Hum. Reprod. Advance Access published online on February 5, 2007
Human Reproduction, doi:10.1093/humrep/del513
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© The Author 2007. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org
Haplotype analysis of the estrogen receptor 1 gene in male genital and reproductive abnormalities
1 Department of Endocrinology and Metabolism, National Research Institute for Child Health and Development, Tokyo, Japan 2 Department of Obstetrics and Gynecology 3 Department of Pediatrics, Keio University School of Medicine, Tokyo, Japan 4 Division of Urology, National Center for Child Health and Development, Tokyo, Japan 5 Department of Urology, Yamagata University School of Medicine and Yamagata Tokushukai Hospital, Yamagata, Japan 6 Division of Statistical Genetics and Genomic Medicine, Department of Applied Biomedical Engineering and Science, Tokyo Women's Medical University, Tokyo, Japan
7 To whom correspondence should be addressed at: Department of Endocrinology and Metabolism, National Research Institute for Child Health and Development, Tokyo 157-8535, Japan. Fax: +81-3-5494-7026; E-mail: tomogata{at}nch.go.jp
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Abstract |
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BACKGROUND: We have recently suggested that homozygosity for a specific ‘AGATA’ haplotype within a
50 kb linkage disequilibrium (LD) block of the gene for estrogen receptor 
(ESR1) may raise the susceptibility to cryptorchidism by enhancing estrogenic effects of environmental endocrine disruptors (EEDs). METHODS: Haplotype analysis of ESR1 was performed in 328 Japanese subjects, i.e. 70 patients with micropenis (MP), 43 patients with hypospadias (HS), 80 patients with spermatogenic failure (SF) and 135 control males. Genotyping was performed by the 5' nuclease assay.
RESULTS: The LD block was identified in each of the patient groups and in the control males. The frequency of homozygotes for the specific ‘AGATA’ haplotype was markedly higher in the HS patients [P = 0.0000033, odds ratio [OR] = 11.26] and slightly higher in the MP patients (P = 0.034, OR = 3.64) than in the control males, and the ‘AGATA’ haplotype was strongly associated with HS (P = 0.0000022, OR = 11.26) and weakly associated with MP (P = 0.040, OR = 3.64) in a recessive mode. There was no significant difference between the SF patients and the control males.
CONCLUSIONS: Our results support the hypothesis that homozygosity for the specific ESR1 ‘AGATA’ haplotype may increase the susceptibility to the development of male genital abnormalities in response to estrogenic EEDs.
Key words: environmental endocrine disruptors/estrogen receptor 1/haplotype analysis/susceptibility/undermasculinization
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Introduction |
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The prevalence of cryptorchidism (CO), hypospadias (HS), spermatogenic failure (SF) and testicular cancer has gradually increased during the last few decades at least in several countries (Toppari et al., 1996
; Hutson et al., 1997; Kurzrock and Karpman, 2004) and that of micropenis (MP) also appears to have increased (Toppari and Skakkebaek, 1998). Such deterioration of male genital and reproductive health has also been observed in many wildlife species (Toppari et al., 1996; McLachlan, 2001). Because of the rapid pace, this phenomenon is primarily ascribed to alteration of a variety of environmental or lifestyle factors including environmental endocrine disruptors (EEDs) sedentary work, and obesity (Toppari et al., 1996; Hutson et al., 1997; McLachlan, 2001; Skakkebaek et al., 2001; Kurzrock and Karpman, 2004; Kishi et al., 2005; Magnusdottir et al., 2005). For EEDs, estrogenic effects exerted by most, not all, EEDs may play a major role in this phenomenon, because exposure to estrogenic agents is known to result in various male genital and reproductive abnormalities (Stillman, 1982; Wilcox et al., 1995; Toppari et al., 1996; Nef et al., 2000; McLachlan, 2001; Klip et al., 2002; Kim et al., 2004).
The effects of EEDs, if they indeed exist, would depend on the genetic susceptibility, in addition to the dosage and character of exposed EEDs and the developmental stage of EEDs exposure. For estrogenic EEDs, genetic susceptibility would primarily be ascribed to variations of the genes for estrogen receptor (ER), because estrogenic effects of EEDs are primarily mediated by ER (Toppari et al., 1996; McLachlan, 2001). Indeed, estrogenic EEDs can bind to both ER(encoded by ESR1 and ER(encoded by ESR2 with variable affinities (McLachlan, 2001).
