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Examination of Generational Impacts of Adolescent Chemotherapy: Ifosfamide and Potential for Epigenetic Transgenerational Inheritance

ABSTRACT: Examination of Generational Impacts of Adolescent Chemotherapy: Ifosfamide and Potential for Epigenetic Transgenerational Inheritance

PROVIDER: PRJNA897002 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR22149500_1.fastq.gz	Fastqsanger.gz
	SRR22149500_2.fastq.gz	Fastqsanger.gz
	SRR22149501_1.fastq.gz	Fastqsanger.gz
	SRR22149501_2.fastq.gz	Fastqsanger.gz
	SRR22149502_1.fastq.gz	Fastqsanger.gz

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Examination of Generational Impacts of Adolescent Chemotherapy: Ifosfamide and Potential for Epigenetic Transgenerational Inheritance

Project description:The current study was designed to use a rodent model to determine if exposure to the chemotherapy drug ifosfamide during puberty can induce altered phenotypes and disease in the grand-offspring of exposed individuals through epigenetic transgenerational inheritance. Numerous toxicant exposures during critical developmental windows can have generational impacts through this non-genetic inheritance mechanism. Pathologies such as delayed pubertal onset, kidney disease and multiple pathologies were observed to be significantly more frequent in the F1 generation offspring of ifosfamide lineage females. The F2 generation grand-offspring ifosfamide lineage males had transgenerational pathology phenotypes of early pubertal onset and reduced testis pathology. Reduced levels of anxiety were observed in both males and females from the exposure lineage in the transgenerational F2 generation grand-offspring. Differential DNA methylated regions (DMRs) were also identified in chemotherapy and control lineages sperm in the F1 and F2 generations. The transgenerational alterations in sperm epigenetics provides a molecular mechanism for the ancestral impacts of chemotherapy. Therefore, chemotherapy exposure can impact pathology and disease susceptibility in subsequent generations.

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Examination of generational impacts of adolescent chemotherapy: Ifosfamide and potential for epigenetic transgenerational inheritance.

Project description:The current study was designed to use a rodent model to determine if exposure to the chemotherapy drug ifosfamide during puberty can induce altered phenotypes and disease in the grand-offspring of exposed individuals through epigenetic transgenerational inheritance. Pathologies such as delayed pubertal onset, kidney disease, and multiple pathologies were observed to be significantly more frequent in the F1 generation offspring of ifosfamide lineage females. The F2 generation grand-offspring ifosfamide lineage males had transgenerational pathology phenotypes of early pubertal onset and reduced testis pathology. Reduced levels of anxiety were observed in both males and females in the transgenerational F2 generation grand-offspring. Differential DNA methylated regions (DMRs) in chemotherapy lineage sperm in the F1 and F2 generations were identified. Therefore, chemotherapy exposure impacts pathology susceptibility in subsequent generations. Observations highlight the importance that prior to chemotherapy, individuals need to consider cryopreservation of germ cells as a precautionary measure if they have children.

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Project description:The potential that adolescent chemotherapy can impact the epigenetic programming of the germ line to influence later life adult fertility and promote epigenetic inheritance was investigated. Adult males approximately ten years after pubertal exposure to chemotherapy were compared to adult males with no previous exposure. Sperm were collected to examine differential DNA methylation regions (DMR) between the exposed and control populations. A statistically significant signature of DMRs was identified in the chemotherapy exposed male sperm. The DMRs, termed epimutations, were found in CpG desert regions of primarily 1 kilobase size. Gene associations and correlations to genetic mutations (copy number variation) were also investigated. Observations indicate adolescent chemotherapy exposure can promote epigenetic alterations that persist in later life. The germline (i.e. sperm) epimutations identified suggest chemotherapy has the potential to promote epigenetic inheritance to the next generation.

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