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

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.

Rapid prolactin induction in adult male rats after treatment with diethylstilbestrol

“…Cholesterol, which is utilised for adrenal steroidogenesis, is primarily obtained via SR‐BI (high‐density lipoprotein receptor)‐mediated uptake from serum high‐density lipoprotein cholesterol in rodents . The mechanism by which adrenal cholesterol is reduced after DES treatment remains unclear; however, adrenal steroidogenesis was also disrupted 1 week after treatment because of a reduced supply of cholesterol and DES also disrupts adrenal steroidogenesis by decreasing apolipoprotein E secretion from the liver . The present study aimed to determine the initial effects of DES on the pituitary gland, which is an endocrine gland that regulates the development and function of other endocrine glands.…”

Suppression of liver Apo E secretion leads to HDL/cholesterol immaturity in rats administered ethinylestradiol

“…In previous reports, the adverse effects by DES were caused by direct damage to the reproductive and endocrine systems 22, 23. Recently, we found the indirect adverse effects of DES on the adrenal steroidogenesis via liver dysfunction 14, 15. In this study, we newly found that another synthetic estrogen, EE, also had the same adverse effects as DES.…”

“…The protein band corresponding to approximately 34 kDa was absent in the sera from the rats administered DES . The protein was identified as Apolipoprotein E (Apo E) by MALDI ‐ TOF MS analysis method, as described previously 15. Figure reproduced from Ref.…”

“…The surgical procedures and the liver perfusion were performed as previously described [15]. The livers of the control and EE-exposed rats were isolated and liver perfusion was performed with 300 mL perfusate as previously described [15]. The perfusate was consisted of Krebs-Henseleit buffer (95%), FBS (5%), glucose (10 mM), and HEPES (10 mM).…”

“…Our laboratory recently identified the indirect adverse effects of diethylstilbestrol (DES) on adrenal steroidogenesis [14]. We showed that DES caused a decrease in serum high-density lipoprotein (HDL) cholesterol, the main source of adrenal steroidogenesis, due to the inhibition of apolipoprotein E (Apo E) secretion from the liver [15]. This is the first report about indirect adverse effects on the target organs of endocrine disruptors.…”