Citation:

Rooney, J., N. Ryan, B. Chorley, S. Hester, E. Kenyon, Judy Schmid, BJ George, M. Hughes, Y. Sey, A. Tennant, D. MacMillan, J. Simmons, C. McQueen, A. Pandiri, C. Wood, AND C. Corton. Genomic effects of androstenedione and sex-specific liver cancer susceptibility in mice. TOXICOLOGICAL SCIENCES. Society of Toxicology, RESTON, VA, 160(1):15–29, (2017).

Impact/Purpose:

Pathway information organized by mode of action (MOA) has played a central role in the assessment of chemical carcinogens for over a decade (Boobis et al., 2006, EPA 2005). In practice, however, use of the MOA framework has been largely retrospective, following identification of a cancer signal in long-term carcinogenicity or epidemiologic studies. Moving forward, a central challenge of toxicological science is to identify shorter-term biomarkers that can be used to predict potential health hazards and inform risk assessment in the absence of traditional toxicity data. This type of approach relies strongly on the mapping of early chemical effects to key events in known biological constructs, called adverse outcome pathways (AOPs) (Villenueve et al., 2014a; Villenueve et al., 2014b), which are intended to integrate newer types of mechanistic information into chemical safety and facilitate the transition toward more prospective molecular endpoints. In the current case study, we examined early markers of steroid effects in the liver mediated by androgen, estrogen, and glucocorticoid receptors. Our evaluation of A4 induced effects indicated that in contrast to the great majority of chemical hepatocarcinogens, A4 exhibited little if any effects on a number of histopathological and genomic effects. These findings show that A4 induces liver cancer by a unique mode of action that is not shared with typical nongenotoxic carcinogens that often act as direct or indirect mitogens. Our study highlights gaps in our understanding of how androgenic chemicals cause liver cancer. The work presented in this manuscript contributes to the RAP product “A portfolio of case studies that highlight novel strategies for developing adverse outcome pathways for cancer, liver disease, and other health outcomes based on early key events.” in the CSS project 17.01.01. Information from this product should be useful to OCSPP and other program offices as part of ongoing efforts to evaluate the health risks of chemicals that cause liver cancer in rodents.

Description:

Current strategies for predicting carcinogenic mode of action for nongenotoxic chemicals are based on identification of early key events in toxicity pathways. The goal of this study was to evaluate short-term key event indicators resulting from exposure to androstenedione (A4), an androgen receptor agonist and known liver carcinogen in mice. Liver cancer is more prevalent in men compared with women, but androgen-related pathways underlying this sex difference have not been clearly identified. Short-term hepatic effects of A4 were compared with reference agonists of the estrogen receptor (ethinyl estradiol, EE) and glucocorticoid receptor (prednisone, PRED). Male B6C3F1 mice were exposed for 7 or 28 days to A4, EE, or PRED. EE increased and PRED suppressed hepatocyte proliferation, while A4 had no detectable effects. In a microarray analysis, EE and PRED altered >3000 and >670 genes, respectively, in a dose-dependent manner, whereas A4 did not significantly alter any genes. Gene expression was subsequently examined in archival liver samples from male and female B6C3F1 mice exposed to A4 for 90 days. A4 altered more genes in females than males and did not alter expression of genes linked to activation of the mitogenic xenobiotic receptors AhR, CAR, and PPARα in either sex. A gene expression biomarker was used to show that in female mice, the high dose of A4 activated the growth hormone-regulated transcription factor STAT5b, which controls sexually dimorphic gene expression in the liver. These findings suggest that A4 induces subtle age-related effects on STAT5b signaling that may contribute to the higher risk of liver cancer in males compared with females.

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