Sex-specific effects of cytotoxic chemotherapy agents cyclophospha-mide 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.

Phage composition of a fermented milk and colostrum product assessed by microbiome array; putative role of open reading frames in reference to cell signaling and neurological development

“…These results may bear relevance in the context of counteracting the side effects of Mitomycin C chemotherapy. It is known that Mitomycin C leads to oxidative DNA damage and decreases global DNA methylation in a sex-specific pattern in mice; it is also known that most of the changes induced by chemotherapy in the pre-frontal cortex of female mice are similar to those occurring during the brain's ageing (80). Considering the effects of Mitomycin C on phage r1t gene expression, it could be hypothesized that chemotherapy also alters the balance between phages and Lactococci in the microbiota, with consequences on the functions regulated by the microbiota and, in particular, on the immune system.…”

Chemo brain or tumor brain - that is the question: the presence of extracranial tumors profoundly affects molecular processes in the prefrontal cortex of TumorGraft mice

“…Epigenetic changes that underlie aberrant gene expression patterns have been well-documented in breast cancer literature. Recently, we analysed the molecular mechanisms of chemo brain [ 14 ] by investigating the gene expression profiles in the prefrontal cortex (PFC) and hippocampus (HPC) of mice 3 weeks after treatment with the cytotoxic chemotherapy agents mitomycin C (MMC) and cyclophosphamide (CPP) [ 14 ]. We showed that chemotherapy altered gene expression profiles in the PFC and HPC tissues; the changes were most prominent in the PFC tissues of females 3 weeks after MMC treatment.…”

Chemo brain: From discerning mechanisms to lifting the brain fog—An aging connection

“…35 We dissected the molecular mechanisms of chemo brain by using a murine model, and we analyzed epigenetic and gene expression changes in the hippocampus and PFC tissues of mice 24 hours and 3 weeks after treatment with cytotoxic chemotherapy agents mitomycin C (MMC) and cyclophosphomade (CPP), 2 agents that have been shown to cause chemo brain; however, the mechanisms of their effects remained elusive. 31 Our data showed that MMC and CPP treatments lead to drug-, sex-, and brain region-specific and persistent changes in global gene expression profiles. Overall, gene expression responses were much more profound for MCC than CPP exposure, and they were most prominent in the PFC tissues of female animals 3 weeks after MMC treatment, affecting pathways responsible for oxidative stress and other effects.…”

“…[26][27][28] Epigenetic changes play key roles in brain and behavior. 29,30 In a recent pioneer study in Aging (2016) 31 we have proposed a new theory of chemo brain in which the mechanisms that underlie the neurotoxic side effects of chemotherapy on the brain are epigenetically regulated and associated with altered gene expression. 31 Our analysis focused on the hippocampus and prefrontal cortex (PFC) and was based on their pivotal roles in memory, learning, and executive functions.…”

“…In our pioneer study, 31 we used Illumina mRNA profiling technology to determine that chemotherapy exposures cause gene expression changes in rodent brain, although mRNAs constitute only a small portion of cellular RNA makeup. Genome sequencing, as well as recent advances in non-coding RNA biology, has shown that more than 98% of our genes encode RNA molecules that are never translated into proteins.…”