BPA and BPS affect the expression of anti-Mullerian hormone (AMH) and its receptor during bovine oocyte maturation and early embryo development.

BACKGROUND: Exposure to endocrine-disrupting chemicals, such as Bisphenol A (BPA) and Bisphenol S (BPS), is widespread and has negative implications on embryonic development. Preliminary evidence revealed that in women undergoing IVF treatment, urinary BPA levels were associated with low serum anti-Mullerian hormone, however a definitive relationship between the two has not yet been characterized. METHODS: This study aimed to evaluate BPA and BPS effects on in vitro oocyte maturation and early preimplantation embryo development through i) analysis of anti-Mullerian hormone (AMH) and anti-Mullerian hormone receptor II (AMHRII), ii) investigation of developmental parameters, such as cleavage, blastocyst rates and developmental arrest, iii) detection of apoptosis and iv) assessment of possible sex ratio skew. An in vitro bovine model was used as a translational model for human early embryonic development. We first assessed AMH and AMHRII levels after bisphenol exposure during oocyte maturation. Zygotes were also analyzed during cleavage and blastocysts stages. Techniques used include in vitro fertilization, quantitative polymerase chain reaction (qPCR), western blotting, TUNEL and immunofluorescence. RESULTS: Our findings show that BPA significantly decreased cleavage (p < 0.001), blastocyst (p < 0.005) and overall developmental rates as well as significantly increased embryonic arrest at the 2-4 cell stage (p < 0.05). Additionally, both BPA and BPS significantly increased DNA fragmentation in 2-4 cells, 8-16 cells and blastocyst embryos (p < 0.05). Furthermore, BPA and BPS alter AMH and AMHRII at the mRNA and protein level in both oocytes and blastocysts. BPA, but not BPS, also significantly skews sex ratios towards female blastocysts (p < 0.05). CONCLUSION: This study shows that BPA affects AMH and AMHRII expression during oocyte maturation and that BPS exerts its effects to a greater extent after fertilization and therefore may not be a safer alternative to BPA. Our data lay the foundation for future functional studies, such as receptor kinetics, downstream effectors, and promoter activation/inhibition to prove a functional relationship between bisphenols and the AMH signalling system.

Peptide Receptor Radionuclide Therapy With 177Lu-DOTATATE for Symptomatic Control of Refractory Carcinoid Syndrome.

CONTEXT: Peptide receptor radionuclide therapy (PRRT) with [Lutetium-177-DOTA0-Tyr3]octreotate (177Lu-DOTATATE) results in an increase of progression-free survival and quality of life in patients with progressive, well-differentiated neuroendocrine neoplasms (NENs). OBJECTIVE: To study the effect of 177Lu-DOTATATE in patients with carcinoid syndrome and radiologically stable or newly diagnosed disease treated solely for the purpose of symptom reduction. DESIGN: Retrospective cohort study. SETTING: Tertiary care hospital. PATIENTS: Twenty-two patients with a metastatic midgut NEN, elevated urinary 5-hydroxyindolacetic acid excretion, and flushing and/or diarrhea despite treatment with a somatostatin analog, without documented disease progression. INTERVENTION: PRRT with 177Lu-DOTATATE (intended cumulative dose: 29.6 GBq) with a primary aim to reduce symptoms. RESULTS: After PRRT, mean bowel movement frequency (BMF) decreased from 6.1 ± 3.4 to 4.6 ± 3.6 per day (P = 0.009). Flushes decreased from 4.3 ± 2.9 to 2.4 ± 2.7 flushes per day (P = 0.002). A decrease of BMF of more than 30% occurred in 47% of patients with baseline BMF of 4 or more (n = 17). In patients with ≥2 episodes of flushing a day (n = 15), 67% of patients had more than 50% decrease of daily flushing. A decrease in urinary 5-hydroxyindolacetic acid excretion of more than 30% was seen in 56% of patients. The European Organization for Research and Treatment of Cancer-Core Module diarrhea subscale score showed a trend toward improvement by an average of 16.7 ± 33.3 points (P = 0.11). CONCLUSION: PRRT with 177Lu-DOTATATE effectively reduced diarrhea and flushing in patients with carcinoid syndrome and can be considered for symptomatic treatment of carcinoid syndrome insufficiently controlled with somatostatin analogs.

Hepatic macrophages act as a central hub for relaxin-mediated alleviation of liver fibrosis.

