Ribosomal DNA copy number: a novel epigenetic modulator and platform for analyses of adaptation and sensitization to repeated chemical exposures.

Principal Investigator: Dr. Bernardo Lemos, R. Ken and Donna Coit Professor of Pharmacology and Toxicology. R. Ken Coit College of Pharmacy, University of Arizona

A leather tannery in Kanpur, India where workers treat buffalo leather hides with lye and chromium. Image via National Geographic. www.heddels.com/2016

Project objective: The goal of this research was to provide an overview of how hexavalent chromium (Cr(VI)) can affect our DNA through a process called DNA methylation. When we are exposed to Cr(VI), it can increase the risk of certain chronic diseases and cancers. Recent studies suggest that changes in DNA methylation, which is a type of chemical modification to our DNA, may play an important role in how Cr(VI) leads to cancer. This review aims to summarize the impact of Cr(VI) on both the overall pattern of DNA methylation in our cells and the specific genes that are affected.

Project’s alignment with the Hoffman Program on Chemicals and Health mission: Hexavalent chromium (Cr(VI)) is an established toxicant, carcinogen, and a significant source of public health concern. By understanding the impact of Cr(VI) on both the overall pattern of DNA methylation in our cells and the specific genes that are affected, we can gain insights into how Cr(VI) can be toxic and carcinogenic, and this knowledge can contribute to better strategies for prevention and treatment.

Some key takeaways:

  • Hexavalent chromium (Cr(VI)) exposure can disrupt DNA methylation, leading to the development of cancer and other diseases. The precise mechanism by which chromium affects DNA methylation is still not fully understood.
  • Oxidative stress induced by chromate, a form of Cr(VI), is believed to play a significant role in the dysregulation of DNA methylation. Reactive oxygen species (ROS) generated during oxidative stress can influence the expression of tumor genes and tumor suppressor genes through DNA methylation modifications.
  • The accumulating evidence suggests that hexavalent chromium exposure can alter both global and gene-specific DNA methylation, which can result in changes in gene expression and contribute to carcinogenesis. However, further research is needed, especially in human populations, to better understand the association between chromium exposure, DNA methylation patterns, and the development of tumors.

Understanding the relationship between hexavalent chromium exposure and changes in DNA methylation is crucial, especially for specific genes like p16 and others associated with cancer. We need to investigate the mechanisms behind these gene changes, including the role of oxidative stress and chromium-DNA interactions. To improve our knowledge in this area, we require studies that examine DNA methylation changes in diverse populations at different stages of life and utilize advanced techniques for comprehensive analysis. It is also important to explore other epigenetic mechanisms, such as histone modification and non-coding RNA regulation, in relation to chromium exposure.

Additional research* underscores the potential health risks associated with exposure to toxic substances like hexavalent chromium and sheds light on the dynamic nature of rDNA copy number variations, which can be influenced by both genetic and environmental factors.

Products resulting from Hoffman support: Guo X, Feng L, Lemos B, Lou J. DNA methylation modifications induced by hexavalent chromium. J Environ Sci Health C Environ Carcinog Ecotoxicol Rev. 2019;37(3):133-145. doi: 10.1080/10590501.2019.1592640. Epub 2019 May 13. PMID: 31084241; PMCID: PMC8479272.

* Lou J, Yu S, Feng L, Guo X, Wang M, Branco AT, Li T, Lemos B. Environmentally induced ribosomal DNA (rDNA) instability in human cells and populations exposed to hexavalent chromium [Cr (VI)]. Environ Int. 2021 Aug;153:106525. doi: 10.1016/j.envint.2021.106525. Epub 2021 Mar 25. PMID: 33774497; PMCID: PMC8477438.