Mol. Hum. Reprod. Advance Access originally published online on April 20, 2007
Molecular Human Reproduction 2007 13(6):399-404; doi:10.1093/molehr/gam018
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Interaction between cytochrome P450 gene polymorphisms and serum organochlorine TEQ levels in the risk of endometriosis
1 Epidemiology and Prevention Division, Research Center for Cancer prevention and Screening, National Cancer Center, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan 2 Department of Obstetrics and Gynecology, The Jikei University School of Medicine, Tokyo, Japan 3 Department of Public Health, University of Miyazaki, Miyazaki, Japan 4 Division of Laboratory Sciences, National Center for Environmental Health, Centers for Disease Control and Prevention, Atlanta, Georgia, USA
5 Correspondence address. Tel: +81-3-3542-2511 (ext 3391); Fax: +81-3-3547-8578; E-mail: moiwasak{at}gan2.res.ncc.go.jp
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Abstract |
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Exposure to dioxins and polychlorinated biphenyls (PCBs) has been suggested as a possible etiologic factor for endometriosis, but the association remains highly controversial. To assess whether cytochrome P450 (CYP) gene polymorphisms modulate the effect of dioxins and/or PCBs in endometriosis risk, we conducted a case–control study among infertile Japanese women. A total of 138 eligible women aged 20–45 were diagnosed laparoscopically and classified into three subgroups: control (no endometriosis), early endometriosis (stages I–II) and advanced endometriosis (stages III–IV). Neither CYP1A1 Ile462Val and CYP1B1 Leu432Val polymorphisms (genotypes with versus genotypes without the minor allele) nor serum dioxin and PCB toxic equivalency (TEQ) levels (low versus high) were independently associated with either early or advanced endometriosis risk. However, genotypes with the CYP1A1 462Val allele showed a statistically significant reduced risk of advanced endometriosis in combination with high serum dioxin TEQ levels (adjusted odds ratio = 0.13, 95% confidence interval: 0.02–0.76) (P for interaction = 0.08). Although no association was found between serum PCB TEQ level and advanced endometriosis in any stratum of CYP1B1 Leu432Val polymorphism, a statistically significant interaction was found (P for interaction = 0.05). CYP1A1 and CYP1B1 polymorphisms may modify the relation between environmental exposure to organochlorine and advanced endometriosis risk.
Key words: CYP1A1/CYP1B1/endometriosis/gene–environment interaction/organochlorine
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Introduction |
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Exposure to certain xenoestrogens, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and polychlorinated biphenyls (PCBs) has been suggested as a possible etiologic factor for endometriosis. The association between endometriosis and these organochlorines has been the subject of a number of studies (Mayani et al., 1997; Lebel et al., 1998; Pauwels et al., 2001; Eskenazi et al., 2002; Heilier et al., 2005; Louis et al., 2005; Tsukino et al., 2005), but remains highly controversial. At this time, there is insufficient evidence to establish a definitive link between endometriosis and organochlorine exposure.
Endometriosis, an estrogen-dependent disease, is regarded as a complex trait influenced by both genetic and environmental factors (Kennedy, 1998). To understand this condition, consideration must be given to both the individual contributions of genetic and environmental factors and their magnitude, and also the interactions of these factors. Gene–environment interactions, the multiplicative joint effects of genetic predisposition and environmental factors, are important in understanding how risk factors act together and in identifying high-risk groups (Brennan, 2002).
Genetic polymorphisms in cytochrome P450 (CYP) 1A1 and CYP1B1 are putative genetic factors associated with inter-individual susceptibility to organochlorines. CYP1A1 and CYP1B1 are phase I drug-metabolizing enzymes that are critical to both xenobiotic and estrogen metabolism. The activities of CYP1A1 and CYP1B1 are determined jointly by genetic and environmental factors (Gonzalez, 1988; Martucci and Fishman, 1993). Inconsistent associations between endometriosis and organochlorine exposure might be attributable to the different genetic susceptibilities in the populations studied.