Relaxin is an antifibrotic peptide hormone previously assumed to directly reverse the activation of hepatic stellate cells for liver fibrosis resolution. Using nanoparticle-mediated delivery, here we show that, although relaxin gene therapy reduces liver fibrosis in vivo, in vitro treatment fails to induce quiescence of the activated hepatic stellate cells. We show that hepatic macrophages express the primary relaxin receptor, and that, on relaxin binding, they switch from the profibrogenic to the pro-resolution phenotype. The latter releases exosomes that promote the relaxin-mediated quiescence of activated hepatic stellate cells through miR-30a-5p. Building on these results, we developed lipid nanoparticles that preferentially target activated hepatic stellate cells in the fibrotic liver and encapsulate the relaxin gene and miR-30a-5p mimic. The combinatorial gene therapy achieves synergistic antifibrosis effects in models of mouse liver fibrosis. Collectively, our findings highlight the key role that macrophages play in the relaxin-primed alleviation of liver fibrosis and demonstrate a proof-of-concept approach to devise antifibrotic strategies through the complementary application of nanotechnology and basic science.

Rapid actions of anti-Müllerian hormone in regulating synaptic transmission and long-term synaptic plasticity in the hippocampus.

Anti-Müllerian hormone (Amh) is a peptide factor that is known to regulate sexual differentiation and gonadal function in mammals. Although Amh is also suggested to be associated with cognitive development and function in the postnatal brain, little is known about its expression or direct effects on neuronal activities in the hippocampus. Therefore, we assessed Amh and its receptor expression in the hippocampus of male and female mice using PCR, Western blot, and immunofluorescence staining. While Amh-specific receptor expression was comparable between males and females, mRNA and protein levels of Amh were higher in females than those of males. Electrophysiological recordings on acute hippocampal slices showed that exogenous Amh protein addition increased synaptic transmission and long-term synaptic plasticity at the Cornu Ammonis (CA) 3-CA1 synapses. Amh exposure also increased the excitatory postsynaptic potential at CA1 synapses. Our findings support direct and rapid actions of Amh as a paracrine and/or autocrine factor in regulating hippocampal neuronal activities. Data provide functional evidence of Amh-mediated postsynaptic modulation of synaptic transmission and Amh-regulated long-term synaptic plasticity in the hippocampus. These results suggest a potential role of Amh in learning and memory, and a possible cause of the sex differences in cognitive development and function.

Targeted Alpha Particle Therapy for Neuroendocrine Tumours: The Next Generation of Peptide Receptor Radionuclide Therapy.

Neuroendocrine tumours (NETs) are being seen increasingly frequently, but to date only complete surgical resection is curative. However, among the various therapeutic options, peptide receptor radionuclide therapy, linking a radioactive moiety to an octreotide derivative, has been shown to be highly efficacious and a well-tolerated therapy, improving progression-free survival and probably overall survival. Nevertheless, the current radionuclides in use are beta particle emitters with non-optimal radiobiological properties. A new generation of alpha particle-emitting radionuclides is being developed, with advantages in terms of very high energy and a short path length, which should theoretically show higher efficacy. We survey the current developments in this field, emphasising the exciting potential of this novel form of therapy for NETs.

Mini-review: regulation of the renal NaCl cotransporter by hormones.

The renal thiazide-sensitive NaCl cotransporter, NCC, is the major pathway for salt reabsorption in the distal convoluted tubule. The activity of this cotransporter is critical for regulation of several physiological variables such as blood pressure, serum potassium, acid base metabolism, and urinary calcium excretion. Therefore, it is not surprising that numerous hormone-signaling pathways regulate NCC activity to maintain homeostasis. In this review, we will provide an overview of the most recent evidence on NCC modulation by aldosterone, angiotensin II, vasopressin, glucocorticoids, insulin, norepinephrine, estradiol, progesterone, prolactin, and parathyroid hormone.

Smoking-induced expression of the GPR15 gene indicates its potential role in chronic inflammatory pathologies.

