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A systematic review of the carcinogenicity of rats and mice by sex due to exposure to phenyl compounds

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Abstract

Objectives

Differences in cancer incidence between men and women are often explained by differences in environmental exposure, or the influence of sex hormones. However, there is little research on the intrinsic differences in sensitivity to chemical carcinogens.

Methods

To predict and consider related in vivo carcinogenicity tests, changes in gene expression were examined in rats and mice (by gender and organ) due to exposure to carcinogenic chemicals such as phenyl compounds, which among chemicals are the main cause of carcinogenesis.

Results

In the case of male SD rats, the genes IL1B, TNF, NOS2, IL6, and NGF were related, and the probability of carcinogenesis in the urinary bladder, kidney, and oral cavity was high. In female SD rats, the genes ADRB2, TNF, HMOX1, CYP1A1, PTGS2, ILB1, CASP3, POR, PRL, TSC22D1, ATEG, REG1, HRH2, NFE2L2, AKR1C2, ADRB2, NR3C1, IL6, ADRB1, ADRB3, and LPO showed high probability of carcinogenesis in the stomach, liver, and nasal cavity. In the male F344 rat, the genes ACACA, ACSL1, ALB, ALCAM, CYP19A1, PPARA, CYP4A1, ACAA1, and ACOX1 were related, and showed a high probability of carcinogenesis in the liver, kidney, stomach, and urinary bladder. In the female F344 rat, no related genes were found, but a high probability of carcinogenesis was shown in the kidney, ear, Zymbal’s gland, stomach, and liver. In male ICR mice, no related genes and organs with a high probability of carcinogenesis were found, while in female ICR mice, genes for KRAS, ACHE, CAT, CYP3A4, and GPT were involved, and carcinogenesis occurred in the stomach, thyroid gland, ovary, liver, etc. The probability was shown to be high. In BALBc mice, no related genes and organs with a high probability of carcinogenesis were found, while in female BALBc mice, the genes NR1I2, CYP3A4, ABCB1, CYP2B6, PRKDC, CYP2C9, and NCOA1 were related, and the liver, etc., had a high probability of carcinogenesis.

Conclusion

Differences in the epigenetics of each sex begin at the moment of fertilization due to differences in sex chromosome gene expression and metabolic profiles between XX and XY embryos. These fundamental sex differences in nutrient utilization and mitochondrial activity may contribute to sex differences in the metabolic reprogramming of cancer cells, which is important during cancer development, cancer progression, and response to anticancer treatment.

Purpose of review

In this study, I compared and considered the degree of toxicity and genome expression in each male and female gender and organ due to exposure to phenyl compounds (PAH, etc.), which are the basis of benzene toxicity as aromatic hydrocarbons, and conducted future inhalation toxicity tests and related carcinogenicity tests.

Recent findings

Differences in the epigenetics of each sex begin at the moment of fertilization due to differences in sex chromosome gene expression and metabolic profiles between XX and XY embryos. Throughout development, additional processes, such as X-chromosome inactivation and gonadal steroid exposure, further distinguish the sexes.

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Acknowledgements

This study was supported by the KOSHA (Ulsan, Republic of Korea), the Ministry of Employment and Labor (Sejong, Republic of Korea), and a Grant-in-Aid for chemical research (2023).

Funding

This study was funded by the Occupational Safety and Health Research Institute, Korea Occupational Safety and Health Agency (KOSHA).

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  1. Inhalation Toxicity Research Center, Occupational Safety and Health Research Institute, Korea Occupational Safety and Health Agency, Daejeon, Korea

    Kyung-Taek Rim

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K-T Rim designed the experiments, analyzed the results, and wrote the manuscript.

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Correspondence to Kyung-Taek Rim.

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Rim, KT. A systematic review of the carcinogenicity of rats and mice by sex due to exposure to phenyl compounds. Mol. Cell. Toxicol. 20, 199–241 (2024). https://doi.org/10.1007/s13273-024-00432-y

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