eagle’s minimal essential medium with Earle’s balanced salt solution supplemented with 10% v/v fetal bovine serum, 2 mM L-glutamine, 2.2 mg/mL sodium bicarbonate, and two antibiotics (penicillin/streptomycin). All biological reagents were from Sigma-Aldrich (St. Louis, MO, USA). Test compounds were dissolved in dimethyl sulfoxide (DMSO), and 1:1000 dilutions in culture medium were tested. Using 96-well plate methodology, we seeded 2 x 105 cells per well and exposed them to six dilutions of the test compounds for 20 hrs at 37°C/5% CO2/95% air. After 24 hrs, the supernatant was discarded from each well, and cell viability was determined by the MTT assay (Kostoryz et al., 1999). To each well, a 200-µL quantity of MTT reagent (2 mg/mL culture medium) was added, and the plate was incubated for 3 hrs at 37°C/5% CO2. The purple formazan product was dissolved in DMSO and read at 550 nm in a microplate reader (Molecular Devices E-Max, Menlo Park, CA, USA).

We used the Ames Salmonella assay to evaluate the mutagenicity of the test compounds with and without rat liver S9 (Maron and Ames, 1983). Five doses of test compound were prepared in DMSO, and aliquots of 100 µL of each chemical dose and 100 µL of an overnight growth of bacterial strain TA100 (2 x 109 cells/mL) were added to a tube containing 2 mL of molten (45°C) soft agar enriched with 0.05 mM histidine and 0.05 mM biotin. This was rapidly mixed and then poured onto the surfaces of minimal glucose agar plates (100-mm-diameter) in triplicate. For assessment of the effects of metabolism, each top agar tube had an extra 500 µL S9-mix, which was added last. The S9-mix consisted of 4% S9 (Aroclor 1254-induced rat liver S9 fraction, ICN Biomedicals Inc., Aurora, OH, USA) with added co-factors NADP and glucose-6-phosphate. Plates were incubated at 37°C for 48 hrs, and revertant colonies were then counted (automated colony-counter, BioTran, Edison, NJ, USA). The positive controls were sodium azide (without S9) and 2-aminofluorene (with S9). DMSO controls were included in the assay. Positive mutagenicity was based on mutation ratio (MR), the quotient of the average total revertants per test compound divided by the average spontaneous revertants or solvent control. If the mutation ratio was equal to or greater than 2 in the dose-response curve, the compound was considered mutagenic.

For estrogenic activity, estrogen-dependent proliferation of MCF-7 human breast cancer cells was used as described (Grady et al., 1991). For routine maintenance, cells were grown in Minimal Essential Medium (MEM, Gibco, Rockville, MD, USA) with phenol red 10 mg/L, containing non-essential amino acids, 10 mM Hepes, insulin 6 ng/mL (Sigma), penicillin (100 units/mL), streptomycin (100 µg/mL), and 5% charcoal-stripped calf serum (Gibco) in an atmosphere of 5%CO2/95% air under saturating humidity at 37°C. For assay of estrogenic activity, MCF-7 cells were plated at 2000 cells per well (96-well plate) in estrogen-free medium (phenol-red-free maintenance medium), and after attachment for 3 days, the cells were treated with the test compounds for 4 days at the indicated concentrations in the estrogen-free medium containing 0.1% solvent ethanol with daily medium changes, 200 µL per well, by means of a Tomtec Quadra 96 robotics unit (Tomtec, Hamden, CT, USA). After the cells were washed once with 200 µL Hanks’ Balanced Salt Solution (HBSS) at the end of the exposure time, cell proliferation was measured as total DNA by means of the diphenylamine (DPA) assay adapted to 96-well format for robotics (Natarajan et al., 1994). Briefly, a 60-µL aliquot of a 1:5 mixture of acetaldehyde (0.16%) and 20 perchloric acid was added along with 100 µL of diphenylamine reagent (4% DPA in glacial acetic acid), and plates were incubated for 24 hrs at 37°C. Absorbance at 595 nm minus the absorbance at 700 nm was measured in a Bio-Tek PowerWave plate reader and compared with a standard curve prepared with calf thymus DNA (type 1, sodium salt, Sigma-Aldrich), 0.1 to 5.0 µg DNA per well in a parallel plate.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS & METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Metabolites
By 10 min, greater than 90% of the initial BISGMA and BFDGE concentrations had disappeared. Their tetrahydroxy metabolites correspondingly appeared in the hepatic S9 fractions and were identified against commercially available compounds with identical chromatographic retention times and LC/MS ion fragmentation patterns as the suspected metabolites from in vitro incubations. The metabolites themselves, when incubated as the primary substrate, showed minimal metabolism in our in vitro model, suggesting that these compounds did not form bisphenol A or bisphenol F. Although methacrylic acid was not quantitated, it was also a metabolite of hydrolysis. Positive controls were metabolized as expected, indicating the integrity of the hepatic incubation system.