Despite the described clear epigenetic effects of smoking, the effect of smoking on genome-wide gene expression in the blood is obscure. We therefore studied the smoking-induced changes in the gene-expression profile of the peripheral blood. RNA was extracted from the whole blood of 48 individuals with a detailed smoking history (24 never-smokers, 16 smokers, and 8 ex-smokers). Gene-expression profiles were evaluated with RNA sequencing, and results were analyzed separately in 24 men and 24 women. In the male smokers, 13 genes were statistically significantly (false-discovery rate <0.1) differentially expressed; in female smokers, 5 genes. Although most of the differentially expressed genes were different between the male and female smokers, the G-protein-coupled receptor 15 gene (GPR15) was differentially expressed in both male and female smokers compared with never-smokers. Analysis of GPR15 methylation identified significantly greater hypomethylation in smokers compared with that in never-smokers. GPR15 is the chemoattractant receptor that regulates T-cell migration and immunity. Up-regulation of GPR15 could explain to some extent the health hazards of smoking with regard to chronic inflammatory diseases.

Transcriptome sequencing of the anterior cingulate in bipolar disorder: dysregulation of G protein-coupled receptors.

OBJECTIVE: Gene expression dysregulation in the brain has been associated with bipolar disorder through candidate gene and microarray expression studies, but questions remain about isoform-specific dysregulation and the role of noncoding RNAs whose importance in the brain has been suggested recently but not yet characterized for bipolar disorder. METHOD: The authors used RNA sequencing, a powerful technique that captures the complexity of gene expression, in postmortem tissue from the anterior cingulate cortex from 13 bipolar disorder case subjects and 13 matched comparison subjects. Differential expression was computed, and a global pattern of downregulation was detected, with 10 transcripts significant at a false discovery rate ≤5%. Importantly, all 10 genes were also replicated in an independent RNA sequencing data set (N=61) from the anterior cingulate cortex. RESULTS: Among the most significant results were genes coding for class A G protein-coupled receptors: SSTR2 (somatostatin receptor 2), CHRM2 (cholinergic receptor, muscarinic 2), and RXFP1 (relaxin/insulin-like family peptide receptor 1). A gene ontology analysis of the entire set of differentially expressed genes pointed to an overrepresentation of genes involved in G protein-coupled receptor regulation. The top genes were followed up by querying the effect of treatment with mood stabilizers commonly prescribed in bipolar disorder, which showed that these drugs modulate expression of the candidate genes. CONCLUSIONS: By using RNA sequencing in the postmortem bipolar disorder brain, an interesting profile of G protein-coupled receptor dysregulation was identified, several new bipolar disorder genes were indicated, and the noncoding transcriptome in bipolar disorder was characterized. These findings have important implications with regard to fine-tuning our understanding of the bipolar disorder brain, as well as for identifying potential new drug target pathways.

Diverse regulation of cardiac expression of relaxin receptor by α1- and ß1-adrenoceptors.

PURPOSE: Relaxin, a new drug for heart failure therapy, exerts its cardiac actions through relaxin family peptide receptor 1 (RXFP1). Factors regulating RXFP1 expression remain unknown. We have investigated effects of activation of adrenoceptors (AR), an important modulator in the development and prognosis of heart failure, on expression of RXFP1 in rat cardiomyocytes and mouse left ventricles (LV). METHODS: Expression of RXFP1 at mRNA (real-time PCR) and protein levels (immunoblotting) was measured in cardiomyocytes treated with α- and ß-AR agonists or antagonists. RXFP1 expression was also determined in the LV of transgenic mouse strains with cardiac-restricted overexpression of α1A-, α1B- or ß2-AR. Specific inhibitors were used to explore signal pathways involved in α1-AR mediated regulation of RXFP1 in cardiomyocytes. RESULTS: In cultured cardiomyocytes, α1-AR stimulation resulted in 2-3 fold increase in RXFP1 mRNA (P < 0.001), which was blocked by specific inhibitors for protein kinase C (PKC) or mitogen-activated protein kinases/extracellular signal-regulated kinases (MAPK/ERK). Activation of ß1-, but not ß2-AR, significantly inhibited RXFP1 expression (P < 0.001). Relative to respective wild-type controls, RXFP1 mRNA levels in the LV of mice overexpressing α1A- or α1B-AR were increased by 3- or 10-fold, respectively, but unchanged in ß2-AR transgenic hearts. Upregulation by α1-AR stimulation RXFP1 expression was confirmed at protein levels both in vitro and in vivo. CONCLUSIONS: Expression of RXFP1 was up-regulated by α1-AR but suppressed by ß-AR, mainly ß1-AR subtype, in cardiomyocytes. Future studies are warranted to characterize the functional significance of such regulation, especially in the setting of heart failure.