Thus, we have previously performed a haplotype analysis of ESR1 in 63 Japanese patients with CO and 47 control males with normal external genitalia, using 15 single nucleotide polymorphisms (SNPs 1–15) that are widely distributed throughout >300 kb genomic sequence of ESR1 (Yoshida et al., 2005). Haplotype is a list of alleles on a single chromosome, and alleles at loci within a linkage disequilibrium (LD) block can be inherited as a unit because of lack of a recombination (Terwilliger and Ott, 1994). Thus, when a significant association is identified between a disease phenotype and a specific haplotype within a LD block, a susceptibility allele(s) is expected to reside on the haplotype-specific sequence within the block (Davidson, 2000).
We identified a significant association of CO with homozygosity for a specific ‘AGATA’ haplotype within an 50 kb LD block spanning SNPs 10–14 in the 3' region of ESR1 (Yoshida et al., 2005). This may suggest the involvement of genetic susceptibility to estrogenic EEDs in the development of CO, although there is no direct evidence for an association between estrogenic EEDs and CO. Here, we examined whether the specific ESR1 ‘AGATA’ haplotype is also associated with various male genital and reproductive abnormalities.
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Materials and methods |
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Subjects
We studied a total of 193 Japanese male patients, consisting of 70 MP patients aged 0–13 (median 6.0 years) (33 with mild MP, from –2.1 to –2.5 SD, and 37 with severe MP, below –2.5 SD), 43 HS patients aged 0–27 (median 7.0 years) [18 with mild glandular (n = 5) or penile (n = 13) HS and 25 with severe scrotal (n = 15) or perineal (n = 10) HS] and 80 SF patients aged 32–52 (median 41.0 years) [69 azoospermic and 11 oligozoospermic (sperm count <20 x 106/mL): 46 biopsied (38 with Sertoli cell-only phenotype and 8 with maturation-arrest phenotype) and 34 non-biopsied]. MP was diagnosed on the basis of the age-matched Japanese reference data (Fujieda and Matsuura, 1987
). HS was diagnosed by physical examination and was surgically treated in all the patients. SF was demonstrated by repeated (two or more times) analyses of semen samples obtained after 5–7 days of abstinence, after excluding hypogonadotropic hypogonadism, seminal tract obstruction, varicocele, retrograde ejaculation and history of CO and mumps orchiditis. None of the MP and SF patients had HS, and 12 of the HS patients manifested apparent MP (the precise penile lengths had not been measured in most of the HS patients).
All the patients satisfied the following selection criteria: (i) lack of extragenital anomalies, (ii) 46,XY karyotype in all the 
20 lymphocytes analysed, (iii) no significant expansion of CAG repeat length at exon 1 of the androgen receptor (AR) gene that is known to raise the susceptibility to male genital and reproductive abnormalities (Dowsing et al., 1999; Lim et al., 2000) and (iv) no demonstrable mutation of AR and SRD5A2. In addition, no Y chromosomal microdeletion was detected by the PCR analysis for 36 loci including RBMY and DAZ in the HS and SF patients. The methods and results of AR and SRD5A2 analyses and those of Y chromosomal deletion analysis have been reported previously (Tateno et al., 2000; Ishii et al., 2001; Muroya et al., 2001; Sasagawa et al., 2001; Itoh et al., 2002; Sasaki et al., 2003), except for the unpublished results of SRD5A2 analysis in the HS patients and those of Y chromosomal deletion analysis in the SF patients (performed by Ogata and Sasagawa). Unfortunately, although serum estrogen values are considered to be an important factor, they were not measured in these patients.
We also examined a total of 135 Japanese control males, consisting of 82 control boys with normal external genitalia aged 4–16 (median 8.5 years), including the previously reported 47 subjects (Yoshida et al., 2005), and 53 control adult males with proven fertility aged 24–50 (median 35.5 years), after obtaining permission. The control boys were seen because of short to low-normal stature (–1.5 to –3.0 SD) and were found to have no discernible abnormality by cytogenetic, skeletal and endocrine studies. The control adult males were normal in height (–2.0 SD to +2.0 SD).
SNP analysis
This study was approved by the Institutional Review Board Committees at National Center for Child Health and Development, Keio University Hospital, and Yamagata University Hospital, and informed consent was obtained from each subject or the parent(s). The SNPs 8–15 covering the LD block identified in the previous study (Yoshida et al., 2005) were analysed using leukocyte genomic DNA of each subject (Figure 1 and Table I). Genotyping was performed by the 5' nuclease assay on an ABI PRISM 7000 Sequence Detection System (Applied Biosystems, Foster City, CA, USA) (De La Vega et al., 2002). Pearson's 
2-test with one degree of freedom was applied to test whether the genotyping data of each SNP are in the Hardy-Weinberg equilibrium (http://en.wikipedia.org/wiki/Hardy-Weinberg).
