Abstract
BackgroundSex steroid hormone receptors are classified into three classes of receptors: estrogen receptors (ER) α and β, androgen receptor (AR), and progesterone receptor (PR). They belong to the nuclear receptor superfamily and activate their downstream genes in a ligand-dependent manner. Since sex steroid hormones are involved in a wide variety of physiological processes and cancer development, synthetic chemical substances that exhibit sex steroid hormone activities have been applied as pharmaceuticals and consumed in large amounts worldwide. They are potentially hazardous contaminants as endocrine disruptors in the environment because they may induce inappropriate gene expression mediated by sex steroid hormone receptors in vivo.ResultsTo develop simple reporter gene assays with enhanced sensitivity for the detection of sex steroid hormones, we newly established mutant yeast strains lacking the CWP and PDR genes encoding cell wall mannoproteins and plasma membrane drug efflux pumps, respectively, and expressing human ERα, ERβ, AR, and PR. Reporter gene assays with mutant yeast strains responded to endogenous and synthetic ligands more strongly than those with wild-type strains. Sex steroid hormone activities in some pharmaceutical oral tablets and human urine were also detectable in these yeast assays.ConclusionsYeast reporter gene assay systems for all six steroid hormone receptors, including previously established glucocorticoid receptor (GR) and mineralocorticoid receptor (MR) assay yeasts, are now available. Environmental endocrine disrupters with steroid hormone activity will be qualitatively detectable by simple and easy procedures. The yeast-based reporter gene assay will be valuable as a primary screening tool to detect and evaluate steroid hormone activities in various test samples. Our assay system will strongly support the detection of agonists, antagonists, and inverse agonists of steroid hormone receptors in the field of novel drug discovery and assessments of environmental pollutants.
Highlights
The sex steroid hormones, estrogens, androgens, and progesterone, play essential roles in sexual differentiation, reproduction, and many other physiological processes by regulating gene expression in vertebrates [1,2,3,4]
Ligand-bound receptors translocate from the cytosol into the nucleus, at which they bind as their homodimers to specific DNA sequences called estrogen response elements (EREs) for estrogen receptors [6, 7] and glucocorticoid response elements (GREs) for androgen receptor (AR) and progesterone receptor (PR) [8, 9]
Response to endogenous ligands of newly constructed sex hormone receptor-expressing yeast strains lacking Cell wall mannoprotein (CWP) and/or ATP-binding cassette (ABC) transporter genes The reporter gene assay yeast strains expressing human ERα, ERβ, PR, and AR established in wild-type W303a showed the dose-dependent induction of the lacZ reporter gene in response to the human endogenous ligands, E2, PS, and TS, respectively (Fig. 1)
Summary
The sex steroid hormones, estrogens, androgens, and progesterone, play essential roles in sexual differentiation, reproduction, and many other physiological processes by regulating gene expression in vertebrates [1,2,3,4] The receptors of these steroids, estrogen receptors α and β (ERα and ERβ), androgen receptor (AR), and progesterone receptor (PR), belong to the nuclear receptor (NR) superfamily, which includes receptors for corticosteroids, vitamin D3, thyroid hormones, and retinoic acids [5]. By influencing the reproductive tract, sexual phenotype, and secondary sexual characteristics of male and female animals including humans, sex steroid hormones entirely control the reproductive process: sexual development and maturation, sex-dependent brain differentiation, and sexual behavior [3, 13,14,15]. They are potentially hazardous contaminants as endocrine disruptors in the environment because they may induce inappropriate gene expression mediated by sex steroid hormone receptors in vivo
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