In this study, we selected 58 styrene-exposed workers, measured personal styrene exposure, evaluated genotypes relevant drug-metabolizing enzymes (CYP2E1, EPHX1, GSTM1 and GSTT1) which may explain the variability in the urinary metabolite excretion. The results showed that, in different levels of styrene exposure groups, there is a significant association between urinary metabolites and some genotypes of styrene-metabolizing enzymes, including CYP2E1 (5-flanking region, RsaI/PstI), GSTM1(gene deletions) and EPHX1(predicted activity).
We collected 58 male workers as study subjects, they are 20 - 42 years old, employed in a fibre glass-reinforced plastic boat plant in China, a questionnaire was also taken to them.
The study was carried out in November, 2013. Prior to the study, a questionnaire was administered to all subjects concerning health status, smoking, alcohol consumption, medication and occupational history.
Environmental and biological monitoring was taken to evaluate the concentration of styrene exposure which including personal air sampling, urine samples and blood samples for DNA extraction.
Based on all above, determination-of-genotypes and statistical analyses was made.
The distribution of genotypes in each group was in Hardy-Weinberg equilibrium, except for GSTM1 and GSTT1 (
It was observed that there was a significant correlation between styrene concentration in air and MA, PGA and PHEMA (
Through statistical analyses, we found that in low-exposure group, the CYP2E1 (5-Flanking RsaI/PstI) C1/C2 and C2/C2 individuals have significantly higher urinary levels of MA, PGA and PHEMA (P < 0.05). In high- exposure group, we can’t find the effect. In both low and high exposure group, the GSTM1 null individuals have significantly lower urinary levels of PHEMA (P < 0.05). As for EPHX1, the levers of MA and PGA in subjects with low enzyme activity was significant lower than that in subjects with medium or high enzyme activity (P < 0.05) in both groups. There are no significant difference found between other genotypes and urinary metabolites.
Genotype | Number (%) |
---|---|
CYP2E1 5_-Flanking RsaI/PstI c1/c1 c1/c2 c2/c2 | 37 (66.07) 18 (32.14) 1 (1.79) |
CYP2E1 intron 6 DraI D/D C/D | 39 (70.16) 17 (29.84) |
EPHX1 Exon 3 Tyr/Tyr Tyr/His His/His | 15 (26.79) 30 (53.57) 11 (19.64) |
EPHX1 Exon 4 His/His His/Arg | 32 (57.14) 24 (42.86) |
EPHX1 Predicted activity* Low activity Medium activity High activity | 27 (48.21) 19 (33.93) 10 (17.86) |
GSTM1 Positive Null | 22 (39.29) 34 (60.71) |
GSTT1 Positive Null 34 | 30 (53.57) 26 (46.43) |
*In DNA extraction,two samples failed; *Low activity: His/His-His/His, His/His-His/Arg, Tyr/His-His/His, His/His-Arg/Arg; medium activity: Tyr/Tyr-His/His, Tyr/His-His/Arg, Tyr/His-Arg/Arg; high activity: Tyr/Tyr-Arg/Arg, Tyr/Tyr-His/Arg.
Variable | MA | PGA | PHEMA |
---|---|---|---|
Styrene exposure | 0.861* | 0.868* | 0.937* |
*p < 0.01.