Peptide receptor radionuclide therapy in a patient with disabling non-functioning pituitary adenoma.

Non-functioning pituitary adenoma (NFPA) with higher proliferation index (WHO II) are often a therapeutical challenge. Low somatostatin receptor expression in these tumors usually prevents a treatment with somatostatin analogs. In 1996, a 55-year-old patient was referred due to right-sided headache. A pituitary macroadenoma with infiltration into the right cavernous sinus was diagnosed. There was no visual field deficit and the clinical and biochemical work up was consistent with a NFPA. The patient underwent transsphenoidal surgery. Residual adenoma remained in the right cavernous sinus. Histologically, a null-cell adenoma with a high proliferation index was documented (MIB-1: 11.6%, WHO II). Somatostatin receptor autoradiography was performed in the surgical specimen showing a homogenous expression of sst2 receptors. Radiosurgery was completed with stable disease for 8 years. In 2004, the patient was diagnosed with an incomplete palsy of the right oculomotorius nerve and a significant increase in the volume of the adenoma in the right cavernous sinus. After a positive Octreoscan(®) the patient consented to an experimental therapy approach using Lutetium DOTATOC (3 × 200 mCi). The palsy of the oculomotorius nerve improved and remained stable until today (March 2013), the follow-up MRI scans demonstrated stable disease. This is the first case of a patient with a NFPA (WHO II) in whom PRRT successfully improved the local complications of the tumor for more than 8 years after ineffective surgery and gamma knife therapy. The determination of sst2 in vitro using autoradiography and in vivo by Octreoscan was instrumental to administer this therapy in a challenging situation.

[Diagnosis and treatment options of neuroendocrine tumours]. / A neuroendokrin daganatok kórisméje és kezelésének irányelvei.

Neuroendocrine neoplasms belong to the group of rare tumours. Their clinical importance may be highlighted by their high prevalence despite low incidence. Since survival rate is similar to other progressive neoplastic diseases in metastatic cases, early recognition and appropriate therapy of these neoplasms are equally important. Classification of neuroendocrine tumours is based on their pathologic characteristics according to the 2010 WHO recommendation. Non-functioning tumours cause local symptoms due to their mass effect, while functioning tumours produce well-defined endocrine syndromes. Among laboratory tests, serum chromogranin-A is considered the most important biomarker of both non-functioning and functioning neuroendocrine tumours. Localization of these tumours includes the use of conventional diagnostic imaging, endoscopic examinations, and functional imaging studies. With respect to treatment, elimination of the primary tumour remains one of the most important issues. In advanced cases of the disease metastasectomy, interventional radiologic methods, medical treatment and endoradiotherapy can be used. The aim of this review is to summarize briefly the symptoms, diagnostic methods and treatment options of neuroendocrine tumours.

Relaxin family peptides and their receptors.

There are seven relaxin family peptides that are all structurally related to insulin. Relaxin has many roles in female and male reproduction, as a neuropeptide in the central nervous system, as a vasodilator and cardiac stimulant in the cardiovascular system, and as an antifibrotic agent. Insulin-like peptide-3 (INSL3) has clearly defined specialist roles in male and female reproduction, relaxin-3 is primarily a neuropeptide involved in stress and metabolic control, and INSL5 is widely distributed particularly in the gastrointestinal tract. Although they are structurally related to insulin, the relaxin family peptides produce their physiological effects by activating a group of four G protein-coupled receptors (GPCRs), relaxin family peptide receptors 1-4 (RXFP1-4). Relaxin and INSL3 are the cognate ligands for RXFP1 and RXFP2, respectively, that are leucine-rich repeat containing GPCRs. RXFP1 activates a wide spectrum of signaling pathways to generate second messengers that include cAMP and nitric oxide, whereas RXFP2 activates a subset of these pathways. Relaxin-3 and INSL5 are the cognate ligands for RXFP3 and RXFP4 that are closely related to small peptide receptors that when activated inhibit cAMP production and activate MAP kinases. Although there are still many unanswered questions regarding the mode of action of relaxin family peptides, it is clear that they have important physiological roles that could be exploited for therapeutic benefit.

Chemical subtleties in small-molecule modulation of peptide receptor function: the case of CXCR3 biaryl-type ligands.