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Haplotype analysis
We first examined whether the LD block spanning SNPs 10–14 detected in our previous study (Yoshida et al., 2005
) could be identified in the patients and the control males. Haplotype inference was performed by the maximum likelihood method using expectation-maximization algorithm (Excoffier and Slatkin, 1995) implemented in the software LDSUPPORT (Kitamura et al., 2002). A pairwise |D'| value (the absolute value for the disequilibrium parameter) that ranges from 0 (complete linkage equilibrium status) to 1.0 (complete LD status) was estimated by the method of Terwilliger and Ott (1994). A haplotype block was determined by the method of Zhu et al. (2003) using the software developed by Kamatani et al. (2004).
Statistical significance of the differences in estimated haplotype frequencies and homozygote frequencies was examined using the R environment (http://www.r-project.org/), together with odds ratio (OR) and the 95% confidence interval. Association of each estimated haplotype with disease phenotype as well as its OR was analysed by PENHAPLO software (Ito et al., 2004) that tests the difference in frequencies of diplotype configurations (combination of two haplotypes in a subject) in a dominant mode (comparison of the frequencies of subjects with one risk haplotype between cases and controls) and in a recessive mode (comparison of the frequencies of subjects with two risk haplotypes between cases and controls). A P < 0.05 was considered statistically significant.
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Results |
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SNP analysis
The genotype frequencies of SNPs 8–15 were in accord with the Hardy–Weinberg equilibrium, except for the increased ‘AA’ genotype frequencies of SNP 10 (P = 0.023) and SNP 12 (P = 0.030) in the HS patients. The raw genotyping data and the results of statistical analysis for the allele and genotype frequencies of each SNP are available on request.
Haplotype analysis
The pairwise LD maps are shown in Figure 1. The LD block spanning SNPs 10–14 was identified in the patients and the control males, with the |D'| value being >0.8 for all the pairs of SNPs 10–14. In particular, the LD block was evident in the HS and SF patients and extended to SNP 9 in the HS patients. Furthermore, when all the patients and the control males were combined, the LD block encompassing SNPs 10–14 was clearly identified, with the |D'| value being >0.95 for all the pairs of SNPs within the LD block except for the |D'| value of 0.93 between SNPs 11 and 14.
Within the LD block, the specific ‘AGATA’ haplotype was identified in the MP, HS and SF patients and in the control males as the second most frequent haplotype, together with three other haplotypes (‘GAGCC’, ‘GGGTA’, and ‘AGGTA’). The frequency of the ‘AGATA’ haplotype was significantly higher in the HS patients than in the control males and that of the ‘AGATA’ homozygotes was markedly higher in the HS patients and mildly higher in the MP patients than in the control males; consistent with this, the ‘AGATA’ haplotype was strongly associated with HS phenotypes and weakly associated with MP phenotype in a recessive mode (Tables II and III). No significant difference was identified in the comparisons between the SF patients and the control males, as well as between subgroups of patients (e.g. the frequency of ‘AGATA’ homozygotes: mild versus severe MP, 3/33 versus 4/37, respectively, P = 0.81; mild versus severe HS, 4/18 versus 7/25, respectively, P = 0.67; azoospermia versus oligozoospermia, 5/69 versus 1/11, respectively, P = 0.83; biopsied versus non-biopsied SF, 4/46 versus 2/34 respectively, P = 0.64; and Sertoli cell-only phenotype versus maturation-arrest phenotype, 1/8 versus 3/38, respectively, P = 0.67).
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For the remaining three haplotypes, no significant difference was identified for the haplotype and homozygote frequencies and for the association of haplotype with phenotype. The results are available on request.
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Discussion |
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The
50 kb LD block at the 3' region of ESR1 was commonly identified in the patients and the control males. Furthermore, four major estimated haplotypes were predominantly detected for the LD block encompassing SNPs 10–14. These findings suggest that the LD block and the four major haplotypes are well preserved in the Japanese population. Furthermore, according to the International HapMap Project (http://www.hapmap.org/), this LD block also appears to be present in various populations.
Homozygosity for the ‘AGATA’ haplotype was significantly more frequent in the HS patients and to a lesser extent in the MP patients than the controls. Consistent with this, the ‘AGATA’ haplotype was strongly associated with HS and weakly associated with MP in a recessive mode. These findings provide further support for the previously proposed notion that homozygosity for the ‘AGATA’ haplotype may raise the susceptibility to undermasculinized genitalia in response to estrogenic EEDs (Yoshida et al., 2005). In this regard, although the genotyping data of SNPs 10 and 12 in the HS patients did not follow the Hardy–Weinberg equilibrium, with increased ‘AA’ genotypes, this would be regarded as a reflection of the strong association between HS and the homozygosity for the ‘AGATA’ haplotype. Indeed, the ‘A’ allele of SNP 10 is nearly specific and that of SNP 12 is completely specific to the ‘AGATA’ haplotype.