Genotypes | n | MA (mg/g Cr), Mean (S.D.) | PGA (mg/g Cr) Mean (S.D.) | PHEMA (mg/g Cr), Mean (S.D.) |
---|---|---|---|---|
CYP2E1 5_-Flanking c1/c1 c1/c2 and c2/c2 | 17 9 | 72.55 (32.64) 112.28 (33.43) | 57.16 (26.40) 87.70 (26.70) | 6.40 (4.06) 9.80 (1.07) |
CYP2E1 intron 6 DraI D/D C/D | 18 8 | 90.67 (40.40) 76.47 (30.28) | 71.82 (32.82) 58.53 (22.52) | 7.23 (5.10) 6.25 (3.53) |
EPHX1 Predicted activity* Low activity Medium activity High activity | 13 9 4 | 68.90 (22.35) 92.57 (39.39) 128.74 (42.35) | 57.72 (22.46) 68.52 (27.24) 98.48 (41.91) | 7.83 (3.89) 8.32 (4.01) 8.98 (2.53) |
GSTM1 Positive Null | 9 17 | 89.37 (36,78) 82.49 (32.77) | 68.87 (33.78) 71.23 (29.89) | 10.41 (4.56) 5.08 (3.55) |
GSTT1 Positive Null | 14 12 | 79.93 (28,97) 87.69 (34.53) | 67.30 (30.93) 72.79 (29.59) | 7.18 (4.58) 6.63 (4.85) |
Genotypes | n | MA (mg/g Cr), Mean (S.D.) | PGA (mg/g Cr) Mean (S.D.) | PHEMA (mg/g Cr), Mean (S.D.) |
---|---|---|---|---|
CYP2E1 5_-Flanking c1/c1 c1/c2 and c2/c2 | 20 10 | 266.99 (126.99) 232.99 (93.34) | 219.60 (100.51) 194.93 (73.84) | 31.05 (7.61) 29.34 (7.89) |
CYP2E1 intron 6 DraI D/D C/D | 21 9 | 248.59 (111.41) 271.69 (132.81) | 214.85 (95.01) 203.28 (89.22) | 30.69 (7.04) 29.88 (9.25) |
EPHX1 Predicted activity* Low activity Medium activity High activity | 14 10 6 | 170.41 (82.96) 304.29 (75.89) 372.80 (93.50) | 146.58 (76.87) 250.54 (70.87) 297.29 (30.44) | 29.96 (4.79) 31.25 (7.24) 32.11 (7.47) |
GSTM1 Positive Null | 13 17 | 256.71 (76.53) 247.28 (89.20) | 207.78 (98.02) 221.23 (87.36) | 34.13 (5.11) 27.63 (8.13) |
GSTT1 Positive Null | 16 14 | 256.36 (102.34) 261.92 (124.57) | 212.58 (103.27) 218.93 (97.63) | 31.89 (8.11) 28.80 (6.93) |
The three urinary metabolites (MA, PGA, PHEMA) can be regarded as biomarkers of occupational exposure to styrene, since a significant correlation was observed between 8h time-weighted average (TWA) and urinary metabolites levels.
The results obtained could be related with genotype of C1/C2 and C2/C2 have stronger transcription activity [
Our study showed that excretion of PHEMA in urine is significantly lower in GSTM1 null individuals. Perhaps, in detoxification of styrene, GSTM1 may perform an important role.
We also found EPHX1 polymorphisms is significant in styrene metabolism. It may be speculated EPHX1 may create some kind of basis for toleration of adverse effects of styrene exposure. Additionally, epoxide hydrolase rapidly converts genotoxic to phenylethylene glycol, which is considered as rather non-toxic. A lack of information exists on the possible adverse effect of phenylethylene glycol accumulation in the case of excessive styrene exposure.
On the other hand, there were a few limitations in this study. First, the possible influence of co-exposure to other chemicals in workshops on styrene metabolism was not considered. Second, our results are encouraging to continue such a kind of study in a larger population, employing more biomarkers and concentrating on metabolic aspects (e.g. concentration in blood) as well as on enzyme phenotypes.
In conclusion, this study shows that the genetic polymorphisms of drug-metabolizing enzymes may have some influence on the main metabolites of styrene. Although urinary styrene metabolites are good biomarkers of internal styrene dose in occupational exposure, our study suggests that genetic susceptibility of the individual should also be considered in biological monitoring of exposure to styrene.
2013 science and technology development plan of Shandong Province Science and Technology Agency (2013YD18027); 2013 Technology Project of Major accident prevention Key technologies for Safe Production (LAJK2013-112).
Wei Qu,Fang Zhang, (2015) Influence of Genetic Polymorphism of Styrene-Metablizing Enzymes on Occupational Exposure Monitoring to Styrene. Journal of Biosciences and Medicines,03,35-38. doi: 10.4236/jbm.2015.33005