Effects of ethanol or ethylene glycol exposure on PPARγ and aromatase expression in adipose tissue

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The estrogen-synthesizing enzyme aromatase is expressed in adipose tissue where it controls the local concentration of estrogen. It has been suggested that the organic solvents ethanol and ethylene glycol can induce estrogen synthesis by inhibiting PPARγ activity. Since elevated estrogen synthesis in adipose tissue is a risk factor for breast cancer development, it is of interest to further characterize the mechanisms regulating aromatase expression. Here, we explored the mechanisms by which ethanol and ethylene glycol modulate aromatase mRNA expression and the ultimate conversion of androgens into estrogens.

NMR spectroscopy revealed that ethanol and ethylene glycol influence the active state of PPARγ. An inhibitory effect on PPARγ was confirmed by adipogenesis assays and PPARγ target gene expression analysis in adipocytes. However, only ethanol increased aromatase mRNA in differentiated human adipocytes. In contrast, ethylene glycol downregulated aromatase in a PPARγ-independent manner. An animal study using female Wistar rats was conducted to assess the acute effects of ethanol and ethylene glycol on aromatase expression in adipose tissue within a physiological context. No changes in aromatase or PPARγ target gene (Adipoq and Fabp4) levels were observed in adipose tissue or ovary in response to the chemical exposures, suggesting an absence of acute PPARγ-mediated effects in these organs.

The results suggest that ethanol and ethylene glycol are weak PPARγ antagonists in mouse and human adipocytes as well as in cell-free NMR spectroscopy. Both compounds seem to affect adipocyte aromatase expression in vitro, where ethanol increased aromatase expression PPARγ-dependently and ethylene glycol decreased aromatase expression independently of PPARγ. No acute effects on aromatase expression or PPARγ activity were observed in adipose tissue or ovary in rats in this study design.
OriginalsprogEngelsk
Artikelnummer101742
TidsskriftBiochemistry and Biophysics Reports
Vol/bind38
Antal sider9
ISSN2405-5808
DOI
StatusUdgivet - 2024

Bibliografisk note

Funding Information:
This work was supported by FFIKA, Focused Research Effort on Chemicals in the Working Environment, from the Danish Government and by the Novo Nordisk Foundation Center for Basic Metabolic Research, an independent research center at the University of Copenhagen partially funded by an unrestricted donation from the Novo Nordisk Foundation. JAS was supported by Idella Foundation, William Demant Foundation, and Christian and Ottilia Brorson Travel Grant. KAB was supported by the National Cancer Institute of the National Institutes of Health grant 1R01CA215797, the Anne Moore Breast Cancer Research Fund, and the Emilie Lippmann and Janice Jacobs McCarthy Research Scholar Award in Breast Cancer. DS was supported by Studienstiftung des Deutschen Volkes. BKK was supported by the Novo Nordisk Foundation Challenge Center REPIN (NNF18OC0033926). NMR data were recorded at cOpenNMR, an infrastructure supported by the Novo Nordisk Foundation (NNF18OC0032996).

Funding Information:
We want to thank the laboratory technicians at the National Food Institute, Heidi Broks\u00F8 Letting, Dorte Lykkegaard Korsbech, and Lillian Sztuk, for assisting with the rat study; Hanna Katarina Lilith Johansson for critically reading the manuscript and suggesting substantial improvements; and Jason A. Spector, Department of Surgery at Weill Cornell Medicine, for facilitating access to reduction mammoplasty tissue. We also acknowledge the personnel in the Bio Facility at DTU Health Tech. Studies were conducted with the support provided by the Center for Translational Pathology at Weill Cornell Medicine. This work was supported by FFIKA, Focused Research Effort on Chemicals in the Working Environment, from the Danish Government and by the Novo Nordisk Foundation Center for Basic Metabolic Research, an independent research center at the University of Copenhagen partially funded by an unrestricted donation from the Novo Nordisk Foundation. JAS was supported by Idella Foundation, William Demant Foundation, and Christian and Ottilia Brorson Travel Grant. KAB was supported by the National Cancer Institute of the National Institutes of Health grant 1R01CA215797, the Anne Moore Breast Cancer Research Fund, and the Emilie Lippmann and Janice Jacobs McCarthy Research Scholar Award in Breast Cancer. DS was supported by Studienstiftung des Deutschen Volkes. BKK was supported by the Novo Nordisk Foundation Challenge Center REPIN (NNF18OC0033926). NMR data were recorded at cOpenNMR, an infrastructure supported by the Novo Nordisk Foundation (NNF18OC0032996).

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© 2024 The Authors

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