The specific ‘AGATA’ haplotype may enhance the ESR1 signaling, facilitating the development of HS and MP as well as CO. Indeed, maternal exposure to estrogenic agents is known to cause HS and CO in the human and the rodents (Stillman, 1982; Nef et al., 2000; Klip et al., 2002; Kim et al., 2004), although there are no data on MP. In this regard, several matters are noteworthy: (i) excessive estrogenic effects not only affect androgen production for external genital development by reducing gonadotropin secretion and testicular steroidogenic enzyme activity (O'Donnell et al., 2001; Shupnik, 2002), but also repress INSL3 expression for the gubernacular development (Nef et al., 2000) (it may also disturb the focal endocrine environment such as the androgen/estrogen ratio in the external genital tissues) (Toppari and Skakkebaek, 1998; Dietrich et al., 2004); (ii) impaired androgen effects around the critical period for sex development usually result in structurally abnormal external genitalia including HS, whereas those after the critical period usually lead to MP and/or CO without structural abnormalities (Grumbach et al., 2002) and (iii) the estrogenic effects of EEDs should be persistent including the critical period, and the sensitivity to EEDs could be higher in the fetal life, especially around the critical period (Wilcox et al., 1995; McLachlan, 2001; Kurzrock and Karpman, 2004).
Our findings suggest that the specific haplotype may raise the susceptibility to HS primarily because of reduced androgen effects around the critical period and to CO primarily because of impaired INSL3 effects after the critical period. In addition, since it is unlikely that reduced androgen effects become obvious after the critical period, this would explain why the association between the specific haplotype and MP remained mild. It should be pointed out, however, that the MP patients were few in number. Thus, a more obvious association may be identified between the specific haplotype and MP, if a larger number of MP patients are analysed.
In contrast, no significant association was identified between the ‘AGATA’ haplotype and SF, although genetic susceptibility may be relevant to the development of SF in response to estrogenic EEDs (Toppari et al., 1996). Indeed, exposure to estrogenic agents is known to result in SF (O'Donnell et al., 2001). However, in contrast to abnormal external genitalia that develop during the fetal life, SF becomes discernible in adulthood and, therefore, could be influenced by multiple genetic and environmental factors for a long time. In addition, the prevalence of HS appears to have increased (Kishi et al., 2005), whereas that of SF may have remained unchanged during the last few decades in Japan (Itoh et al., 2001). Thus, the involvement of genetic susceptibility to estrogenic EEDs in the development of SF seems obscure in contemporary Japanese males, although it may become clearer in the future. Alternatively, a variant(s) of ESR2 may play an important role in the development of SF in response to EEDs, because ESR2 is clearly expressed in fetal and adult testes, especially in germ cells (O'Donnell et al., 2001). Indeed, an association of ESR2 polymorphisms with SF as well as HS has been reported recently (Aschim, et al., 2005; Beleza-Meireles, et al. 2006). In addition, variations in serum estrogens, though not measured here, may also be relevant to the lack of association.
In summary, the present study suggests the involvement of genetic susceptibility in the development of external genital abnormalities, and this may be in response to estrogenic EEDs. However, several points should be made in this study. First, although all the patients and control males were Japanese, this does not exclude a possible contribution of ethnic differences to the positive results. Indeed, the Japanese are derived from at least two different ancestral populations (Hammer et al., 2006). Second, the number of analysed subjects is small, and the present study focused on the LD block region rather than the whole ESR1 gene. Third, it remains to be determined whether the positive results for undermasculinization can be reproduced in other countries or populations with an increased prevalence of male genital abnormalities, whether the specific ESR1 haplotype is truly not associated with SF and whether an ESR2 variant(s) is involved in the susceptibility to male genital and reproductive abnormalities. Lastly, the notion concerning EEDs is still conceptual, and other environmental or lifestyle factors are also likely to be involved in the deterioration of male genital and reproductive health (Skakkebaek et al., 2001; Magnusdottir et al., 2005). Thus, further studies are necessary to clarify the relevance of genetic susceptibility to the male genital and reproductive abnormalities in response to EEDs.
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We thank Mr Shigeo Kamitsuji, Genome Diversity Team, Biological Information Research Center, National Institute of Advanced Industrial Science and Technology, for his help in the statistical analyses. This work was supported by a grant for Child Health and Development from the Ministry of Health, Labor and Welfare (17C-2) and by a Grant-in-Aid for Scientific Research on Priority Areas from the Ministry of Education, Science, Sports and Culture (16086215).
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8 The first and the second authors equally contributed to this work.
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Submitted on May 29, 2006; resubmitted on October 30, 2006; accepted on December 14, 2006.
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