The magnitude of risk associated with gene–environment interactions can be estimated from a case–control study. In the present study, we tested the hypothesis that the genetic polymorphisms CYP1A1 Ile462Val and CYP1B1 Leu432Val modulate the effect of dioxins and/or PCBs in the risk of endometriosis, and thereby assessed the possibility that altered risk arises from genetic predisposition.
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Materials and Methods |
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Study population
This study was part of a case–control study conducted on a Japanese population to investigate associations between genetic and environmental factors in endometriosis (Tsukino et al., 2005). Consecutive female patients aged 20–45 who attended the Department of Obstetrics and Gynecology at Jikei University School of Medicine Hospital for infertility between 1999 and 2000 were recruited. Since pregnancy commonly results in complete resolution of minimal or mild endometriosis, women who had given birth or lactated were ineligible, leaving a total of 159 women who met the criteria. After excluding 15 women who did not give consent, 5 who did not undergo blood screening or laparoscopic examination and 1 whose DNA sample was not available, a total of 138 women were available for the study (participation rate = 87%). No participants had undergone prior empiric therapy before laparoscopic examination.
All study protocols were approved by the Institutional Review Boards of Jikei University, National Cancer Center, University of Miyazaki, National Institute for Environmental Studies and the US Centers for Disease Control and Prevention (CDC). All participants provided written informed consent before laparoscopic examination.
Before the laparoscopic examination, participants were interviewed by a single trained interviewer using a structured questionnaire. Participants also gave a fasting blood sample before the laparoscopic examination. Blood samples were divided into plasma and buffy layers and stored at – 80°C until analysis.
Diagnosis of endometriosis
In the present study, all participants underwent diagnostic laparoscopy as part of an infertility work-up. Laparoscopy is essential to the accurate diagnosis of endometriosis because one-third of women with endometriosis are asymptomatic (Rawson, 1991). The degree of endometriosis was diagnosed according to the Revised American Fertility Society (r-AFS) classification (American Fertility Society, 1985) and/or histologic diagnosis. Endometriosis was absent in 59 women (43%), stage I in 21 women (15%), stage II in 10 women (7%), stage III in 23 women (17%) and stage IV in 25 women (18%). Current theories of endometriosis suggest that what is defined as minimal/mild endometriosis may actually represent a normal physiologic process. Furthermore, a lack of consistency between laparoscopic and histologic diagnosis has been reported, particularly for minimal/mild endometriosis (Marchino et al., 2005). Considering the more severe stages as a separate category thus appears reasonable (Zondervan et al., 2002). Although women without endometriosis and with stage I were designated as controls and women with stage II or more severe endometriosis were designated as cases in the previous study (Tsukino et al., 2005), considering the current theories of endometriosis mentioned earlier, we classified cases into two subgroups in the present study: early (stages I–II) or advanced endometriosis (stages III–IV). Women without endometriosis were defined as controls. Among controls, several conditions known to cause infertility were confirmed laparoscopically, including myoma of the uterus (34%) and polycystic ovary (19%).
DNA extraction and genotyping
Genomic DNA was extracted from peripheral white blood cells using a conventional protease K method. CYP1A1 Ile462Val (dbSNP rs1048943) and CYP1B1 Leu432Val (dbSNP rs1056836) polymorphisms were genotyped using PCR-RFLP analysis as described previously (Huang et al., 1999; Tang et al., 2000). Genotyping was conducted by laboratory personnel blinded to case–control status. To validate the genotyping, duplicate samples from some patients were provided in a manner blinded to the laboratory personnel; concordance for the blinded samples was 100%. Thus, experimenter bias was demonstrably minimized.
Measurement of organochlorines
Serum organochlorines were measured as described in our previous study (Tsukino et al., 2005). Briefly, analyses were performed at the US CDC using gas chromatography/high-resolution isotope dilution mass spectrometry for 58 compounds: 8 polychlorinated dibenzo-p-dioxin (PCDDs), 10 polychlorinated dibenzo-p-furans (PCDFs), 4 coplanar PCBs (cPCBs) and 36 ortho-substituted PCBs. The serum levels for these compounds were adjusted for serum lipid levels.
