Estrogen receptor and aryl hydrocarbon receptor signaling pathways

Estrogen receptors (ERs) and the aryl hydrocarbon receptor (AhR) are ligand activated transcription factors and members of the nuclear receptor and bHLH-PAS superfamilies, respectively. AhR is involved in xenobiotic metabolism and in mediating the toxic effects of dioxin-like compounds. Crosstalk has been observed among AhR and nuclear receptors, but has been most well studied with respect to ER signaling. Activated AhR inhibits ER activity through a number of different mechanisms, whereas ERα has been reported to have a positive role in AhR signaling. Here we will discuss recent data revealing that dioxin bound AhR recruits ERα to AhR regulated genes. We will also consider the implications of ER recruitment to AhR target genes on ER and AhR signaling

Levels of 17β-Estradiol Receptors Expressed in Embryonic and Adult Zebrafish Following In Vivo Treatment of Natural or Synthetic Ligands

The nuclear receptors encompass a group of regulatory proteins involved in a number of physiological processes. The estrogen receptors (ERs), of which one alpha and one beta form exist in mammals function as transcription factors in response to 17β-estradiol (E2). In zebrafish there are three gene products of estrogen receptors and they are denoted esr1 (ERalpha), esr2a (ERbeta2) and esr2b (ERbeta1). Total RNA of zebrafish early life stages (<3, 6, 12, 24, 48, 72, 96 and 120 hours post fertilization) and of adult fish (liver, intestine, eye, heart, brain, ovary, testis, gill, swim bladder and kidney) were isolated following in vivo exposures. Using specific primers for each of the three zebrafish ERs the expression levels were quantified using real time PCR methodology. It was shown that in absence of exposure all three estrogen receptors were expressed in adult fish. The levels of expression of two of these three ER genes, the esr1 and esr2a were altered in organs such as liver, intestine, brain and testis in response to ligand (E2, diethylstilbestrol or 4-nonylphenol). During embryogenesis two of the three receptor genes, esr1 and esr2b were expressed, and in presence of ligand the mRNA levels of these two genes increased. The conclusions are i) estrogen receptor genes are expressed during early development ii) altered expression of esr genes in response to ligand is dependent on the cellular context; iii) the estrogenic ligand 4-nonylphenol, a manufactured compound commonly found in sewage of water treatment plants, acts as an agonist of the estrogen receptor during development and has both agonist and antagonist properties in tissues of adult fish. This knowledge of esr gene function in development and in adult life will help to understand mechanisms of interfering mimicking endocrine chemicals in vivo

Impact of estrogen receptor gene polymorphisms and mRNA levels on obesity and lipolysis – a cohort study

<p>Abstract</p> <p>Background</p> <p>The estrogen receptors α and β (<it>ESR1, ESR2</it>) have been implicated in adiposity, lipid metabolism and feeding behaviour. In this report we analyse <it>ESR1 </it>and <it>ESR2 </it>gene single nucleotide polymorphisms (SNPs) for association with obesity. We also relate adipose tissue <it>ESR1 </it>mRNA levels and <it>ESR1 </it>SNPs to adipocyte lipolysis and lipogenesis phenotypes.</p> <p>Methods</p> <p>23 <it>ESR1 </it>and 11 <it>ESR2 </it>tag-SNPs, covering most of the common haplotype variation in each gene according to HAPMAP data, were analysed by Chi²for association with obesity in a cohort comprising 705 adults with severe obesity and 402 lean individuals. Results were replicated in a cohort comprising 837 obese and 613 lean subjects. About 80% of both cohorts comprised women and 20% men. Adipose tissue <it>ESR1 </it>mRNA was quantified in 122 women and related to lipolysis and lipogenesis by multiple regression. <it>ESR1 </it>SNPs were analysed for association with adipocyte lipolysis and lipogenesis phenotypes in 204 obese women by simple regression.</p> <p>Results</p> <p>No <it>ESR1 </it>SNP was associated with obesity. Five <it>ESR2 </it>SNPs displayed nominal significant allelic association with obesity in women and one in men. The two <it>ESR2 </it>SNPs associated with obesity with nominal P value < 0.01 were genotyped in a second cohort where no association with obesity was observed. There was an inverse correlation between <it>ESR1 </it>mRNA levels in abdominal subcutaneous (sc) adipose tissue and basal lipolysis, as well as responsiveness to adrenoceptor agonists independent of age and BMI (P value 0.009–0.045). <it>ESR1 </it>rs532010 was associated with lipolytic sensitivity to noradrenaline (nominal P value 0.012), and <it>ESR1 </it>rs1884051 with responsiveness to the non-selective beta-adrenoceptor agonist isoprenaline (nominal P value 0.05). These associations became non-significant after Bonferroni correction.</p> <p>Conclusion</p> <p><it>ESR1 </it>gene alleles are unlikely to be a major cause of obesity in women. A minor importance of <it>ESR2 </it>on severe obesity cannot be excluded. The inverse correlation between <it>ESR1 </it>mRNA levels and lipolytic responsiveness to adrenoceptor agonists implies that low adipose tissue <it>ESR1 </it>levels attenuate catecholamine resistance in sc fat cells of obese women hereby contributing to loss of sc and gain of visceral fat. There is no evidence for a genetic impact of <it>ESR1 </it>on lipolysis or lipogenesis.</p

Sptrx-2, a fusion protein composed of one thioredoxin and three tandemly repeated NDP-kinase domains is expressed in human testis germ cells

42 páginas, 9 figuras.Background Thioredoxins (Trx) are small redox proteins that function as general protein disulphide reductases and regulate several cellular processes such as transcription factor DNA binding activity, apoptosis and DNA synthesis. In mammalian organisms, thioredoxins are generally ubiquitously expressed in all tissues, with the exception of Sptrx-1 which is specifically expressed in sperm cells. Results We report here the identification and characterization of a novel member of the thioredoxin family, the second with a tissue-specific distribution in human sperm, termed Sptrx-2. The Sptrx-2 ORF (open reading frame) encodes for a protein of 588 amino acids with two different domains: an N-terminal thioredoxin domain encompassing the first 105 residues and a C-terminal domain composed of three repeats of a NDP kinase domain. The Sptrx-2 gene spans about 51 kb organized in 17 exons and maps at locus 7p13-14. Sptrx-2 mRNA is exclusively expressed in human testis, mainly in primary spermatocytes, while Sptrx-2 protein expression is detected from the pachytene spermatocytes stage onwards, peaking at round spermatids stage. Recombinant full-length Sptrx-2 expressed in bacteria displayed neither thioredoxin nor NDP kinase enzymatic activity. Conclusions The sperm specific expression of Sptrx-2, together with its chromosomal assignment to a position reported as a potential locus for flagellar anomalies and male infertility phenotypes such as primary ciliary dyskinesia, suggests that it might be a novel component of the human sperm axonemal organization.This work was supported by grants from the Swedish Medical Research Council (Projects 03P-14096-01A, 03X-14041-01A and 13X-10370), the Åke Wibergs Stiftelse, the Karolinska Institutet, the Södertörns Högskola and the Medical Research Fund of Tampere University Hospital.Peer reviewe