Chem. Res. Toxicol. 2008, 21, 467–471
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Methylation of Dimethyltin in Mice and Rats Koichi Furuhashi,*,† Masanori Ogawa,‡ Yoshihiro Suzuki,‡ Yoko Endo,‡ Yangho Kim,§ and Gaku Ichihara† Department of Occupational and EnVironmental Health, Field of Social Life Science, Nagoya UniVersity Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan, Clinical Research Center for Occupational Poisoning, Tokyo Rosai Hospital, Japan Labour, Health and Welfare Organization, 4-13-21 Omori-minami, Ota-ku, Tokyo 143-0013, Japan, and Department of Occupational and EnVironmental Medicine, Ulsan UniVersity Hospital, UniVersity of Ulsan College of Medicine, 290-3 Cheonha-Dong, Dong-Gu, Ulsan 682-060, South Korea ReceiVed September 7, 2007
Organotins are widely used as stabilizers of polyvinyl chloride and as catalysts or biocides. It is well known that dimethyltin (DMT) is less neurotoxic than trimethyltin (TMT). A Korean worker who was exposed to DMT compounds showed neurological symptoms similar to those of TMT encephalopathy, in association with high levels of both DMT and TMT in the urine and blood. The case suggested the possibility of the methylation of DMT in humans. Here, we investigated whether TMT is detected in the urine of mice and rats exposed only to DMT dichloride (DMTC). Three Slc:ICR mice and three Slc: Wistar rats were placed in individual metabolic cages, and one day later, they were injected intraperitoneally with DMTC (10 mg/kg body weight (wt); 5.4 mgSn/kg body wt; 45.5 µmol/kg body wt) over 4 consecutive days. Twenty-four hour urine samples were collected every evening for 11 consecutive days starting at baseline (before treatment). Speciation analyses of methyltin compounds in urine were performed using a combination of high performance liquid chromatograph-inductively coupled plasma mass spectrometry. High concentrations of DMT and time-dependent increase in TMT concentrations were found in both mice and rats during the 4-day treatment, and their concentrations decreased gradually after the cessation of treatment. The chemical compound of the detected peak was confirmed to be TMT by liquid chromatography-tandem mass spectrometry. Neither DMT nor TMT was detected in the samples collected at baseline. Our results indicate urinary excretion of TMT in mice and rats injected with DMTC, confirming the production of TMT in ViVo, probably through methylation of DMT. Introduction Organotin compounds are widely used as stabilizers of polyvinyl chloride (PVC1), catalysts, and biocides (1, 2). A recently reported case of a human intoxicated with dimethyltin (DMT) described neurological abnormalities similar to those of trimethyltin (TMT) intoxication, and both DMT and TMT were found in the urine and blood of the worker (3). Although the authors could not rule out possible exposure to a trace of TMT, which is a byproduct of DMT, they suggested that DMT could potentially convert to TMT in humans. Such reaction is feasible because other researchers attributed the associated encephalopathy simply to TMT, although many cases of alkyltins-induced encephalopathy were actually exposed to a mixture of DMT and TMT (4–6). Such assumption may be based on studies showing that TMT compounds are more neurotoxic than DMT compounds (1, 7–14). More than 1000 * To whom correspondence should be addressed. Tel: +81-52-744-2124. Fax: +81-52-744-2126. E-mail:
[email protected]. † Nagoya University Graduate School of Medicine. ‡ Tokyo Rosai Hospital. § University of Ulsan College of Medicine. 1 Abbreviations: DMT, dimethyltin; DMTC, dimethyltin dichloride; ESI, electrospray ionization; HD, hospitalization days; HPLC-MS/MS, high performance liquid chromatography-tandem mass spectrometry; ICP-MS, inductively coupled plasma mass spectrometry; LC50, median lethal concentration; MMT, monomethyltin; MMTC, monomethyltin trichloride; MRI, magnetic resonance imaging; MRM, multiple reaction monitoring; PP, polypropylene; PVC, polyvinyl chloride; TMT, trimethyltin; TMTC, trimethyltin chloride.
people in southeast China were poisoned by misusing organotincontaminated industrial lard as cooking oil in 1999 (15). The contaminated lards contained mainly DMT compounds, but TMT was detected in the urine and blood at levels higher than those of DMT. They also inferred that DMT was absorbed and methylated to TMT in ViVo. In the present study, we measured urinary levels of TMT in mice and rats exposed to DMT dichloride (DMTC) by high performance liquid chromatograph-inductively coupled plasma mass spectrometry (HPLC-ICP-MS) and mass spectral analysis by high performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS).
