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Adrenal steroidogenesis disruption caused by HDL/cholesterol suppression in diethylstilbestrol-treated adult male rat

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Abstract

The synthetic estrogen diethylstilbestrol is used to prevent miscarriages and as a therapeutic treatment for prostate cancer, but it has been reported to have adverse effects on endocrine homeostasis. However, the toxicity mechanism is poorly understood. Recently, we reported that diethylstilbestrol impairs adrenal steroidogenesis via cholesterol insufficiency in adult male rats. In the present study, we found that the adrenal cholesterol level was significantly reduced without of the decrease in other precursors in the adrenal steroidogenesis 24 h after a single dose of diethylstilbestrol (0.33 μg/g body mass). The serum HDL/cholesterol level was also reduced only 12 h after the diethylstilbestrol exposure. The level of Apo E, which is indispensable for HDL/cholesterol maturation, was decreased in both the HDL and VLDL/LDL fractions, whereas the level of Apo A1, which is an essential constituent of HDL, was not altered in the HDL fraction. Because the liver is a major source of Apo E and Apo A1, the secretion rates of these proteins were examined using a liver perfusion experiment. The secretion rate of Apo A1 from the liver was consistent between DES-treated and control rats, but that of Apo E was comparatively suppressed in the DES-treated rats. The disruption of adrenal steroidogenesis by diethylstilbestrol was caused by a decrease in serum HDL/cholesterol, which is the main source of adrenal steroidogenesis, due to the inhibition of Apo E secretion from the liver.

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Abbreviations

HDL:

High-density lipoprotein

LDL:

Low-density lipoprotein

VLDL:

Very low-density lipoprotein

DES:

Diethylstilbestrol

Apo E:

Apolipoprotein E

Apo A1:

Apolipoprotein A1

StAR:

Acute regulatory protein

ER:

Estrogen receptor

SR-B1:

Scavenger receptor class B type 1

MALDI-TOF MS:

Matrix-assisted laser desorption ionization-time-of-flight mass spectrometry

LC–MS:

Liquid chromatography–mass spectrometry

CHAPS:

3-((3-cholamidopropyl)dimethylammonium)-1-propanesulfonate

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Acknowledgments

The authors are grateful to Mr. Michio Sasaki of Japan Meat Science and Technology Institute for his suggestions and helpful advice. This work was supported in part by the Supported Program for the Strategic Research Foundation at Private Universities (2013–2017) of the Ministry of Education, Culture, Science and Technology, Japan.

Author Contributions

Conceived and designed the experiments: SH and HY. Performed the experiments: SH, NM, KY, MS and AU. Analyzed the data: SH, NM and HY. Contributed reagents/materials/analysis tools: SH, NM, KY, MS, AU and HY. Wrote the paper: SH and HY.

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Authors and Affiliations

  1. Laboratory of Veterinary Biochemistry, School of Veterinary Medicine, Rakuno Gakuen University, Ebetsu, Hokkaido, 069-8501, Japan

    Satoko Haeno, Naoyuki Maeda, Kousuke Yamaguchi, Michiko Sato, Aika Uto & Hiroshi Yokota

  2. Safety Research Institute for Chemical Compounds Co. LTD, Shin-ei, Kiyota-ku, Sapporo, Hokkaido, 004-0839, Japan

    Naoyuki Maeda

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  1. Satoko Haeno
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Correspondence to Hiroshi Yokota.

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Conflict of Interest

Author H. Yokota has received research grant from a Grant-in-aid and Support Project to Assist Private Universities in Developing Bases for Research from the Ministry of Education, Science, Sports and Culture and Technology in Japan.

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12020_2015_732_MOESM1_ESM.eps

Supplementary material 1 Fig. 1 Illustrated procedure of liver perfusion. Rats were orally administered DES (0.33 µg/g of body mass), and livers were prepared as described in the Materials and Methods. Oxygenated Krebs–Ringer buffer was perfused into the liver via the portal vein as described in the Materials and Methods. The resultant perfusate (100 μl) was sampled at each time point. The amount of Apo A1 and Apo E secreted from the liver into the perfusate was assayed by western blotting analysis using each antibody. (EPS 1342 kb)

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Haeno, S., Maeda, N., Yamaguchi, K. et al. Adrenal steroidogenesis disruption caused by HDL/cholesterol suppression in diethylstilbestrol-treated adult male rat. Endocrine 52, 148–156 (2016). https://doi.org/10.1007/s12020-015-0732-5

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  • DOI: https://doi.org/10.1007/s12020-015-0732-5

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