Downregulation of cytochrome P450scc as an initial adverse effect of adult exposure to diethylstilbestrol on testicular steroidogenesis

Maeda, Naoyuki; Okumura, Kanako; Tanaka, Eijirou; Suzuki, Tomokazu; Miyasho, Taku; Haeno, Satoko; Hoshi, Nobuhiko; Yokota, Hiroshi

doi:10.1002/tox.21875

Cited by 12 publications

(14 citation statements)

References 32 publications

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“…The mechanism by which adrenal cholesterol is decreased upon DES treatment remains unclear; however, DES was shown to disrupt the cholesterol supply for optimal corticosterone synthesis. The mechanism of DES toxicity in the adrenal glands appears to be distinct from that in the testis, as has been previously reported by us, in which DES influences the proteins associated with steroidogenesis (including P450scc (Maeda et al 2013b)) but does not disrupt cholesterol content of the testis (data not shown). Plasma lipoprotein deficiency in mice as a result of feeding with probucol is associated with decreased adrenal cortex cholesterol levels, a lower basal and stress-induced plasma glucocorticoid level (Hoekstra et al 2010).…”

Section: Figuresupporting

confidence: 55%

“…We found adverse effects on the testicular proteins at the lower dose (0.1 mg/rat every 2 days; Li et al 2011, Maeda et al 2013b. In this study, we found adrenal abnormalities only after 1 week of treatment with DES (0.1 mg/rat every 2 days), and revealed that the endocrine disruptor DES disrupts corticosteroid biosynthesis via cholesterol insufficiency.…”

Section: Discussionmentioning

confidence: 63%

“…6A and B). Recently, we have found that an initial target of DES in testicular steroidogenesis dysfunction is the reduction in the expression and the enzyme activity of P450scc (Maeda et al 2013b). In the case of the adrenal, the mRNA expression level of P450scc tended to increase after a 1-week of treatment with DES (Fig.…”

Section: Rate-limiting Factors In Adrenal Steroidogenesis and Levels mentioning

confidence: 99%

“…Enzymatic activities were assayed as described previously (Maeda et al 2013b) using a 20-hydroxycholesterol as a substrate, and the reaction product, pregnenolone, was identified as shown in Supplementary Fig. 2, see section on supplementary data given at the end of this article, and determined using MS analysis (Maeda et al 2013a).…”

Section: Enzymatic Activity Assay Of Cholesterol Side Chain Cleavage mentioning

confidence: 99%

“…The cell lysate for the detection of LDL receptor (LDLR) and scavenger receptor type B1 (SR-B1) and the mitochondrial fraction for the P450scc were separated via SDS-PAGE and then transferred to PVDF membranes (ATTO, Tokyo, Japan) for western blot analysis. The membranes were probed with the following primary antibodies as described previously (Sakaguchi et al 2013): rabbit polyclonal antibody against rat P450scc (purchased from Millipore Corp. (Billerica, MA, USA), AB1244) as described previously (Maeda et al 2013b), SR-B1 (Sigma-Aldrich), chicken polyclonal antibody against LDLR (Sigma-Aldrich) and rabbit polyclonal antibody against b-actin (Abcam, Cambridge, UK). The expression levels of each protein were analysed densitometrically using CS Analyzer ver 3.0 (ATTO).…”

Section: Western Blot Analysismentioning

confidence: 99%

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Diethylstilbestrol decreased adrenal cholesterol and corticosterone in rats

Haeno

Maeda

Yagi

et al. 2014

Journal of Endocrinology

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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.