The term dioxins refers collectively to a group of PCDDs, PCDFs and cPCBs. To calculate the toxic equivalency (TEQ) of these compounds, a TEQ factor (TEF) was assigned to each of the PCDDs, PCDFs and cPCBs (Van den Berg et al., 1998). Summation of the TEQs of PCDDs, PCDFs and cPCBs gives the TEQ of dioxins (pg TEQ/g lipid). In contrast, most of the PCBs are assigned a TEF of zero. Summation of the TEQs of mono-ortho-substituted PCBs (mPCBs) gives the TEQ of PCBs (pg TEQ/g lipid).
Statistical analysis
CYP1A1 Ile462Val and CYP1B1 Leu432Val polymorphisms were classified into two subgroups: genotypes homozygous for the major allele (CYP1A1: Ile/Ile; CYP1B1: Leu/Leu) and pooled heterozygous and minor allele homozygous genotypes (CYP1A1: Ile/Val and Val/Val; CYP1B1: Leu/Val and Val/Val). Concentrations of lipid-adjusted serum dioxins and PCB TEQ levels were defined as low or high based on the median value of control subjects.
To assess the main genetic and environmental effects on endometriosis, odds ratios (ORs) and their 95% confidence intervals (95% CIs) were calculated independently for CYP gene polymorphisms and serum levels of organochlorines using multivariate logistic regression analyses. To control for possible confounding factors, age was adjusted for in the multivariable logistic regression models. Secondly, risks of endometriosis were compared by a stratified model of genetic polymorphisms and organochlorine exposure. Multiplicative interactions were assessed by introducing a cross-product term between two-category genotypes and levels of serum organochlorines into the logistic regression models.
A two-sided P < 0.05 was considered significant in the analysis of main effects, whereas P < 0.1 was used when testing for the presence of interactions. SPSS for Windows software (version 11.0, SPSS JAPAN, Tokyo, Japan) was used for statistical analysis.
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Results |
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Table 1 shows baseline characteristics of cases and controls. No significant difference was seen in mean age or body mass index between groups, or in the distribution of menstrual bleeding, hypermenorrhea and smoking. The advanced endometriosis group displayed a significantly shorter menstrual cycle than controls (controls, 30.7 ± 6.1 days; advanced endometriosis, 28.3 ± 3.0 days; P = 0.01) and was more likely to have menstrual cramp and dyspareunia.
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The distributions of CYP gene polymorphisms and serum organochlorine levels are shown in Table 2. The genotypic distributions of CYP1A1 Ile462Val and CYP1B1 Leu432Val polymorphisms were concordant with Hardy–Weinberg equilibrium (
2 test: CYP1A1 Ile462Val, P = 0.42; CYP1B1 Leu432Val, P = 0.52). In the statistical analyses of dioxins and PCBs, we excluded one sample from each because the serum concentrations could not be reliably measured due to sample shortage. The range of concentrations among all subjects was 3.39–38.33 pg TEQ/g lipids for serum dioxins and 0.00–7.55 pg TEQ/g lipids for PCBs. Median values of serum dioxin and PCB concentrations were 18.18 and 1.21 pg TEQ/g lipids for controls, 17.69 and 1.05 pg TEQ/g lipids for early endometriosis and 16.03 and 1.11 pg TEQ/g lipids for advanced endometriosis, respectively.
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In the present study, there were no independent associations between the CYP gene polymorphisms and risk of either early or advanced endometriosis (Table 2). Although serum dioxin levels showed a non-significant inverse association with advanced endometriosis (Table 2, adjusted OR: 0.46, 95% CI: 0.20–1.06), no other associations were seen between serum organochlorines and either early or advanced endometriosis. Further adjustment for menstrual cycle and duration of menstrual bleeding did not substantially affect the results (data not shown).