The LC/MS conditions represent selected ion monitoring (SIM) of the ammoniated adduct of BISGMA (M+17+H+ = 530) and the ammoniated adduct of the tetrahydroxy metabolite (M+17+H+ = 394). Also, BFDGE (M+17+H+ = 330) and the metabolite (M+17+H = 366) were identified via metabolism with liver S9 fractions (Fig. 1Go).



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  		Figure 1. Structures of BISGMA, BFDGE, metabolites, and respective ammoniated mass from LC/MS analyses. Finnigan TSQ-700 mass spectrometer, Digital Unix work station, Finnigan software ICIS ver. 8.3, HP 1100 binary pump, Perkin Elmer autosampler, and Eppendorf TC-50 column heater. Chromatographic separation was achieved on a Metachem pre-column filter, a 2 x 4 mm C18 guard column, and a 2 x 30 mm C18 3µ Luna analytical column by Phenomenex at 40°C. The MS ionization mode was positive electrospray. The manifold pressure was 2 x 10-6 torr. The ESI spray voltage was 4.5 kV, and the current was 10 µA. The capillary temperature was 200°C. The electron multiplier was set at 1600 V. The CID argon gas pressure was 1.7 mTorr, and the CID offset was -18.0 volts. The injection volume was 20 µL, and the split ratio was 1:3.

 
Cellular Toxicity
The monomers and metabolites exhibited decreases in percent cell survival as their doses increased. From these dose-response curves (Fig. 2Go), the dose that produced the 50% cell survival (TC50) was extrapolated. Larger TC50 doses indicate less cytotoxicity. BFDGE-4OH exhibited a TC50 dose of 4100 ± 1032 µM, while the TC50 dose for the parent monomer, BFDGE, was 67 ± 4 µM. The TC50 doses for BADPE-4OH and BISGMA were 722 ± 122 µM and 55 ± 8 µM, respectively. The mean TC50 values were compared by ANOVA followed by Bonferroni post hoc testing, F(3,14) = 889. Significant differences were established at an alpha level of 0.05 (SPSS Version 11.5, Chicago, IL, USA). The mean TC50 value of each metabolite was significantly different from the TC50 value exhibited by the parent monomer.



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  		Figure 2. Dose-response curves illustrate that the monomers BISGMA and BFDGE are more cytotoxic than their respective metabolites, BADPE-4OH and BFDPE-4OH. Cell survival was determined after L929 cell exposure to the test compounds for 20 hrs. Cell survival was indicated by metabolic conversion of the MTT reagent to formazan.

 
Mutagenic Activity
The number of spontaneous revertants of strain TA100 was in the normal range of 110 to 147 revertant colonies per plate (Ames et al., 1983). Both metabolites in the dose range of 0.025 to 15 µmoles per plate produced mutation ratios in the range of 0.8 to 1.35, similar to those of the solvent control 5% DMSO, which produced mutation ratios in the range of 0.8 to 1.28. Metabolite doses above 15 µmoles per plate (100 µL of 150 mM solutions) presented solubility problems, and the metabolites were not tested above these doses. The parent monomer BFDGE was mutagenic with and without metabolism, exhibiting mutation ratios up to 8.5 (Fig. 3Go). The addition of rat S9 fraction (+S9) decreased this mutagenicity in a dose-dependent manner. At doses of 2 µmoles per plate and lower, the mutagenicity of BFDGE was abolished in the presence of S9 fraction, producing mutation ratios below 2.