The G protein-coupled chemokine receptor CXCR3 plays a role in numerous inflammatory events. The endogenous ligands for the chemokine receptors are peptides, but in this study we disclose small-molecule ligands that are able to activate CXCR3. A class of biaryl-type compounds that is assembled by convenient synthetic routes is described as a new class of CXCR3 agonists. Intriguingly, structure-activity relationship and structure-function relationship studies reveal that subtle chemical modifications on the outer aryl ring (e.g., either the size or position of a halogen atom) result in a full spectrum of agonist efficacies on CXCR3. Quantum mechanics calculations and nuclear Overhauser effect spectroscopy NMR studies suggest that the biaryl dihedral angle and the electronic nature of ortho-substituents play an important role in determining agonist efficacies. Compounds 38 (VUF11222) and 39 (VUF11418) are the first reported nonpeptidomimetic agonists on CXCR3, rendering them highly useful chemical tools for detailed assessment of CXCR3 activation as well as for studying downstream CXCR3 signaling.

Mullerian inhibiting substance induces apoptosis of human endometrial stromal cells in endometriosis.

CONTEXT: Müllerian inhibiting substance (MIS) is produced in Sertoli cells of fetal testis and causes regression of müllerian ducts in male embryos. MIS also can induce the cell cycle arrest and apoptosis in müllerian duct-derived tumors in vivo and in vitro. OBJECTIVE: Our objective was to investigate the expression of MIS type II receptor (MISR II) and whether MIS can inhibit the proliferation and induce apoptosis in primary cultures of endometrial stromal cells (ESC) of endometriosis. DESIGN AND SETTINGS: In vitro experiments were performed in the university research laboratory. PARTICIPANTS: Tissue samples from 12 patients who had undergone evisceration for ovarian endometrial cysts were included in this study. INTERVENTIONS AND MAIN OUTCOME MEASURES: The expression of MISR II in ESC was investigated by immunohistochemistry. The cell viability and apoptosis in ESC treated with MIS was measured by methylthiazoletetrazolium assay and annexin V analysis. The expression of regulatory proteins in ESC treated with MIS was shown by Western blotting. RESULTS: ESC showed specific immunostaining for the MISR II. ESC treated with MIS exhibited 32% growth inhibition (P = 0.0001). The changes in cell cycle distribution after MIS exposure at 72 h demonstrated that S and G(2)M phases were decreased; G(0)G(1) and sub-G(0)G(1) phases were increased. ESC treated with MIS showed 13.72% annexin V-fluorescein isothiocyanate positivity. In the ESCs, which contain defective p16, MIS increased the expression of pocket proteins p107 and p130 and decreased E2F transcription factor 1. CONCLUSIONS: The results support a central role for MIS in endometriosis. Although the precise mechanism of MIS-mediated inhibition of ESC growth has not been fully defined, these data suggest that MIS has activity against ESC in vitro and may also be an effective targeted therapy for endometriosis.

The potential for induction peptide receptor chemoradionuclide therapy to render inoperable pancreatic and duodenal neuroendocrine tumours resectable.

AIMS: To assess the clinical utility of peptide receptor chemoradionuclide therapy (PRCRT) using (177)Lu-octreotate (LuTate) with concurrent 5FU chemotherapy in patients with inoperable primary pancreatic and duodenal neuroendocrine tumours (NETs). METHODS: Between December 2006 and October 2009, five patients with progressive inoperable pancreatic and duodenal NETs without distant metastatic disease or with a potentially resectable solitary distant metastasis were treated with PRCRT; in combination with external beam radiotherapy in one case. Patients were followed up three months post-treatment with somatostatin receptor scintigraphy, radiology, biochemical markers and clinical assessment. Radiological response classification was defined by Response Evaluation Criteria in Solid Tumours (RECIST) with the addition of a minor response (MR; 10-30% size reduction) classification. Long-term follow up was performed until July 2011. RESULTS: At three months post-treatment, all five patients had a scintigraphic response, four had a radiological response and three of the four symptomatic patients responded clinically. All five patients had an ongoing treatment response beyond three months including one where further tumour shrinkage facilitated curative surgery. All five patients are alive with 12-42 months of follow-up post-treatment. CONCLUSION: PRCRT can be effective in inoperable pancreatic and duodenal neuroendocrine tumours and may play a role as neoadjuvant therapy in this patient group.

Emodepside and SL0-1 potassium channels: a review.