Materials and Methods Chemicals. Monomethyltin trichloride (MMTC), DMTC, and trimethyltin chloride (TMTC) were purchased from Wako Pure Chemical Industries (Osaka, Japan). No TMT was detected in the DMT reagent used in the present study by HPLC-ICP-MS measurement. Methanol and formic acid (HPLC grade) were purchased from Wako Pure Chemical Industries. Ammonia solution (25–27.9%, atomic absorption grade) was purchased from Kanto Chemical Co. Inc. (Tokyo, Japan). Ammonium formate (99.995+%) was purchased from Sigma-Aldrich (St. Louis, MO). Animals. ICR mice (Slc:ICR, 9-week-old male mice) and Wistar rats (Slc:Wistar, 9-week-old male rats) were purchased from Japan SLC, Inc., Japan. After acclimatization for one week, the animals were housed in metabolic cages one day prior to the administration of DMTC, provided food and water ad libitum and kept on a 12-h light/12-h dark cycle (lights on at 09:00 h) at a constant temperature
10.1021/tx700320a CCC: $40.75 2008 American Chemical Society Published on Web 12/29/2007
468 Chem. Res. Toxicol., Vol. 21, No. 2, 2008 (23.0–25.0 °C) and relative humidity (57–60%). The Japanese law concerning the protection and control of animals, the standard related to care and management of experimental animals, and the Guide of Animal Experimentation of Nagoya University Graduate School of Medicine were followed throughout the study. Experimental Design. This experiment was designed to investigate the types of organotin in the urine of animals exposed to DMTC. After one week of acclimatization, each of three mice and three rats was placed in individual metabolic cages at 17:00 h. The next day (day 0), 24-h urine was collected, followed by ip injection of DMTC [10 mg/kg body weight (wt); 5.4 mg Sn/kg body wt; 45.5 µmol/kg body wt) at 17:00 h. DMTC was dissolved in 0.9% saline, and fresh solutions were prepared daily. DMTC was administrated over 4 consecutive days (days 0–3) at 17:00 h. The 24-h urine was collected over 11 consecutive days (days 0–10) at 17:00 h. Measurement of Methyltins in Urine Samples. Speciation analysis of methyltin in urine was performed using a combination of HPLC (model HP1100, Agilent, Santa Clara, CA) and ICP-MS (Model HP4500, Agilent). Urine was diluted five times with ultrapure water, which was purified tap water through Milli-Q-ICPMS (Millipore Japan, Tokyo), and then placed into a polypropylene (PP) vial for analysis. MMT, DMT, and TMT were separated by HPLC using a cation-exchange column of Shodex RSpak NN-614 (150 × 4.6 mm i.d., Shodex, Japan) maintained at 40 °C and a mobile phase (5.0 mM HNO3, 6.0 mM NH4NO3, and 1.5 mM pyridinedicarbonic acid) at a flow rate of 1.0 mL/min. Fifty microliters of the sample was injected into the HPLC column. For precise measurements, 0.1 mg/L of germanium solution was used as the internal standard for ICP-MS. The ICP-MS detection mass was set at m/z 116 (116Sn+), m/z 118 (118Sn+), m/z 120 (120Sn+), and m/z 72 (72Ge+). The detection limits (S/N ) 3) for MMT, DMT, and TMT were 0.2, 0.1, and 1.0 µgSn/L, respectively. Preparation of Urine Samples for HPLC-MS/MS. For HPLCMS/MS analysis, urine samples were prepared by passing through an Oasis MCX cation-exchange cartridge (Waters, Milford, MA) to purify TMT. We used the protocol provided by the manufacturer as follows: the cartridge was conditioned and equilibrated with 1 mL of methanol and ultrapure water, respectively. After loading 1 mL of urine, the cartridge was washed with 1 mL of 2% aqueous formic acid and then 1 mL of methanol. TMT was then eluted with 1 mL of ammonia solution-methanol (5:95), and the resulting eluate was analyzed by HPLC-MS/MS. Mass-Spectral Analysis of TMT. In order to confirm the chemical species of the detected peaks, mass spectral analysis was performed by the HPLC-MS/MS (Alliance 2695-Quattro micro API, Waters, USA) system. Separation of methyltin compounds using Shodex Asahipak ODP-50 2D reversed-phase polymer column (150 × 2.0 mm i.d., Shoko Co., Tokyo) was performed under the following conditions: mobile phase, 10 mM ammonium formate with 0.1% formic acid; flow rate, 0.2 mL/min; and injection