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Steroidogenesis studied in a human adrenocortical cell line

effects of single chemicals and mixtures

Ohlsson, Åsa (2010). Steroidogenesis studied in a human adrenocortical cell line. Diss. (sammanfattning/summary) Uppsala : Sveriges lantbruksuniv., Acta Universitatis agriculturae Sueciae, 1652-6880 ; 2010:47
ISBN 978-91-576-7460-9
[Doctoral thesis]

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Abstract

Steroidogenesis may be a target for endocrine disrupting chemicals; unfortunately data of such effects is limited. The aim of this thesis was to study effects on steroidogenesis of single chemicals and mixtures in the human adrenocarcinoma cell line H295R. Screening for effects on steroid secretion was performed by ELISA. Mechanisms were elucidated by analysing levels of steroid intermediates, gene expression and enzyme activity. Results from 30 tested chemicals showed qualitative and quantitative differences in effect on cortisol and aldosterone secretion; inhibition, stimulation and dissimilar effects on basal vs. induced steroid secretion. Mechanistic studies on the fungicide prochloraz revealed dose-dependent inhibition of cortisol secretion, in contrast to a biphasic effect, with low-dose stimulation and high-dose inhibition, of aldosterone secretion. The specific effects could be explained by inhibition of CYP17A1 and CYP21A2, and by down-regulation of steroidogenic genes. Effects of single chemicals and equimolar mixtures were compared to estimated effects from the concentration addition and independent action prediction models. The imidazole mixture of prochloraz, ketoconazole and imazalil caused additive effects similar to individual imidazole compounds, with inhibition of cortisol and biphasic effects on aldosterone secretion. A modification of the concentration addition model was required to predict the biphasic effect. The flavonoids daidzein, genistein and to a lesser extent apigenin inhibited cortisol, aldosterone and testosterone secretion. The flavonoid mixture inhibited the secretion of all tested steroids, including oestradiol, and in general acted in an additive way. The additive effects of the mixtures emphasize the need to assess chemicals together as a group. We conclude that the H295R cell line is a promising model for both screening of effects on steroidogenesis by single chemicals and mixtures, and for mechanistic analysis. The prediction models are valuable tools for assessment of mixture effects on steroidogenesis.

Authors/Creators:Ohlsson, Åsa
Title:Steroidogenesis studied in a human adrenocortical cell line
Subtitle:effects of single chemicals and mixtures
Year of publishing :2010
Volume:2010:47
Number of Pages:63
Papers/manuscripts:
NumberReferences
ALLI. Ullerås E., Ohlsson Å., Oskarsson A (2008). Secretion of cortisol and aldosterone as a vulnerable target for adrenal endocrine disruption ! screening of 30 selected chemicals in the human H295R cell model. Journal of Applied Toxicology 28(8), 1045-1053. II. Ohlsson Å., Ullerås E., Oskarsson A (2009). A biphasic effect of the fungicide prochloraz on aldosterone, but not cortisol, secretion in human adrenal H295R cells ! underlying mechanisms. Toxicology Letters 191(2- 3), 174-180. III. Ohlsson Å., Cedergreen N., Oskarsson A., Ullerås E (2010). Mixture effects of imidazole fungicides on adrenal cortisol and aldosterone secretion (submitted). IV. Ohlsson Å., Ullerås E., Cedergreen N., Oskarsson A (2010). Mixture effects of dietary flavonoids on steroid hormone synthesis (submitted).
Place of Publication:Uppsala
ISBN for printed version:978-91-576-7460-9
ISSN:1652-6880
Language:English
Publication Type:Doctoral thesis
Full Text Status:Public
Agrovoc terms:adrenal glands, secretion, glucocorticoids, mineralocorticoids, testosterone, oestrogens, chemicals, mathematical models
Keywords:adrenal gland, H295R, steroidogenesis, cortisol, aldosterone, testosterone, oestradiol, mixtures, concentration addition, independent action
URN:NBN:urn:nbn:se:slu:epsilon-3080
Permanent URL:
http://urn.kb.se/resolve?urn=urn:nbn:se:slu:epsilon-3080
ID Code:2306
Department:(VH) > Dept. of Biomedical Sciences and Veterinary Public Health
Deposited By: Åsa Ohlsson
Deposited On:03 Jun 2010 00:00
Metadata Last Modified:02 Dec 2014 10:17

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