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Dietary Intake of 17α-Ethinylestradiol Promotes HCC Progression in Humanized Male Mice Expressing Sex Hormone-Binding Globulin.

ABSTRACT: Hepatocellular carcinoma (HCC) is a male-oriented malignancy; its progression is affected by sex hormones. 17α-ethinylestradiol (EE2) is a synthetic estrogen widely used as an oral contraceptive; however, it is unknown whether EE2 regulates sex hormone action in HCC. We investigated whether EE2 influences HCC risk in male androgenic environments, using mice expressing human sex hormone-binding globulin (SHBG). Two-week-old male mice were injected with diethyl-nitrosamine (DEN, 25 mg/kg) and fed an EE2 diet for 10 weeks from 30 weeks of age. Development and characteristics of liver cancer were evaluated in 40-week-old mice via molecular and histological analyses. Although EE2 did not increase HCC progression in wild-type mice, SHBG mice exhibited remarkably higher HCC risk when fed EE2. The livers of EE2-treated SHBG mice exhibited substantially increased pro-inflammatory necrosis with high plasma levels of ALT and HMGB1, and intrahepatic injury and fibers. Additionally, increased androgen response and androgen-mediated proliferation in the livers of EE2-treated SHBG mice and EE2-exposed hepatocytes under SHBG conditions were observed. As a competitor of SHBG-androgen binding, EE2 could bind with SHBG and increase the bioavailability of androgen. Our results revealed that EE2 is a novel risk factor in androgen-dominant men, predisposing them to HCC risk.

SUBMITTER: Lee SR

PROVIDER: S-EPMC8620028 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:The objective of this study was to gain mechanistic insight into how mummichog are able to produce eggs during exposures to high levels of EE2. Mummichog were exposed to 0, 50 or 250 ng/L of EE2 for 14 d. A mummichog microarray was used to identify genomic responses associated with high EE2 exposure, and effects of EE2 on target genes involved in lipid mobilization and transport and steroidogenesis, two important (EE2 regulated) pathways involved in egg production, were measured using real-time PCR. In addition, changes at higher level biological endpoints such as plasma steroid production and gonad morphology were measured to examine downstream responses to EE2. There were no differences in gonadosomatic index, liversomatic index, gonad development, or plasma estradiol levels after exposure to EE2, although testosterone decreased with EE2 exposures. Similar to other species, mummichog showed alterations to plasma steroid levels, and similar processes at the molecular level were identified as being altered by EE2, including cell processes associated with lipids. However, unlike other species, mummichog showed no differences in GSI or ovarian development. Fatty acids were affected at both the transcript and translation level, which suggests they are a major target of estrogens. Lipids are important for both growth and reproduction, and provide oocytes with nutrients. Interestingly, mummichog showed no effect on apolipoprotein expression, which is important in lipid transport. Therefore, it is hypothesized that mummichog are normally able to transport lipids for energy and nutrients to the ovary, while this is affected in other species. Novel gene regulatory networks for protein modification targets were also constructed to learn more about the potential roles of estrogens in the teleost liver. Although post-translational modifications (PTMs) are important regulatory mechanisms, the roles of PTMs in protein regulation in fish and the susceptibility of PTMs to aquatic pollutants are largely unexplored and may offer novel insight into mechanisms of endocrine disruption.

Dataset Information

Dietary Intake of 17α-Ethinylestradiol Promotes HCC Progression in Humanized Male Mice Expressing Sex Hormone-Binding Globulin.

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