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Functional Manipulation of Maternal Gene Products Using In Vitro Oocyte Maturation in Zebrafish
Published on: April 22, 2017
Deregulation of gene expression in fetal oocytes exposed to doxorubicin
Edmundo Bonilla1, Jesús del Mazo
1Departamento de Ciencias de la Salud, Universidad Autónoma Metropolitana-Iztapalapa, 09340 Mexico DF, Mexico.
Abstract:
Doxorubicin is an effective anticancer drug but its use is limited due to its adverse side effects such as infertility and cardiomyopathy. Some possible mechanisms of the action of doxorubicin have been postulated, but the initial gene deregulation response has not been investigated. Fetal life stages are critical periods in mammalian oogenesis. This study analyzes gene expression alterations in mouse fetal oocytes exposed in vitro to this anticancer agent. cDNA libraries were generated from isolated fetal oocytes and differential screenings performed with cDNAs from in vitro doxorubicin-treated and -untreated oocytes. Differentially expressed genes were assessed by real-time RT-PCR to quantify the extent of their transcriptional control in doxorubicin-exposed oocytes. The results show that doxorubicin alters the expression of genes involved in the mitochondrial respiratory chain, intracellular transport and cell differentiation. Finally, the up-regulation of a differentially expressed gene (metaxin) mediated by its promoter was evaluated in a functional assay. When treated with doxorubicin, somatic cells transfected with a genetic construct including the promoter of metaxin and a reporter gene showed increases in expression similar to those observed in fetal oocytes. This demonstrates the direct effect of agent on the regulation of a specific gene.
Insights
Doxorubicin, an anticancer drug, alters gene expression in fetal mouse oocytes, impacting genes for mitochondrial function and cell differentiation. This study reveals direct effects on gene regulation, offering insights into drug toxicity mechanisms.
Area of Science:
- Reproductive Biology
- Developmental Biology
- Molecular Toxicology
Background:
- Doxorubicin is a vital chemotherapy agent with dose-limiting toxicities, including infertility and cardiotoxicity.
- The precise molecular mechanisms underlying doxorubicin's adverse effects, particularly early gene deregulation in oocytes, remain incompletely understood.
- Fetal oogenesis is a sensitive developmental window susceptible to environmental insults.
Purpose of the Study:
- To investigate the impact of in vitro doxorubicin exposure on gene expression profiles in mouse fetal oocytes.
- To identify specific genes and pathways affected by doxorubicin during early oocyte development.
- To elucidate the direct regulatory effects of doxorubicin on gene transcription.
Main Methods:
- Generation of cDNA libraries from isolated mouse fetal oocytes.
- Differential screening to identify genes with altered expression upon doxorubicin treatment.
- Quantitative assessment of gene expression using real-time RT-PCR.
- Functional assay to evaluate promoter-mediated gene regulation (metaxin).
Main Results:
- Doxorubicin exposure significantly altered the expression of genes involved in mitochondrial respiration, intracellular transport, and cell differentiation.
- Real-time RT-PCR confirmed differential expression of key genes in doxorubicin-treated oocytes.
- A functional assay demonstrated that doxorubicin directly up-regulates the expression of the metaxin gene via its promoter in transfected somatic cells.
Conclusions:
- Doxorubicin induces significant gene expression changes in mouse fetal oocytes, affecting critical cellular processes.
- The study provides evidence for the direct transcriptional regulation of specific genes, such as metaxin, by doxorubicin.
- These findings contribute to understanding the molecular basis of doxorubicin-induced oocyte toxicity and potential infertility.
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