volume, 10 µL. TMT was eluted at 3.7 min under these conditions. TMT was detected by positive electrospray ionization (ESI+) with a capillary voltage setting of 500 V, ion source temperature of 120 °C, desolvation gas temperature of 400 °C, desolvation gas of 600 L/h, and cone gas of 50 L/h. Multiple reaction monitoring (MRM) was applied to detect collision-induced fragmentations of TMT, that is, specific pairs of precursor and product ions of m/z 165.0 and 134.9, m/z 165.0 and 150.0, m/z 183.1 and 134.9, and m/z 183.1 and 150.0 were detected with setting the cone voltage and collision energy to 25 V and 20 eV, 25 V and 15 eV, 30 V and 25 eV, and 30 V and 20 eV, respectively.
Results No decrease in body weight and no gross abnormalities were observed throughout the experiment in our mice and rats injected intraperitoneally with DMTC. Figure 1 shows representative HPLC-ICP-MS chromatograms of the standard, mouse urine, and rat urine. The urine samples of both types of animals contained DMT and TMT. To confirm the results of TMT
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Figure 1. Representative HPLC-ICP-MS chromatograms of methyltin compounds. HPLC-ICP-MS chromatograms for (A) an aqueous solution of MMTC, DMTC, and TMTC mixture at 200 µg Sn/L each, (B) 5-fold dilution of mouse urine, and (C) 5-fold dilution of rat urine were recorded at m/z 118 (corresponding to 118Sn+).
analysis on the HPLC-ICP-MS, we performed mass spectral analyses by HPLC-MS/MS. The spectrum of 10 mgSn/L of TMTC standard (Figure 2A, center) showed two major ions with m/z of 165.0 and 183.1, which corresponded to the monovalent trimethyltin cation ([SnMe3]+) and its hydrated ion ([SnMe3+H2O]+), respectively. Furthermore, the patterns of detected isotopic ions also indicated the presence of one tin atom. The MS/MS spectra for m/z 165.0 (Figure 2A, left) and m/z 183.1 (Figure 2A, right) precursor ions showed the same two fragment ions of m/z 134.9 ([SnMe]+) and 150.0 ([SnMe2]+), which indicated collision-induced demethylation of trimethyltin. Because the mass and MS/MS spectra did not have sufficient signal-to-noise ratios to confirm the presence of TMT in the urine samples of mice and rats, we recorded the MRM chromatograms by monitoring four ion pairs of precursor and product ions such as m/z 165.0 and 134.9, m/z 165.0 and 150.0, m/z 183.1 and 134.9, and m/z 183.1 and 150.0. Peaks corresponding to TMT were clearly detected on the MRM chromatograms of both the pretreated urine samples of mice and rats at 3.7 min, the same retention time as that of the TMTC standard (Figure 2B). Tables 1 and 2 list mice and rat urinary DMT and TMT concentrations from day 0 to 10. DMT and TMT were not detected on day 0. High concentrations of DMT and a timedependent increase in TMT were found in urine samples of mice and rats during the 4-day period of administration of DMTC, and their concentrations decreased after stopping the treatment. DMT was detected until day 10. TMT was detected consistently from day 1 to 10. Table 3 summarizes the DMT excretion rates and the DMTto-TMT conversion rates. The urinary DMT excretion rate was calculated by dividing the total amount of DMT excretion (µgSn) by the total dose of administrated DMTC (µgSn). The urinary DMT excretion rates of mice and rats were 43 ( 2 and 43 ( 11, respectively. The DMT-to-TMT conversion rate was obtained by dividing the total amount of TMT excretion (µgSn)
Methylation of Dimethyltin in Animals
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Figure 2. (A) Mass spectrum and MS/MS spectra of the TMTC standard and (B) MRM chromatograms of trimethyltin measured by HPLC-MS/MS (ESI+). Mass spectrum of the TMTC standard (A, center) showed two major ions such as m/z 165.0 ([SnMe3]+) and 183.1 ([SnMe3+H2O]+). Both MS/MS spectra for m/z 165.0 (A, left) and m/z 183.1 (A, right) precursor ions showed two fragment ions of m/z 134.9 ([SnMe]+) and 150.0 ([SnMe2]+). MRM chromatograms (B) were recorded for 4 pairs of TMT-specific precursors and product ions including m/z 165.0 and 134.9, m/z 165.0 and 150.0, m/z 183.1 and 134.9, and m/z 183.1 and 150.0.