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  		Figure 3. Mutagenicity of bisphenol A diglycidyl ether (BFDGE) with and without liver S9 metabolism in strain TA100 of Salmonella typhimurium reverse-mutation assay. The tetrahydroxylated metabolite, BFDPE-4OH, was non-mutagenic.

 
Estrogenic Activity
The estrogen-dependent proliferation response of MCF-7 cells was validated with estradiol (E2) in the absence and presence of the estrogen antagonist raloxifene (keoxifene). The natural estrogen estradiol stimulated MCF-7 cell growth, producing 1.082 ± 0.026 and 1.672 ± 0.065 µg DNA per well at doses of 0.01 nM and 0.1 nM, respectively, compared with hormone-free control growth of approximately 0.55 µg DNA per well (see below). The estrogen antagonist abolished the activity of 0.1 nM E2, causing DNA levels to drop to 0.597 ± 0.041 µg DNA per well. The DNA level for cells without a test compound added (negative control) was 0.546 ± 0.011 µg per well. The solvent 0.1% ethanol produced DNA levels of 0.551 ± 0.007 µg per well. The proliferation response of the cells was further validated with bisphenol A (BPA). BPA produced a dose-response in the dose range of 56 to 3630 nM, to a full efficacy of just over 100% maximal stimulation compared with E2 (Fig. 4Go). The monomer BFDGE did not stimulate cell proliferation in the dose range of 56 to 3630 nM. DNA levels were in the range of 0.534 to 0.555 µg/well, indistinguishable from the solvent and negative controls. Both metabolite compounds, in the dose ranges of 5.8 to 1000 nM, also did not stimulate cell proliferation above control. Fig. 4Go illustrates the estrogenic activity of BPA compared with the metabolites and BFDGE. DNA content was calculated as percent of maximal stimulation by 0.1 nM estradiol. The half-maximal stimulation of cell proliferation occurred at 150 nM for BPA and at 1 to 2 pM for E2 (not shown). In relation to E2, BFDGE and both hydroxylated metabolites exhibited no stimulation of cell proliferation (Fig. 4Go).



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  		Figure 4. The monomer BFDGE, its metabolite BFDPE-4OH, and the hydroxylated metabolite BADPE-4OH did not stimulate MCF-7 cell proliferation. Estrogen-dependent cell proliferation was evaluated as total DNA per well. The half-maximal stimulation of cell proliferation by bisphenol A (BPA) was 150 nM. Values are expressed as percent of response between solvent control (approximately 0.55 µg DNA per well) and maximal response by estradiol (E2) at 0.1 nM (approximately 1.67 µg DNA per well).

 

   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS & METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
BISGMA and BFDGE were metabolized rapidly in S9 fractions. In vitro incubation of BISGMA or BFDGE with S9 fractions demonstrated that the predominant metabolite was the respective hydroxylated metabolite. BISGMA was metabolized to the hydroxylated metabolite and methacrylic acid, while BFDGE was metabolized to the hydroxylated metabolite (Fig. 1Go). Each metabolite did not appear to be further metabolized, suggesting that bisphenol A and F were not metabolites of BISGMA or BFDGE.

From cytotoxicity results, the metabolites were less cytotoxic than the respective parent monomers. The reduced cytotoxicity of the metabolite of BISGMA supports the reduced cytotoxicity of BISGMA observed in the presence of S9 mix (Hikage et al., 1999). S9 fractions contain phase I and phase II metabolic systems that render xenobiotics generally harmless (Parkinson, 1996). From our results, the cellular toxicity of BISGMA or BFDGE may be reduced when swallowed because of its potential detoxification by the liver. However, in situ effects on cells in the oral environment may derive mainly from the parent monomer. In this study, where fibroblast cells were used, the cytotoxicities of BISGMA and BFDGE were less than observed earlier (Hanks et al., 1991; Kostoryz et al., 1999, 2001). This may be because we used purified monomers.

