title: 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.
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.
authors.affiliation: Department of Neuroscience, University of Lethbridge, Lethbridge, AB, T1K3M4, Canada.
authors.forename: Anna
authors.initials: A
authors.lastname: Kovalchuk
authors.affiliation: Department of Biological Sciences, University of Lethbridge, Lethbridge, AB, T1K3M4, Canada.
authors.forename: Rocio
authors.initials: R
authors.lastname: Rodriguez-Juarez
authors.affiliation: Department of Biological Sciences, University of Lethbridge, Lethbridge, AB, T1K3M4, Canada.
authors.forename: Yaroslav
authors.initials: Y
authors.lastname: Ilnytskyy
authors.affiliation: Department of Biological Sciences, University of Lethbridge, Lethbridge, AB, T1K3M4, Canada.
authors.forename: Boseon
authors.initials: B
authors.lastname: Byeon
authors.affiliation: Division of Biochemical Toxicology, Food and Drug Administration National Center for Toxicological Research, Jefferson, AR 72079, USA.|Department of Pediatrics, University of Arkansas for Medical Sciences, Little Rock, AR 72202, USA.
authors.forename: Svitlana
authors.initials: S
authors.lastname: Shpyleva
authors.affiliation: Department of Pediatrics, University of Arkansas for Medical Sciences, Little Rock, AR 72202, USA.
authors.forename: Stepan
authors.initials: S
authors.lastname: Melnyk
authors.affiliation: Division of Biochemical Toxicology, Food and Drug Administration National Center for Toxicological Research, Jefferson, AR 72079, USA.
authors.forename: Igor
authors.initials: I
authors.lastname: Pogribny
authors.affiliation: Department of Neuroscience, University of Lethbridge, Lethbridge, AB, T1K3M4, Canada.|Alberta Epigenetics Network, Calgary, AB, T2L 2A6, Canada.|Canadian Institute for Advanced Research, Toronto, ON, M5G 1Z8, Canada.
authors.forename: Bryan
authors.initials: B
authors.lastname: Kolb
authors.affiliation: Department of Biological Sciences, University of Lethbridge, Lethbridge, AB, T1K3M4, Canada.|Alberta Epigenetics Network, Calgary, AB, T2L 2A6, Canada.
authors.forename: Olga
authors.initials: O
authors.lastname: Kovalchuk
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D003520:Cyclophosphamide / Q000494:pharmacology*; D004249:DNA Damage / Q000187:drug effects*; D044127:Epigenesis, Genetic / Q000187:drug effects*; D005260:Female; D015870:Gene Expression / Q000187:drug effects*; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000187:drug effects; D006624:Hippocampus / Q000187:drug effects*; D008297:Male; D051379:Mice; D016685:Mitomycin / Q000494:pharmacology*; D018384:Oxidative Stress / Q000187:drug effects; D017397:Prefrontal Cortex / Q000187:drug effects*; D012737:Sex Factors
chemical_list: D000970:Antineoplastic Agents; D016685:Mitomycin; D003520:Cyclophosphamide
keywords: DNA hydroxymethylation; DNA methylation; aging; chemo brain; chemotherapy; epigenetics; oxidative stress; transcriptome