Table 1. Concentrations of Dimethyltin and Trimethyltin in the Urine of Micea concentration of DMT
concentration of TMT
day
µgSn/L
µgSn/gCr
µgSn
µgSn/L
µgSn/gCr
µgSn
0 1 2 3 4 5 6 7 8 9 10
ND 36100 ( 3400 38800 ( 7900 45800 ( 1700 37400 ( 6400 708 ( 151 324 ( 22 328 ( 36 134 ( 35 117 ( 27 148 ( 65
ND 82700 ( 8200 141000 ( 53000 170000 ( 49000 59700 ( 8300 1990 ( 440 764 ( 103 658 ( 101 362 ( 41 248 ( 57 307 ( 129
ND 85.7 ( 14.8 98.0 ( 17.5 93.3 ( 11.7 82.0 ( 18.2 1.91 ( 0.17 0.793 ( 0.083 0.974 ( 0.143 0.400 ( 0.125 0.309 ( 0.073 0.416 ( 0.189
ND 212 ( 32 284 ( 37 573 ( 101 589 ( 52 218 ( 29 164 ( 27 83.7 ( 10.0 47.7 ( 3.3 31.3 ( 2.3 18.7 ( 2.4
ND 474 ( 31 999 ( 321 1940 ( 380 955 ( 106 620 ( 129 391 ( 97 166 ( 21 144 ( 34 66.3 ( 6.4 39.0 ( 5.0
ND 0.484 ( 0.043 0.709 ( 0.057 1.12 ( 0.05 1.26 ( 0.06 0.596 ( 0.008 0.398 ( 0.061 0.243 ( 0.015 0.139 ( 0.012 0.0827 ( 0.0030 0.0540 ( 0.0064
a Data are the mean ( SEM. Cr, creatinine; ND, not detected. (The detection limit is equivalent to 0.5 µgSn/L for DMT and 5.0 µgSn/L for TMT.) The numbers represent the concentration (µgSn/L), the concentration relative to creatinine (µgSn/gCr), and the amount (µgSn) of DMT and TMT.
by the total dose of administrated DMTC (µgSn). The urinary conversion rate of mice and rats were 0.59 ( 0.02 and 0.40 ( 0.04, respectively. The estimated half-lives of DMT and TMT in urine of mice and rats are shown in Table 4. The half-lives of DMT in urine samples of mice and rats were almost identical, although the half-life of TMT in rats was much larger than that in mice.
Discussion To our knowledge, the present study is the first to report the detection of TMT in the urine of animals exposed to DMT. We first confirmed by HPLC separation and ICP-MS detector the absence of TMT in the DMT reagent used in this experiment.