To assess possible effect modifications by CYP gene polymorphisms, we evaluated the association between serum organochlorine TEQ levels and risk of endometriosis stratified by CYP genotypes. No interaction between serum organochlorine level and CYP genotype was observed in early endometriosis (Tables 3 and 4). On the other hand, the CYP1A1 Ile462Val pooled Ile/Val and Val/Val genotypes showed a statistically significant reduced risk of advanced endometriosis in combination with a high serum dioxin TEQ level (Table 3, adjusted OR: 0.13, 95% CI: 0.02–0.76). There was a statistically significant interaction between the CYP1A1 Ile462Val polymorphism and serum dioxin TEQ level (Table 3, P for interaction = 0.08). Although no association was found between serum PCB TEQ level and advanced endometriosis in any stratum of CYP1B1 Leu432Val polymorphism, a statistically significant interaction was noted (Table 4, P for interaction = 0.05). For advanced endometriosis, no interaction was found in other combinations of CYP gene polymorphism and serum organochlorine level (Tables 3 and 4).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionAcknowledgementsReferences |
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In the present study, we demonstrated statistically significant interactions between the CYP1A1 Ile462Val and CYP1B1 Leu432Val polymorphisms and serum organochlorine TEQ levels in the risk of advanced endometriosis. This interaction would suggest the presence of an underlying biologic effect modification, possibly resulting in an altered disease phenotype. The results of this study provide epidemiologic clues to the etiology and pathogenesis of endometriosis and identify populations at altered risk because of CYP gene polymorphisms and serum organochlorine TEQ levels.
Genetic factors were implicated in endometriosis by a large study in twins, which found that 51% of the variance of susceptibility may be attributable to genetic influences (Treloar et al., 1999). The effect of single genetic or environmental factors is usually weak; rather, multiple genetic and environment factors collaboratively contribute to the phenotypic variation of endometriosis. Indeed, the analysis of gene–environment interactions in our present study identified synergistic effects between CYP gene polymorphisms and serum organochlorines, although genetic or environmental factors alone did not cause statistically significant differences in the risk of endometriosis.
In this study, we found that the presence of a CYP1A1 462Val allele was associated with a statistically significant decreased risk of advanced endometriosis among women with high serum dioxins. The CYP1A1 462Val allele has been reported to be positively associated with TCDD-induced CYP1A1 mRNA expression (Landi et al., 2005). The most plausible hypothesis to explain our results is that sustained activation of CYP1A1 by dioxins alters estrogen metabolism, resulting in a lower susceptibility to endometriosis.
Significant interactions indicate that the effect of organochlorines differ between two strata of CYP gene polymorphism. In contrast to the relationship between CYP1A1 Ile462Val and serum dioxin TEQ, we observed a statistically significant interaction between CYP1B1 Leu432Val polymorphism and serum PCB TEQ, and the CYP1B1 432Val allele seemed to be associated with an increased risk of endometriosis in combination with a high serum PCB TEQ. Considering the relatively small number of subjects, the statistically significant interactions observed may have occurred merely by chance. Intrinsically, some PCBs have estrogenic properties whereas dioxins and dioxin-like PCBs have antagonistic effects (Toppari et al., 1996). The effect of organochlorines in individuals might be defined by the variety of different activations by CYP gene polymorphisms.
The frequency of CYP1A1 Ile462Val and CYP1B1 Leu432Val polymorphisms is known to vary widely in different populations (Solus et al., 2004). The discrepancy in previous studies of organochlorine exposure and endometriosis may arise in part from inter-individual variability in susceptibility to organochlorines and to a dose-related bimodal effect (Yang et al., 2000). The CYP1A1 Ile462Val and CYP1B1 Leu432Val polymorphisms may be a useful genetic marker predicting susceptibility to dioxins. It is preferable to include both genetic and environmental assessment in the study of complex traits.
The present study showed statistically significant interactions between CYP gene polymorphisms and serum organochlorine TEQ levels in the risk of advanced endometriosis, but not in that of early endometriosis. This apparent inconsistency might be attributable to diagnostic bias in early endometriosis, as mentioned in Methods earlier. If early endometriosis reflects normal physiology rather than ‘real endometriosis’, it would lead to a null result. In this regard, we clarified the effect of case and control definitions on the results by repeating the analyses in Tables 2–4 using the previous definition by Tsukino et al. (2005), namely control (no endometriosis and stage I) and cases (stages II–IV). However, these additional analyses did not change the results, and the definition of cases and controls had no effect on our conclusions.