Contrary to the non-mutagenicity of BISGMA (Schweikl et al., 1998) and its hydroxylated metabolite, the oxirane BFDGE was mutagenic with and without liver S9. However, the decreased mutagenicity of BFDGE in the presence of the S9 fraction indicates that the parent monomer was metabolized to some extent to the non-mutagenic metabolite. Non-mutagenicity may be due to the absence of epoxy groups in the hydroxylated metabolite. This indicates that epoxide hydrolase activity may be the primary route for detoxification of BFDGE. In vivo studies are needed to confirm this observation.

Estrogenicity, the potential of a chemical to stimulate an estrogenic response through estrogen receptors, appears not to be of concern for BISGMA, BFDGE, or their metabolites.

In summary, our results supported our hypothesis that the tetrahydroxylated metabolites of BISGMA and BFDGE were less toxic than their respective parent monomers. Bisphenol F diglycidyl ether must be avoided in biomaterials development because of its genotoxic potential.


   ACKNOWLEDGMENTS
 
This study was supported in part by the NIH/National Institute of Dental and Craniofacial Research Grants DE09696 (DMY) and MO-VMF00018 (WW).

Received June 18, 2002; Last revision January 24, 2003; Accepted February 3, 2003


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS & METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Bentley P, Bieri F, Kuster H, Muakkassah-Kelly S, Sagelsdorff P, Staubli W, et al. (1989). Hydrolysis of bisphenol A diglycidylether by epoxide hydrolases in cytosolic and microsomal fractions of mouse liver and skin: inhibition by bis epoxycyclophenylether and the effects upon the covalent binding to mouse skin DNA. Carcinogenesis 10:321–327.[Abstract/Free Full Text]

Climie IJ, Hutson DH, Stoydin G (1981). Metabolism of epoxy resin component 2,2-bis[4](2,3)]epoxypropoxy)phenyl]propane, the diglycidyl ether of bisphenol A (DGEBPA) in the mouse. Part I. A comparison of the fate of a single dermal application and of a single oral dose of 14C-DGEBPA. Xenobiotica 11:391–399.[ISI][Medline]

Eick JD, Kostoryz EL, Rozzi SM, Jacobs DW, Oxman JD, Chappelow CC, et al. (2002). In vitro biocompatibility of oxirane/polyol dental composites with promising physical properties. Dent Mater 18:413–421.[ISI][Medline]

Gerzina TM, Hume WR (1996). Diffusion of monomers from bonding resin-resin composite combinations through dentine in vitro. J Dent 24:125–128.[ISI][Medline]

Grady LH, Nonneman DJ, Rottinghaus GE, Welshons WV (1991). pH-dependent cytotoxicity of contaminants of phenol red for MCF-7 breast cancer cells. Endocrinology 129:3321–3330.[Abstract]

Hanks CT, Strawn SE, Wataha JC, Craig RG (1991). Cytotoxic effects of resin components on cultured mammalian fibroblasts. J Dent Res 70:1450–1455.[Abstract/Free Full Text]

Hikage S, Sato A, Suzuki S, Cox CF, Sakaguchi K (1999). Cytotoxicity of dental resin monomers in the presence of S9 mix enzymes. Dent Mater J 18:76–86.[Medline]

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Maron DM, Ames BN (1983). Revised methods for the Salmonella mutagenicity test. Mutat Res 113:173–215.[ISI][Medline]

Natarajan N, Shambaugh GE 3rd, Elseth KM, Haines GK, Radosevich JA (1994). Adaptation of diphenylamine (DPA) assay to a 96-well plate tissue culture format and comparison with the MTT assay. Biotechniques 17:166–171.[ISI][Medline]

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Suarez S, Sueiro RA, Garrido J (2000). Genotoxicity of the coating lacquer on food cans, bisphenol A diglycidyl ether (BADGE), its hydrolysis products and a chlorohydrin of BADGE. Mutat Res 470:221–228.[ISI][Medline]

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