Aging
Navigate
Submit an Article
Research Paper|Volume 8, Issue 4|pp 697—708

Sex-specific effects of cytotoxic chemotherapy agents cyclophosphamide and mitomycin C on gene expression, oxidative DNA damage, and epigenetic alterations in the prefrontal cortex and hippocampus – an aging connection

Anna Kovalchuk1, Rocio Rodriguez-Juarez2, Yaroslav Ilnytskyy2, Boseon Byeon2, Svitlana Shpyleva3,4, Stepan Melnyk4, Igor Pogribny3, Bryan Kolb1,5,6, Olga Kovalchuk2,5
  • 1Department of Neuroscience, University of Lethbridge, Lethbridge, AB, T1K3M4, Canada
  • 2Department of Biological Sciences, University of Lethbridge, Lethbridge, AB, T1K3M4, Canada
  • 3Division of Biochemical Toxicology, Food and Drug Administration National Center for Toxicological Research, Jefferson, AR 72079, USA
  • 4Department of Pediatrics, University of Arkansas for Medical Sciences, Little Rock, AR 72202, USA
  • 5Alberta Epigenetics Network, Calgary, AB, T2L 2A6, Canada
  • 6Canadian Institute for Advanced Research, Toronto, ON, M5G 1Z8, Canada
Received: January 8, 2016Accepted: January 30, 2016Published: March 30, 2016
https://doi.org/10.18632/aging.100920

Copyright: © 2016 Kovalchuk et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Abstract

Recent research shows that chemotherapy agents can be more toxic to healthy brain cells than to the target cancer cells. They cause a range of side effects, including memory loss and cognitive dysfunction that can persist long after the completion of treatment. This condition is known as chemo brain. The molecular and cellular mechanisms of chemo brain remain obscure. Here, we analyzed the effects of two cytotoxic chemotherapy drugs—cyclophosphamide (CPP) and mitomycin C (MMC) - on transcriptomic and epigenetic changes in the murine prefrontal cortex (PFC) and hippocampal regions. We for the first time showed that CPP and MMC treatments led to profound sex- and brain region-specific alterations in gene expression profiles. Gene expression changes were most prominent in the PFC tissues of female mice 3 weeks after MMC treatment, and the gene expression response was much greater for MCC than CPP exposure. MMC exposure resulted in oxidative DNA damage, evidenced by accumulation of 8-oxo-2′-deoxyguanosine (8-oxodG) and a decrease in the level of 8-oxodG repair protein OGG1 in the PFC of female animals 3 weeks after treatment. MMC treatment decreased global DNA methylation and increased DNA hydroxymethylation in the PFC tissues of female mice. The majority of the changes induced by chemotherapy in the PFC tissues of female mice resembled those that occur during the brain's aging processes. Therefore, our study suggests a link between chemotherapy-induced chemo brain and brain aging, and provides an important roadmap for future analysis.