Although this is probably the first study of CYP gene polymorphisms and organochlorines in endometriosis, the CYP1A1 462Val allele has been reported to be mainly associated with increased risk of post-menopausal breast cancer in women with high serum PCBs (Moysich et al., 1999; Laden et al., 2002; Zhang et al., 2004; Li et al., 2005). This discrepancy between breast cancer and endometriosis may be attributable to different effects of organochlorines on carcinogenesis (Whysner and Williams, 1996), different responsiveness of mammary gland and endometrium (Gottardis et al., 1988) and the interaction of serum organochlorines with estradiol levels (Ohtake et al., 2003). Further, more detailed molecular studies are needed to clarify the relationships between CYP gene polymorphism and organochlorines in the risk of endometriosis.
Participants in the present study were infertile. Given previous reports that factors associated with endometriosis differed between parous women, who experienced neither primary nor secondary infertility, and nulliparous infertile women (Missmer et al., 2004a,b), our present findings may be limited to infertile women. In addition, the use of infertile women as the control group should also be considered. When the study population comprises infertile women only, comparing infertile cases with a control group comprising infertile women without endometriosis may yield results very different from those that would be observed when comparisons are made with fertile women without endometriosis (Signorello et al., 1997). This is particularly true when the exposure of interest, such as menstrual cycle characteristics or reproductive history, is correlated with endometriosis and infertility. As a result of this use of infertile women as the control group, an association between serum organocholorines and the risk of endometriosis might be weakened or masked. Further, we cannot rule out the possibility that serum organocholorines are associated with both endometriosis and infertility.
The major limitation of this study was the small sample size, which limits its statistical power. A larger sample size would allow a more precise estimate of main effects and interactions. Therefore, our results should be interpreted with caution. After reanalysis using a case-only design, which is an efficient and valid method for screening gene–environment interactions (Yang et al., 1997), however, the interaction term between CYP 1A1 Ile462Val polymorphism and serum dioxin level was calculated as 0.045. Measurement of serum estradiol and its CYP1A1/1B1 metabolites would allow further refinement of the association between CYP1A1 and CYP1B1 gene polymorphisms and serum organochlorines, as well as any drug–drug interaction between serum estradiol and organochlorines, in the risk of endometriosis.
In conclusion, this study suggests that the CYP1A1 Ile462Val polymorphism is an effect modifier of the relationship between serum dioxins and the risk of advanced endometriosis. The CYP1B1 Leu432Val polymorphism modulates the effect of PCBs in the risk of advanced endometriosis. Better understanding of the relationships between genetic and environmental factors in complex traits may enable the prediction of widely differing risks of individuals or populations. Genetic susceptibility to the effects of organochlorines may affect a woman's likelihood of developing endometriosis.
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We are grateful for the collaboration of Dr Amanda Sue Niskar (Israel Center for Disease Control, Gertner Institute) in designing the study protocol. We also thank Drs Tomoyuki Hanaoka (Epidemiology and Prevention Division, Research Center for Cancer Prevention and Screening, National Cancer Center, Tokyo, Japan) for conducting the study and his helpful comments, Hiroyuki Nakao (Department of Public Health, University of Miyazaki, Miyazaki, Japan) for his support of the statistical analysis and Michinori Kabuto (National Institute for Environmental Studies, Ibaraki, Japan) for his helpful comments. This study was supported by Grants-in-Aid for Research on Risk of Chemical Substances, and for the Third Term Comprehensive 10-Year Strategy for Cancer Control from the Ministry of Health, Labour and Welfare of Japan. Masaki Tsuchiya and Hiromasa Tsukino are Awardees of Research Resident Fellowships from the Foundation for Promotion of Cancer Research for the Third and Second Term Comprehensive 10-Year Strategy for Cancer Control.
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Submitted on January 22, 2007; resubmitted on February 28, 2007; accepted on March 1, 2007.
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