Second, neither DMT nor TMT was detected in the urine before the administration of DMT; however, both were detected in the urine from the next day after the first injection until the end of the experiment. The results indicate that TMT found in the urine was derived from DMT administrated to animals, that is, DMT was converted to TMT in ViVo. The structure of TMTs detected in the urine of both mice and rats was confirmed by HPLCMS/MS. In the Korean case, the worker exposed to DMT showed severe hypokalemia and various neurological abnormalities such as motor ataxia, memory loss, disorientation, and speech difficulty, similar to those seen in TMT intoxication, in association with the presence of both DMT and TMT in the urine and blood (3). Magnetic resonance imaging (MRI) in this
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Table 2. Concentrations of Dimethyltin and Trimethyltin in the Urine of Ratsa concentration of DMT
concentration of TMT
day
µgSn/L
µgSn/gCr
µgSn
µgSn/L
µgSn/gCr
µgSn
0 1 2 3 4 5 6 7 8 9 10
ND 24000 ( 6700 24600 ( 9900 31000 ( 10600 32700 ( 4900 3330 ( 640 713 ( 54 365 ( 79 280 ( 60 216 ( 31 305 ( 16
ND 65500 ( 23200 52200 ( 27000 71000 ( 28000 69600 ( 1000 4240 ( 290 1130 ( 50 617 ( 107 454 ( 67 354 ( 79 446 ( 34
ND 675 ( 229 524 ( 282 774 ( 285 845 ( 19 52.0 ( 5.0 15.7 ( 0.7 7.96 ( 1.05 6.31 ( 1.15 4.59 ( 0.85 6.30 ( 0.50
ND 114 ( 98 189 ( 139 105 ( 24 136 ( 34 156 ( 42 125 ( 23 115 ( 23 111 ( 18 115 ( 22 118 ( 27
ND 220 ( 176 322 ( 217 212 ( 21 286 ( 58 193 ( 30 199 ( 36 194 ( 31 186 ( 37 187 ( 43 170 ( 37
ND 2.43 ( 1.97 3.32 ( 2.33 2.45 ( 0.39 3.49 ( 0.71 2.36 ( 0.36 2.77 ( 0.51 2.53 ( 0.38 2.54 ( 0.42 2.43 ( 0.50 2.40 ( 0.49
Data are the mean ( SEM. Cr, creatinine; ND, not detected. (The detection limit is equivalent to 0.5 µgSn/L for DMT and 5.0 µgSn/L for TMT.) The numbers represent the concentration (µgSn/L), the concentration relative to creatinine (µgSn/gCr), and the amount (µgSn) of DMT and TMT. a
Table 3. Dimethyltin Excretion Rates and Dimethyltin-to-Trimethyltin Conversion Rates in Mice and Ratsa animals mice rats
excretion rate (%)
conversion rate (%)
43 ( 2 43 ( 11
0.59 ( 0.02 0.40 ( 0.04
a Data are the mean ( SEM. The urinary DMT excretion rate was calculated by dividing the total amount of excreted DMT (µgSn) by the total dose of administrated DMTC (µgSn). The DMT-to-TMT conversion rate was calculated by dividing the total amount of excreted TMT (µgSn) by the total dose of administrated DMTC (µgSn).
case showed extensive, symmetrically high signal lesions throughout the white matter of the brain. In the same study, edema confined to the white matter caused by trialkyltin was found in humans and animals (3). For these reasons, Yoo et al. (3) diagnosed their case as alkyltin intoxication. This case suggested the possibility of DMT methylation in humans. Previous studies indicated that TMT compounds are more neurotoxic than those of DMT (1, 7–14). Thus, TMT derived from DMT could have produced the neurotoxicity in the case of the Korean worker (3). In the Chinese cases, people were poisoned by organotin-contaminated lard, mainly containing DMT compounds, but the amounts of TMT detected in the urine and blood were more than those of DMT (15). The report added further probability for the methylation of DMT in ViVo. The suggestion that DMT conversion to TMT in ViVo advocated in the above human cases was confirmed by our study in animals. Our study showed that the half-life of TMT in the urine of rats was longer than that in the urine of mice. In the Korean worker, the circulatory level of TMT was highest on the 7th day after the end of the 4-day exposure, while that in urine was highest on the 14th day after the end of the 4-day exposure (3). Several studies indicated that TMTC is more toxic than DMTC (8–11, 16, 17), although one study reported the opposite result (18). For instance, regarding rat pheochromocytoma cells (PC12 cells), TMTC significantly inhibited neurite outgrowth and caused cell death at concentrations approximately half those of the lowest toxic concentrations of DMTC (11). The median lethal concentration (LC50) values for TMTC and DMTC on Artemia franciscana were 0.22 and 80.7 mgSn/L, respectively (17). Therefore, we could not disregard the possibility of
