Microcystins and Microcystis aeruginosa PCC7806 extracts modulate steroidogenesis differentially in the human H295R adrenal model

Vittoria Mallia; Steven Verhaegen; Bjarne Styrishave; Gunnar Sundstøl Eriksen; Malene Louise Johannsen; Erik Ropstad; Silvio Uhlig

doi:10.1371/journal.pone.0244000

Microcystins and Microcystis aeruginosa PCC7806 extracts modulate steroidogenesis differentially in the human H295R adrenal model

PLoS One. 2020 Dec 15;15(12):e0244000. doi: 10.1371/journal.pone.0244000. eCollection 2020.

Authors

Vittoria Mallia^{1

2}, Steven Verhaegen³, Bjarne Styrishave⁴, Gunnar Sundstøl Eriksen¹, Malene Louise Johannsen⁴, Erik Ropstad³, Silvio Uhlig¹

Affiliations

¹ Toxinology Research Group, Norwegian Veterinary Institute, Oslo, Norway.
² Department of Chemistry, University of Oslo, Oslo, Norway.
³ Faculty of Veterinary Medicine, Department of Production Animal Clinical Sciences, Norwegian University of Life Sciences, Oslo, Norway.
⁴ Faculty of Health and Medical Sciences, Toxicology and Drug Metabolism Group, Department of Pharmacy, University of Copenhagen, Copenhagen, Denmark.

Abstract

The aim of this study was to investigate the potential interference of cyanobacterial metabolites, in particular microcystins (MCs), with steroid hormone biosynthesis. Steroid hormones control many fundamental processes in an organism, thus alteration of their tissue concentrations may affect normal homeostasis. We used liquid chromatography-tandem mass spectrometry (LC-MS/MS) to investigate the modulation of 14 hormones involved in the adrenal steroid biosynthesis pathway using forskolin-treated H295R cells, following exposure with either microcystin-LR (MC-LR) alone, a mixture made up of MC-LR together with eight other MCs and nodularin-R (NOD-R), or extracts from the MC-LR-producing Microcystis aeruginosa PCC7806 strain or its MC-deficient mutant PCC7806mcyB-. Production of 17-hydroxypregnenolone and dehydroepiandrosterone (DHEA) was increased in the presence of MC-LR in a dose-dependent manner, indicating an inhibitory effect on 3β-hydroxysteroid dehydrogenase (3β-HSD). This effect was not observed following exposure with a MCs/NOD-R mixture, and thus the effect of MC-LR on 3β-HSD appears to be stronger than for other congeners. Exposure to extracts from both M. aeruginosa PCC7806 and M. aeruginosa PCC7806mcyB- had an opposite effect on 3β-HSD, i.e. concentrations of pregnenolone, 17-hydroxypregnenolone and DHEA were significantly decreased, showing that there are other cyanobacterial metabolites that outcompete the effect of MC-LR, and possibly result instead in net-induction. Another finding was a possible concentration-dependent inhibition of CYP21A2 or CYP11β1, which catalyse oxidation reactions leading to cortisol and cortisone, by MC-LR and the MCs/NOD-R mixture. However, both M. aeruginosa PCC7806 and M. aeruginosa PCC7806mcyB- extracts had an opposite effect resulting in a substantial increase in cortisol levels. Our results suggest that MCs can modulate steroidogenesis, but the net effect of the M. aeruginosa metabolome on steroidogenesis is different from that of pure MC-LR and independent of MC production.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

17-alpha-Hydroxypregnenolone / metabolism*
3-Hydroxysteroid Dehydrogenases / antagonists & inhibitors*
Cell Line, Tumor
Cytochrome P450 Family 11 / antagonists & inhibitors
Cytochrome P450 Family 21 / antagonists & inhibitors
Dehydroepiandrosterone / biosynthesis*
Enzyme Inhibitors / pharmacology*
Humans
Microcystins / pharmacology*
Microcystis / chemistry*

Substances

Enzyme Inhibitors
Microcystins
17-alpha-Hydroxypregnenolone
Dehydroepiandrosterone
3-Hydroxysteroid Dehydrogenases
Cytochrome P450 Family 21
Cytochrome P450 Family 11

Grants and funding

This project has received funding from the European Union’s Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie grant agreement No. 722634.