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The ureic-based herbicide linuron and the model anti-androgen flutamide regulate common gene networks in the fathead minnow (Pimephales promelas) ovary

ABSTRACT: The herbicide linuron is an endocrine disruptor with a suspected anti-androgenic mode of action (MOA) but the complete MOA for LIN is not fully characterized. The objectives of this study were to better characterize the MOA of LIN in the fathead minnow (FHMs) ovary by comparing expression profiles of LIN to dihydrotestosterone (DHT) and flutamide (FLUT), both model compounds with well defined androgenic and anti-androgenic MOAs respectively. Ovarian explants from vitellogenic FHMs were exposed to 10-6 M, 10-7 M, and 10-8 M of DHT, FLUT, and LIN in vitro in a12 hour incubation experiment. Ovary explants exposed to DHT showed a significant increase in E2 production compared to controls but FLUT and LIN did not affect E2 production. Microarray analysis and support vector machine classification revealed that expression patterns of FLUT and LIN in the ovary were more similar to each other compared to DHT and other androgens. Gene set enrichment analysis identified the notch signaling cascade was affected by all three chemicals. DHT down-regulated the WNT-Frizzled pathway while LIN down-regulated angiopoietin receptor signaling and increased biosynthesis of cholesterol. LIN shared 27 expression sub-networks (e.g. beta-3 adrenergic receptor, MAP3K1, interleukin, signlaing) in common with FLUT, and only 4 sub-networks with DHT. A reciprocal gene expression network was constructed using DHT and FLUT data, and the network revealed that steroid metabolism, translation, and DNA replication are potentially regulated through AR signaling. This study characterizes cell pathways associated with E2 production and identifies cell signaling cascades that may be disrupted by ureic-based herbicides in the ovary.

ORGANISM(S): Pimephales promelas

PROVIDER: GSE38287 | GEO | 2012/07/02

SECONDARY ACCESSION(S): PRJNA167621

REPOSITORIES: GEO

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Project description:This a model from the article: Mathematical model for the androgenic regulation of the prostate in intact and castrated adult male rats. Potter LK, Zager MG, Barton HA. Am J Physiol Endocrinol Metab. 2006:91(5):E952-64. 16757547 , Abstract: The testicular-hypothalamic-pituitary axis regulates male reproductive system functions. Understanding these regulatory mechanisms is important for assessing the reproductive effects of environmental and pharmaceutical androgenic and antiandrogenic compounds. A mathematical model for the dynamics of androgenic synthesis, transport, metabolism, and regulation of the adult rodent ventral prostate was developed on the basis of a model by Barton and Anderson (1997). The model describes the systemic and local kinetics of testosterone (T), 5alpha-dihydrotestosterone (DHT), and luteinizing hormone (LH), with metabolism of T to DHT by 5alpha-reductase in liver and prostate. Also included are feedback loops for the positive regulation of T synthesis by LH and negative regulation of LH by T and DHT. The model simulates maintenance of the prostate as a function of hormone concentrations and androgen receptor (AR)-mediated signal transduction. The regulatory processes involved in prostate size and function include cell proliferation, apoptosis, fluid production, and 5alpha-reductase activity. Each process is controlled through the occupancy of a representative gene by androgen-AR dimers. The model simulates prostate dynamics for intact, castrated, and intravenous T-injected rats. After calibration, the model accurately captures the castration-induced regression of the prostate compared with experimental data that show that the prostate regresses to approximately 17 and 5% of its intact weight at 14 and 30 days postcastration, respectively. The model also accurately predicts serum T and AR levels following castration compared with data. This model provides a framework for quantifying the kinetics and effects of environmental and pharmaceutical endocrine active compounds on the prostate. This model was taken from the CellML repository and automatically converted to SBML. The original model was: Potter, Zager, Barton (2006) - version03 The original CellML model was created by: Lloyd, Catherine, May c.lloyd@auckland.ac.nz The University of Auckland Auckland Bioengineering Institute This model originates from BioModels Database: A Database of Annotated Published Models (http://www.ebi.ac.uk/biomodels/). It is copyright (c) 2005-2011 The BioModels.net Team. To the extent possible under law, all copyright and related or neighbouring rights to this encoded model have been dedicated to the public domain worldwide. Please refer to CC0 Public Domain Dedication for more information. In summary, you are entitled to use this encoded model in absolutely any manner you deem suitable, verbatim, or with modification, alone or embedded it in a larger context, redistribute it, commercially or not, in a restricted way or not.. To cite BioModels Database, please use: Li C, Donizelli M, Rodriguez N, Dharuri H, Endler L, Chelliah V, Li L, He E, Henry A, Stefan MI, Snoep JL, Hucka M, Le Novère N, Laibe C (2010) BioModels Database: An enhanced, curated and annotated resource for published quantitative kinetic models. BMC Syst Biol., 4:92.

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The ureic-based herbicide linuron and the model anti-androgen flutamide regulate common gene networks in the fathead minnow (Pimephales promelas) ovary

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