neurotoxicity by the methylation of DMTC even if the DMTto-TMT conversion rate was low (below 1%) in mice and rats in our study. In the Chinese cases, the concentrations of DMT and TMT in urine (ng/mL) were 79.7 ( 1.8 and 83.3 ( 2.3 (urine 1), and 20.4 ( 0.6 and 42.0 ( 1.0 (urine 2), respectively, and those in blood (ng/g) were ND (not detected) and 70.0 ( 3.3, respectively (15). In the Korean worker, the ratio of TMTto-DMT in urine was more than 1.0 during hospitalization, ranging from 1.04 (hospitalization day (HD) 31) to 2.28 (HD6), except for 0.43 (HD9) and 0.99 (HD17). The ratio of TMT-toDMT in blood was more than 1.0 during hospitalization, ranging from 2.02 (HD38) to 8.27 (HD3) (3). Thus, humans intoxicated with DMT showed more TMT than DMT in the majority of urine and blood samples. We have no data about the conversion rate in humans, but the DMT-to-TMT conversion rate of humans might be higher than that of mice and rats, and TMT derived from DMT might cause neurotoxicity in humans. Accordingly, the difference in DMT methylation among species might result in differences in neurotoxicity. Jenkins et al. (11) pointed the need to investigate DMT neurotoxicity in ViVo, and we agree with them on this point. Although alkyltin is reported to be converted by demethylation in mammals (19), the injected DMT was methylated to TMT in mice and rats in our study. This is of great importance since our study indicates that methylation of DMT seems common in the two species. Methylation is a common but generally minor pathway of xenobiotic biotransformation. Methylation differs from most other phase II reactions because it generally decreases the water solubility of xenobiotics and masks functional groups that might otherwise be conjugated by other phase II enzymes (20). It is well known that oxidation by cytochrome P450 and glutathione conjugation of dihalogenated hydrocarbons can activate xenobiotics (21–24). The present study suggests that methylation can also activate some xenobiotics. The mechanism of conversion of DMT to TMT is not clear at present and needs to be investigated further. There was considerable variability among the three animals of each species. This might be due to individual differences among the ICR mice and Wistar rats used here, which were from a closed colony and were of different genetic background.
Table 4. Half-Lives of Dimethyltin (DMT) and Trimethyltin (TMT) in Urine Samples of Mice and Ratsa half-life of DMT (days) animals mice rats a
half-life of TMT (days)
all days (µgSn/gCr)
days 4–6 (µgSn)
days 6–10 (µgSn)
(µgSn/g Cr)
0.94 ( 0.12 0.92 ( 0.01
0.30 ( 0.01 0.35 ( 0
6.6 ( 4.8 2.9 ( 0.3
1.3 ( 0 11.6 ( 2.1
Data are the mean ( SEM. Cr: creatinine.
Methylation of Dimethyltin in Animals
The present study has the following limitations. First, we chose intraperitoneal injections, taking into account the operator’s safety and the stability of the administered amount. The i.p. administration did not reflect the actual exposure route in humans and might affect biokinetics such as the agent’s halflife. Second, our study was designed to investigate animal models compared with the Korean human case where feces were not analyzed, and thus, we did not collect and analyze fecal material. The methylation reaction studied here could occur in the intestinal flora, and we could have obtained more information had feces been analyzed. However, these limitations should not affect the basic finding of our study that DMT is converted to TMT in ViVo. In conclusion, our study is the first to show urinary excretion of TMT from mice and rats exposed to DMT. TMT might be produced by the methylation of DMT in ViVo. The formation of TMT from DMT might explain the neurotoxicity in patients exposed to DMT only. Further studies are needed to determine the mechanism of conversion of DMT to TMT and the neurotoxicity of DMT. Acknowledgment. We thank Dr. Liu Fang and Mr. Sheik Mohideen Sahabudeen for their generous help with the experiment. We also thank Dr. Li Weihua and Dr. Ding Xuncheng from Shanghai Institute of Planned Parenthood Research for their valuable information on the Chinese cases of organotin intoxication and Dr. Wang Hailan from the Hospital for Occupational Disease Control of Guangdong Province for her generous help in the reviewing process of the Chinese studies.
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