Haplotype analysis of the estrogen receptor 1 gene in male genital and reproductive abnormalities

Abstract

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.

Haplotype analysis of ESR2 in Japanese patients with spermatogenic failure

“…In this context, as SF becomes discernible in adulthood, such minor differences, if they exist, may exert unfavorable influences on spermatogenic function for a long time, leading to SF. This may explain why the OR obtained in this study remained low, in contrast to the high ORs identified in cryptorchidism (7.55) and hypospadias (13.75) 6,7 (and our unpublished updated observation) which develop during the fetal life. Sixth, although it is known that EEDs also exert anti-androgenic effects and influence aromatization, 25,26 these have not been examined in this study.…”

“…1, 3 To examine this possibility, we have previously performed haplotype analysis of ESR1 in Japanese male patients with genial and reproductive abnormalities as well as in control males, using 15 single nucleotide polymorphisms (SNPs 1-15) that are widely distributed throughout the 4300-kb genomic sequence of ESR1. 6,7 Consequently, we identified an B50-kb linkage disequilibrium (LD) block spanning SNPs 10-14 in the 3 0 region of ESR1, and found that homozygosity of a specific 'AGATA' haplotype within the LD block was strongly associated with cryptorchidism (P ¼ 0.0040; odds ratio (OR) ¼ 7.55) and hypospadias (P ¼ 0.000057; OR ¼ 13.75) 6,7 (and our unpublished updated observation). This finding provides strong evidence that homozygosity of the specific ESR1 haplotype raises the susceptibility to the development of male genital abnormalities.…”

“…7 The selection criteria included: (1) azoospermia or severe oligozoospermia (o5 million sperms per ml) demonstrated by two consecutive analyses of semen obtained after 4-7 days of abstinence; (2) lack of extragenital anomalies such as cryptorchidism and hypospadias; (3) hypergonadotropic hypogonadism indicative of primary testicular dysfunction; (4) no seminal tract obstruction, varicocele, or retrograde ejaculation; (5) a 46,XY karyotype with no demonstrable structural or numerical abnormality after examining X30 lymphocytes; (6) absence of a Y chromosomal microdeletion after examining 36 loci from SRY to DYZ1, including multiple Yq loci in the azoospermia factor regions (AZFa, b, c) such as RBMY and DAZ; 9 (7) no significant expansion of CAG repeat length at exon 1 of AR that is known to raise the susceptibility to male reproductive abnormalities; 10 and (8) lack of a disease episode that could affect fertility such as mumps orchiditis. For controls, 119 control adult males with proven fertility aged 24-50 years (median 35.5 year) were similarly analyzed with permission.…”

“…7 In this context, as ESR2 is clearly expressed in various developmental stages of male germ cells, 5 it may be possible that the deleterious effects of estrogenic EEDs on spermatogenesis may primarily be mediated by ERb. Thus, we carried out haplotype analysis of ESR2 in Japanese patients with SF.…”

Hypospadias: Interactions between environment and genetics

“…Polymorphisms of the estrogen receptor may also facilitate the deleterious effects of xenoestrogens since their effects are mainly mediated through this receptor. The AGAGA haplotype of the estrogen receptor 1 (ESR1) gene is strongly associated with hypospadias [117]. The ESR1 C-A haplotype, for ESR1 XbaI and ESR2 2681-4A>G, respectively, increases the risk of malformation, as well [118].…”