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Section: Figuresupporting

confidence: 55%

Section: Discussionmentioning

confidence: 63%

Section: Rate-limiting Factors In Adrenal Steroidogenesis and Levels mentioning

confidence: 99%

Section: Enzymatic Activity Assay Of Cholesterol Side Chain Cleavage mentioning

confidence: 99%

Section: Western Blot Analysismentioning

confidence: 99%

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Diethylstilbestrol decreased adrenal cholesterol and corticosterone in rats

Haeno

Maeda

Yagi

et al. 2014

Journal of Endocrinology

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n‐butylparaben induces male reproductive disorders via regulation of estradiol and estrogen receptors

Zhang

Ding

Qiao

et al. 2016

J of Applied Toxicology

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It is well known that inappropriate exposure to exogenous hormones during fetal or neonatal life, such as testosterone (T) and estradiol (E 2 ), leads to adverse reproductive outcomes. In our previous study, the reproductive dysfunction of male rats was characterized by an E 2 increase and T decrease after in utero and lactation exposures to n-butylparaben (n-BP). In this study, we investigated the synthesis and metabolism pathways of steroid hormones, hormone receptors and the epigenetic modification of male offspring on postnatal day (PND) 21 and PND90 to explore the possible mechanisms of endocrine and reproductive disorders. The expression of steroidogenic acute regulatory protein (StAR), cytochrome cholesterol side-chain cleavage enzyme (P450scc), estrogen sulfotransferase (SULT1E1) and androgen receptor (AR) in the testes was significantly decreased at the transcript and protein levels; in addition, aromatase (CYP19) and estrogen receptor α (ERα) expression was significantly increased and the methylation rate of the ERα promoter was significantly decreased. These results suggest that increased CYP19 expression and decreased SULT1E1 expression are responsible for the E 2 increase. This effect promotes the expression of ERα, which plays a pivotal role in regulating reproductive and endocrine disorders of male rats exposed to n-BP. Furthermore, the epigenetic hypomethylation of ERα is involved in this regulation processes. Our study is the first to report on the possible mechanism of male rat reproductive disorders induced by the xenoestrogenic chemical n-BP.

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Pharmaceuticals and personal care products in waters: occurrence, toxicity, and risk

et al. 2015

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Pharmaceuticals and personal care products (PPCP) are compounds with special physical and chemical properties that address the care of animal and human health. PPCP have been detected in surface water and wastewater in the ng/L to µg/L concentration range worldwide. PPCP ecotoxicity has been studied in a variety of organisms, and multiple methods have been used to assess the risk of PPCP in the environment to ecological health. Here we review the occurrence, effects, and risk assessment of PPCP in aquatic systems, as well as the sustainability of current methods for managing PPCP contamination in aquatic systems. The major points are the following: (1) a number of PPCP present potential concerns at environmentally relevant concentrations. PPCP mixtures may produce synergistic toxicity. (2) Various methods have been used for the ecological risk assessment of PPCP in aquatic systems. There are similarities in these methods, but no consensus has emerged regarding best practices for the ecological risk assessment of these compounds. (3) Human health risk assessments of PPCP contamination in aquatic systems have generally indicated little cause for concern. However, there is a lack of information regarding whether antibiotic contamination in wastewater and aquatic systems could lead to an increase in clinically relevant antibiotic-resistant bacteria and antibiotic-resistant genes. (4) Over the next century, the combination of increasing global population size and potential droughts may result in reduced water availability, increased need for water reuse, and increasing concentrations of PPCP in wastewaters. The current wastewater treatment methods do not remove all PPCP effectively. This, coupled with the possibility that antibiotics may promote the development of antibiotic-resistant bacteria and antibiotic-resistant genes, leads to concerns about the sustainability of global water supplies.

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Downregulation of cytochrome P450scc as an initial adverse effect of adult exposure to diethylstilbestrol on testicular steroidogenesis

Cited by 12 publications

References 32 publications

Diethylstilbestrol decreased adrenal cholesterol and corticosterone in rats

Diethylstilbestrol decreased adrenal cholesterol and corticosterone in rats

n‐butylparaben induces male reproductive disorders via regulation of estradiol and estrogen receptors

Pharmaceuticals and personal care products in waters: occurrence, toxicity, and risk

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