Nematode parasites infect humans and domestic animals; treatment and prophylaxis require anthelmintic drugs because vaccination and sanitation is limited. Emodepside is a more recently introduced cyclooctadepsipeptide drug that has actions against GI nematodes, lungworm, and microfilaria. It has a novel mode of action which breaks resistance to the classical anthelmintics (benzimidazoles, macrocyclic lactones and cholinergic agonists). Here we review studies on its mode of action which suggest that it acts to inhibit neuronal and muscle activity of nematodes by increasing the opening of calcium-activated potassium (SLO-1) channels.

[Pharmacologic therapy for neuroendocrine tumours]. / Neuroendokrin daganatok gyógyszeres kezelése.

Neuroendocrine tumours are heterogeneous and rare malignancies arising from endocrine cells located in various anatomical locations. Neuroendocrine tumours can be functional and may produce a wide variety of mediators, however, the majority of neuroendocrine tumours do not produce biologically active hormones (non-functioning tumours). On the basis of their pathological and biological characteristics they can be well differentiated as low malignant and poorly differentiated highly malignant tumours. In the case of the advanced low malignant tumours the application of somatostatin analogues not only may control symptoms but they also have direct anti-tumour effect. The use of higher doses of somatostatin analogues or new subtype selective agonists, and chimeric or pan-somatostatin analogues will probably improve the clinical management of the patients who fail to respond to standard somatostatin analogue treatment. Data show that somatostatin analogues and interferon have a synergistic effect. The currently used chemotherapy in progressive neuroendocrine tumors is mainly devoted to poorly differentiated tumours, but also to well differentiated carcinomas which are either not eligible or resistant to other therapies. However, the new anti-tumoural agents, could eventually replace these old recipes in the near future. Clinical trials show that telozomide with capecitabine result in more favorable toxic profile and higher and longer response rate in the case of well-differentiated tumours. Targeted therapy became a new possibility in neuroendocrine tumours too. The monoclonal antibody bevacizumab, which affects the vascular endothelial growth factor receptors, has beneficial effects both in monotherapies and in combination with somatostatin analogues or with oxaliplatine and capecitabine. Recently, the low molecular multikinase inhibitor, sunitinib has demonstrated efficacy in pancreas neuroendocrine tumors, which was proven in a phase 3 trial. The mammalian target of the rapamycin inhibitor everolimus, currently investigated in phase 3 trials, was also efficient in the same subtype. Further trials are needed to determine that in the case of other types of neuroendocrine tumours which targeted therapy could be efficient. Radioisotope-labeled peptide receptor therapy with ¹³¹I-MIBG, 9°Y-DOTA-TOC or ¹77Lu-DOTA-TOC may offer a highly effective option for patients with progressive and advanced stage of neuroendocrine tumours. The purpose of this review is to review and analyze data available regarding contemporary chemotherapeutic management of neuroendocrine tumours in order to determine which therapy should be applied in the therapeutic arsenal.

Effect of perinatal and postnatal bisphenol A exposure to the regulatory circuits at the hypothalamus-pituitary-gonadal axis of CD-1 mice.

Bisphenol A (BPA) is used in the manufacture of many products and is ubiquitous in the environment. Adverse effects of BPA on animal reproductive health have been reported, however most of the studies relied on the approaches in the assessment of conventional histology and anatomical features. The mechanistic actions of BPA are not clear. In the present study, a murine model was used to study potential effects of BPA exposure during perinatal and postnatal periods on endocrine functions of hypothalamic-pituitary-gonadal (HPG)-axis. At the hypothalamic-pituitary level, BPA exposure resulted in the up-regulation of the expression levels of KiSS-1, GnRH and FSH mRNA in both male and female pups. At the gonadal levels, BPA caused inhibition in the expressions of testicular steroidogenic enzymes and the synthesis of testosterone in the male pups. Conversely exposure to BPA resulted in a greater aromatase expression level and the synthesis of estrogen in the female pups. BPA is a weak estrogen agonist and its effects reported on animal studies are difficult to reconcile with mechanistic action of estrogen. In this study we hypothesized that the effects of BPA on reproductive dysfunction may be due to its actions on gonadal steroidogenesis and so the anomalous releases of endogenous steroid hormones. This non-ER-mediated effect is more potent in affecting the feedback regulatory circuits in the HPG-axis.