Tom K. Hei, PhD

Ever since X-rays were discovered by Röentgen more than a century ago, it has always been assumed that nucleus, or specifically DNA, as the main target of radiation induced mutation and cancer. As such, generations of students in radiation biology have been taught that such heritable biological effects are the consequence of a direct radiation-nuclear interaction. Using a precision charged particle microbeam, my laboratory showed that targeted cytoplasmic irradiation induced mutation in the nucleus of hit cells and that the type of mutations induced was very different from those generated through direct nuclear irradiation. This initial observation set forth the concept of extranuclear effects of ionizing radiation. Since the original study published in 1999, we have further shown that mitochondria are the ultimate targets and that reactive radical species, coupled with membrane lipid peroxidation and induction of cyclooxygenase 2(COX2), mediated the genotoxic response of targeted cytoplasmic irradiation.

• Wu, L.J., Randers-Pehrson, G., Waldren, C.A., Geard, C.R., Yu, Z.Y., and Hei, T.K.(1999) Targeted cytoplasmic irradiation by alpha particles induces gene mutations. Proc. National Academy Science U.S.A. 96: 4959-4964. PMCID: PMC21799
• Hei, T.K., Wu. L.J., Liu, S.X., Vannais, D., Waldren, C.A., and Randers-Pehrson, G.(1997) Mutagenic effects of a single and an exact number of alpha particles in mammalian cells. Proc. National Academy Sciences U.S.A. 94: 3765-3770. PMCID: PMC20515
• Hong, M., Xu, A., Zhou, H., Wu, L., Randers-Pehron, G., Santella, R., Yu, Z., and Hei, T.K. (2010) Mechanism of genotoxicity induced by targeted cytoplasmic irradiation. Brit. J. Cancer 103: 1263-1268. PMCID: PMC2967061
• Zhang, B., Davidson, MM., Zhou, H.N., Walker, WF., Hei, T.K. (2013) Cytoplasmic irradiation results in mitochondrial dysfunction and DRP1-dependent mitochondrial fission. Cancer Research 73: 6700-6710. PMCID: PMC3934017.
• Wu, J, Zhang B, Wuu, YR, Davidson MM, Hei TK. (2017) Targeted cytoplasmic irradiation and autophagy. Mutation Res 806: 88-97. PMCID: PMC5581273

Following up on the targeted cytoplasmic studies and using the single particle microbeam, my laboratory further shows unequivocally that cells that are NOT directly hit by a charged particle but in the vicinity of one that is or having received signals from such cells can also participate in the damage process. Radiation- induced non-targeted/ bystander effects, as it is called, represent a paradigm shift in our understanding of the target theory of ionizing radiation. My laboratory plays a major role in elucidating the mechanisms involved and the role of the out of field response in animal models.

• Zhou, H.N., Randers-Pehrson, G., Waldren, C.A., Vannais, D., Hall, E.J. and Hei, T.K. (2000) Induction of a bystander mutagenic effect of alpha particles in mammalian cells. Proc. National Academy Science U.S.A. 97: 2099-2104. PMCID: PMC15760
• Zhou, H.Z., Suzuki, K., Randers-Pehrson, G., Vannais, D., Trosko, J., Waldren, C.A., and Hei, T.K. (2001) Radiation risk at low doses may be greater than we thought. Proc. National Academy Sci. U.S.A. 98:14410-14415. PMCID: PMC64695
• Zhou, H.N., Ivanov, V., Gillespie, J., Geard, C.R., Amundson, S.A., Lieberman, H.B., and Hei, T.K. (2005) Mechanism of radiation induced bystander effect: role of COX-2 signaling pathway. Proc. National Academy Science U.S.A. 102: 14641-14646. PMCID: PMC 1253564
• Chai, Y., Calaf, G.M., Zhou, H. Ghandhi, S.A., Elliston, C.D., Wen, G., Nohmi, T., Amundson, S. and Hei, T.K. (2013) Radiation induced COX-2 expression and mutagenesis at non-targeted lung tissues of gpt delta transgenic mice. British J. Cancer 108: 91-98. PMCID: PMC3553512
• Pei, H., Hu, W, Guo, Z, Chen H, Ma J, Mao W, Li B, Wang A, Wan J, Zhang J, Nie J, Zhou G, Hei TK. (2018) Long noncoding RNA CRYBG3 blocks cytokinesis by directly binding G-actin. Cancer Res. 78:4563-4572. PMCID: PMC6095725

