Title
Mechanistic profiling of the cAMP-dependent steroidogenic pathway in the H295R endocrine disrupter screening system : new endpoints for toxicity testing Mechanistic profiling of the cAMP-dependent steroidogenic pathway in the H295R endocrine disrupter screening system : new endpoints for toxicity testing
Author
Faculty/Department
Faculty of Sciences. Biology
Publication type
article
Publication
Amsterdam ,
Subject
Biology
Pharmacology. Therapy
Source (journal)
Toxicology letters. - Amsterdam
Volume/pages
208(2012) :2 , p. 174-184
ISSN
0378-4274
ISI
000300272600010
Carrier
E
Target language
English (eng)
Full text (Publishers DOI)
Affiliation
University of Antwerp
Abstract
The need for implementation of effects on steroid synthesis and hormone processing in screening batteries of endocrine disruptive compounds is widely acknowledged. In this perspective, hormone profiling in the H295R adrenocortical cell system is extensively examined and recently OECD validated (TG 456) as a replacement of the minced testis assay. To further elucidate the complete mechanisms and endocrine responsiveness of this cell system, microarray-based gene expression profiling of the cAMP response pathway, one of the major pathways in steroidogenesis regulation, was examined in H295R cells. Next to the steroid synthesis pathway, a broader lipid metabolic pathway, including cholesterol uptake/biosynthesis, hormone metabolization and many hormone and nuclear receptors, are sensitive towards cAMP stimulation in this cell system. Moreover, these pathways were clearly dose and time responsive, indicating early regulation (10 h) of cholesterol uptake and mobilization genes and later expression (2448 h) of cholesterol biosynthesis and steroid synthesis. Transcription network analysis suggested several important transcription factors that could be involved in regulation of the steroid hormone pathway, of which HNF4α, a broader lipid metabolism related transcription factor, might indicate some new transcription regulation patterns in this cell line. Overall we can conclude that the time dependent gene expression patterns of the strongly coordinated cholesterol supply and steroidogenesis pathways in the H295R cell system seem to reflect well the in vivo ACTH/cAMP signalling cascade in adrenal cells. Moreover, the completeness of the steroidogenic related pathways in terms of gene expression sensitivity, indicates the H295R cell line as a promising cell line in omics-based endocrine disruption screening.
E-info
https://repository.uantwerpen.be/docman/iruaauth/cd6277/eb6f2b0a20f.pdf
http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcApp=PARTNER_APP&SrcAuth=LinksAMR&KeyUT=WOS:000300272600010&DestLinkType=RelatedRecords&DestApp=ALL_WOS&UsrCustomerID=ef845e08c439e550330acc77c7d2d848
http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcApp=PARTNER_APP&SrcAuth=LinksAMR&KeyUT=WOS:000300272600010&DestLinkType=FullRecord&DestApp=ALL_WOS&UsrCustomerID=ef845e08c439e550330acc77c7d2d848
http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcApp=PARTNER_APP&SrcAuth=LinksAMR&KeyUT=WOS:000300272600010&DestLinkType=CitingArticles&DestApp=ALL_WOS&UsrCustomerID=ef845e08c439e550330acc77c7d2d848
Handle