Testosterone Exacerbates the Formation of Liver Cancer Induced by Environmental N-Nitrosamines Exposure: Potential Mechanisms and Implications for Human Health

Abstract

Background

Humans are frequently exposed to N-nitrosamines through various sources, including diet, cigarette smoking, contaminated water, the atmosphere, and endogenous nitrosation. Exposure to these carcinogens may also contribute to the gender-specific incidence of liver cancer, which is significantly higher in males than in females, possibly due to the influence of endogenous hormones such as testosterone. However, the effect of testosterone on N-nitrosamine-induced liver cancer and its underlying mechanism remains unclear.

Purpose

To investigate the effect of testosterone on the development of liver cancer induced by N-nitrosamines exposure.

Patients and Methods

Histopathological and immunohistochemical staining techniques were employed to analyze the expression levels and nuclear localizations of key signaling molecules, including androgen receptor (AR), β-catenin, and HMGB1, in both tumor and non-tumor regions of liver samples obtained from human patients and mice.

Results

The findings demonstrated a strong correlation between AR and β-catenin in the nuclear region of tumor areas. AR also showed a significant correlation with HMGB1 in the cytoplasmic region of non-tumor areas in both human and mice samples. The study further analyzed the expression levels and patterns of these three proteins during the progression of liver tumors.

Conclusion

This study confirms that AR has the ability to modulate the expression levels and patterns of β-catenin and HMGB1 in vivo, thereby exacerbating the progression of liver cancer induced by environmental N-nitrosamines exposure. Importantly, the effect of testosterone on the formation of liver cancer induced by environmental N-nitrosamine exposure intensifies this progression. These findings have important implications for drug safety in clinical practice and emphasize the significance of reducing N-nitrosamines exposure through conscious choices regarding diet and lifestyle to ensure environmental safety.

Keywords:

• N-nitrosamines
• testosterone
• exposure
• hepatic carcinoma
• androgen receptor

Data Sharing Statement

The data used to support the findings of this study are available from the corresponding author upon request.

Institutional Review Board Statement

All animal experiments were approved by the Ethics Committee of the South-Central University for Nationalities for the use of animals and conducted in accordance with the National Institutes of Health Laboratory Animal Care and Use Guidelines.All research on mice was approved by the Animal Experiment Ethics Committee of the South-Central University for Nationalities, Wuhan, China (permit number: 2019-SCUEC-AEC-013).

Acknowledgments

We would like to thank the specialists and the staff members for involved in the research for their valuable advice.

Disclosure

The authors report no conflicts of interest in this work.

Additional information

Funding

This work was funded by the National Natural Science Foundation of China (82174110, 81673711, 81573887) and by the Health Research Foundation of Wuhan Municipal Health Commission, China (WZ19A16).