Arsenic is an important environmental contaminant affecting more than 100 million people worldwide through contaminated drinking water. Using a mutagenic assay system that can detect chromosomal mutations, my laboratory has shown that arsenic is genotoxic and the process involves generation of reactive oxygen and reactive nitrogen species. More recently, we have shown that arsenic induces apoptosis and altered differentiation in neural stem cells and may contribute to the reduced IQ and loss of cognitive function observed in children exposed to chronic environmental arsenic.

• Hei, T.K., Liu, S.X., and Waldren, C.A. (1998) Mutagenicity of arsenic in mammalian cells: Role of reactive oxygen species. Proc. National Academy Science U.S.A. 95:8103-8107. PMCID: PMC20936.
• Liu, S.X., Athar, M., Lippai, I., Waldren, C.A., and Hei, T.K. (2001) Induction of oxyradicals by arsenic: implications for mechanisms of genotoxicity. Proc. National Academy Science U.S.A. 98:1643-1648. PMCID: PMC29310.
• Liu SX, Davidson MM, Tang XW, Walker WF, Athar M, Ivanov V and Hei TK. (2005) Mitochondrial damage mediates genotoxicity of arsenic in mammalian cells. Cancer Research 65: 3236-3242. PMID: 15833855.
• Gong, X, Ivanov, VN and Hei TK. (2016) Tetramethylpyrazine down regulated arsenic induced heme oxygenase I and ARS2 expression by inhibiting Nrf2, NFkB,AP-1 and MAPK pathways in human proximal tubular cells. Arch. Toxicology 90(9):2187-200. PMCID: PMC4808507

Asbestos is a well-established human carcinogen and induces lung cancer and mesothelioma. The carcinogenic mechanism of asbestos is not clear. For over 30 years, my laboratory has been studying the how and why of fiber carcinogenesis. We have shown that asbestos, contrary to earlier belief that it is a non- genotoxic carcinogen, is indeed mutagenic when assay using model system that can detect large chromosomal deletions. The finding provide an epidemiological link to asbestos associated human mesothelioma that frequently show large scale chromosomal mutations. We further demonstrate that role of reactive radical species and the role of mitochondrial damage in the genotoxic process.

• Hei, T.K., Piao, C.Q., He, Z.Y., Vannais, D., and Waldren, C.A. (1992) Chrysotile fiber is a potent mutagen in mammalian cells. Cancer Research 52: 6305-6309. PMID: 1330290
• Xu, A., Wu, L.J., Santella, R., and Hei, T.K. (1999) Role of oxyradicals in mutagenicity and DNA damage induced by asbestos in mammalian cells. Cancer Research 59: 5615-5624. PMID: 10606236
• Huang, S.X., Partridge, M.A., Ghandhi, S.A., Davidson, M. M., Amundson, S.A., and Hei, T.K. (2012) Mitochondrial derived reactive intermediate species mediated asbestos induced genotoxicity and oxidative stress-responsive signaling pathways. Environ. Hlth. Perspect. 120:840-847. PMCID: PMC3385428
• Wang, M.M, Wang, Y.C, Wang, X.N, Liu, Y, Zhang, H, Chen, S.P, Hei, T.K, Wu, L.J, Xu, A (2015) Mutagenicity of ZnO nanoparticles in mammalian cells: Role of physicochemical transformations under the aging process. Nanotoxicology 9:972-982. PMID: 25676621