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      Endocrine Disrupting Chemicals Interfere With Leydig Cell Hormone Pathways During Testicular Descent in Idiopathic Cryptorchidism

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          Abstract

          Cryptorchidism, a frequent genital malformation in male newborn, remains in most cases idiopathic. On the basis of experimental, epidemiological, and clinical data, it has been included in the testicular dysgenesis syndrome and believed to be influenced, together with genetic and anatomic factors, by maternal exposure to endocrine disrupting chemicals (EDCs). Here, we analyze how EDCs may interfere with the control of testicular descent, which is regulated by two Leydig cell hormones, testosterone, and insulin like peptide 3 (INSL3).

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          Most cited references64

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          Difference in prevalence of congenital cryptorchidism in infants between two Nordic countries.

          Several investigators have shown striking differences in semen quality and testicular cancer rate between Denmark and Finland. Since maldescent of the testis is a shared risk factor for these conditions we undertook a joint prospective study for the prevalence of congenital cryptorchidism. 1068 Danish (1997-2001) and 1494 Finnish boys (1997-99) were consecutively recruited prenatally. We also established prevalence data for all newborns at Turku University Central Hospital, Finland (1997-99, n=5798). Testicular position was assessed by a standardised technique. All subtypes of congenital cryptorchidism were included, but retractile testes were considered normal. Prevalence of cryptorchidism at birth was 9.0% (95% CI 7.3-10.8) in Denmark and 2.4% (1.7-3.3) in Finland. At 3 months of age, prevalence rates were 1.9% (1.2-3.0) and 1.0% (0.5-1.7), respectively. Significant geographic differences were still present after adjustment for confounding factors (birthweight, gestational age, being small for gestational age, maternal age, parity, mode of delivery); odds ratio (Denmark vs Finland) was 4.4 (2.9-6.7, p<0.0001) at birth and 2.2 (1.0-4.5, p=0.039) at three months. The rate in Denmark was significantly higher than that reported 40 years ago. Our findings of increasing and much higher prevalence of congenital cryptorchidism in Denmark than in Finland contribute evidence to the pattern of high frequency of reproductive problems such as testicular cancer and impaired semen quality in Danish men. Although genetic factors could account for the geographic difference, the increase in reproductive health problems in Denmark is more likely explained by environmental factors, including endocrine disrupters and lifestyle.
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            Antiandrogenic effects of bisphenol A and nonylphenol on the function of androgen receptor.

            By using a yeast detection system for androgenic and antiandrogenic effects of chemicals, we identified bisphenol A (BPA) and nonylphenol (NP) as antiandrogens. In this study, we report molecular mechanisms for the antiandrogenic action of BPA and NP. In the ARhLBD-activating signal cointegrator 1 (ASC1) yeast two-hybrid system, which reflects the androgen-dependent interaction between androgen receptor (AR) and its coactivator, ASC1, BPA and NP acted as potent AR antagonists comparable to a known strong antagonist, cyproterone acetate. Ligand competition assays revealed that [3H]5alpha-dihydroxytestosterone (DHT) binding to AR is inhibited a maximum of 30 and 40% at approximately 5 nM of NP and 50 nM of BPA, respectively. In addition, the nuclear translocation of green fluorescent protein (GFP)-AR fusion protein in the presence of testosterone was affected by the addition of BPA and NP, which cause rather dispersed distribution of GFP-AR between the nuclear and the cytoplasmic compartments. Furthermore, in transient transfection assays, BPA and NP inhibited androgen-induced AR transcriptional activity. Taken together, the results suggest that BPA and NP affect multiple steps of the activation and function of AR, thereby inhibiting the binding of native androgens to AR, AR nuclear localization, AR interaction with its coregulator, and its subsequent transactivation. These data may help us better understand the biological alterations induced by these environmental compounds.
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              Cryptorchidism in mice mutant for Insl3.

              L Parada, S Nef (1999)
              Impaired testicular descent (cryptorchidism) is one of the most frequent congenital abnormalities in humans, involving 2% of male births. Cryptorchidism can result in infertility and increases risk for development of germ-cell tumours. Testicular descent from abdomen to scrotum occurs in two distinct phases: the trans-abdominal phase and the inguino-scrotal phase. Currently, little is known about the factors that regulate the trans-abdominal phase of testicular descent. Leydig insulin-like hormone (Insl3) is a member of the insulin hormone superfamily expressed in the developing testis. We show here that mice mutant for Insl3 are viable, but exhibit bilateral cryptorchidism due to developmental abnormalities of the gubernaculum, resulting in abnormal spermatogenesis and infertility. Female homozygotes have impaired fertility associated with deregulation of the oestrus cycle. These findings reveal roles for Insl3 in the development of the urogenital tract and in female fertility. Insl3 may act as a hormone to regulate the growth and differentiation of the gubernaculum, thereby mediating intra-abdominal testicular descent.
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                Author and article information

                Contributors
                Journal
                Front Endocrinol (Lausanne)
                Front Endocrinol (Lausanne)
                Front. Endocrinol.
                Frontiers in Endocrinology
                Frontiers Media S.A.
                1664-2392
                10 January 2019
                2018
                : 9
                : 786
                Affiliations
                [1] 1Department of Reproductive Endocrinology, University Hospital of Nice , Nice, France
                [2] 2Institut National de la Recherche Médicale, UMR U1065, Université Nice-Sophia Antipolis , Nice, France
                [3] 3Department of Hormonology and Metabolic Disorders, Hôpital Cochin, APHP, Paris-Descartes University , Paris, France
                [4] 4Institut Sophia-Agrobiotech (INRA-CNRS, Nice University) , Nice, France
                [5] 5Pediatric Endocrinology, Department of Pediatrics, CHU Lenval , Nice, France
                [6] 6Institut National de la Recherche Médicale, U1060 CaRMen, Fédération d'Endocrinologie, Hospices Civils de Lyon-1 , Bron, France
                [7] 7Department of Biochemistry, University Hospital of Nice , Nice, France
                Author notes

                Edited by: Ren-Shan Ge, Wenzhou Medical University, China

                Reviewed by: Ellis Fok, The Chinese University of Hong Kong, China; Richard Ivell, University of Nottingham, United Kingdom

                *Correspondence: Patrick Fénichel Fenichel.p@ 123456chu-nice.fr

                This article was submitted to Reproduction, a section of the journal Frontiers in Endocrinology

                Article
                10.3389/fendo.2018.00786
                6335363
                2a965255-93cb-4281-a944-8f507d078b2a
                Copyright © 2019 Fénichel, Chevalier, Lahlou, Coquillard, Wagner-Mahler, Pugeat, Panaïa-Ferrari and Brucker-Davis.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                : 03 May 2018
                : 13 December 2018
                Page count
                Figures: 2, Tables: 0, Equations: 0, References: 71, Pages: 8, Words: 6424
                Categories
                Endocrinology
                Mini Review

                Endocrinology & Diabetes
                cryptorchidism,endocrine disrupting chemicals,testosterone,insulin like peptide 3,leydig cells

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