Diethylstilbestrol decreased adrenal cholesterol and corticosterone in rats

Abstract

The synthetic oestrogen diethylstilbestrol (DES), which is known to bind oestrogen receptors (ERs), has been reported to have adverse effects on endocrine homeostasis; however, the molecular mechanisms underlying these effects are poorly understood. In this study, we treated rats with DES and found high levels of this compound in the liver, adrenal glands and pituitary gland, as compared with other tissues. We have also detected early adverse effects of DES in the adrenal glands. The adrenal glands of rats treated with DES (340 mg/kg body weight every 2 days) for 2 weeks showed increased weight and size and a decreased fat droplet size. Following 1 week of treatment with DES, the blood and adrenal corticosterone levels were substantially decreased without any histological alterations. The levels of the precursors for corticosteroid biosynthesis in the adrenal glands were also decreased, as determined using mass spectroscopy. Cholesterol, the principal material of corticosteroid biosynthesis, decreased substantially in the adrenal glands after only 1 week of treatment with DES. In conclusion, cholesterol insufficiency results in a reduction in adrenal corticosterone biosynthesis, which may lead to endocrine dysfunction, such as reproductive toxicity.

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.…”

“…insufficient supply of HDL cholesterol to the adrenal glands [14]. This insufficient supply of HDL cholesterol is caused by a reduction in Apo E secretion from the liver [15].…”

“…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].…”

Rapid prolactin induction in adult male rats after treatment with diethylstilbestrol

“…We previously reported that several important testicular proteins are oxidatively modified after 2 weeks of treatment with 0.1 mg 2 d ‐1 DES to rats and that DES also causes a decrease in the expression of cytochrome P450scc, an enzyme essential for testicular steroidogenesis, 1 week after treatment . We have recently identified new adrenal toxicities, by which cholesterol, the principal material of corticosteroid biosynthesis, drastically decreased in the adrenal glands after 1 week of treatment with 0.1 mg 2 d ‐1 DES in adult male rats, and that the decrease in adrenal cholesterol resulted in a reduction of adrenal corticosterone biosynthesis, which might lead to endocrine disruption in other organs . 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 .…”

“…30 We have recently identified new adrenal toxicities, by which cholesterol, the principal material of corticosteroid biosynthesis, drastically decreased in the adrenal glands after 1 week of treatment with 0.1 mg 2 d -1 DES in adult male rats, and that the decrease in adrenal cholesterol resulted in a reduction of adrenal corticosterone biosynthesis, which might lead to endocrine disruption in other organs. 31 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. 32 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 31 and DES also disrupts adrenal steroidogenesis by decreasing apolipoprotein E secretion from the liver.…”