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Paternal malnutrition programs offspring’s breast cancer risk and tumor metabolism in a mouse model (MBD-seq)

ABSTRACT: Paternal malnutrition programs offspring’s breast cancer risk and tumor metabolism in a mouse model (MBD-seq)

PROVIDER: PRJNA471326 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR7162910_1.fastq.gz	Fastqsanger.gz
	SRR7162910_2.fastq.gz	Fastqsanger.gz
	SRR7162911_1.fastq.gz	Fastqsanger.gz
	SRR7162911_2.fastq.gz	Fastqsanger.gz
	SRR7162912_1.fastq.gz	Fastqsanger.gz

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Project description:Maternal malnutrition remains one the major early-life adversities contributing poor health in one in five children worldwide. Clinical studies demonstrate that malnourished children are growth-impaired, exhibit behavioral changes and suffer from cognitive impairments. These health effects can persist even if nutrition becomes adequate later in life. Experimental studies on rodents have shown that maternal protein restriction is associated with the emergence of several adverse effects of offspring neurological development. In addition, reported effects of prenatal and/or postnatal protein malnutrition on the offspring include changes in exploratory behavior and anxiety, altered learning and memory abilities and a different response to aversive stimuli. These behavioral alterations characterize the symptoms of various psychiatric disorders that has been increasingly regarded as developmental disorders. Social behavioral deficits in psychiatric diseases have been hypothesized to arise form elevation in the cellular balance of excitation and inhibition within the cortex generally, and PFC specifically. Such imbalance may be caused either by increased activity in excitatory neurons or by reduction in inhibitory neuron function. Interestingly, decreases in inhibitory neurotransmission are a common finding in animal models of ASD. In addition, direct alterations of E/I balance within the PFC in adult mice have strong effect on social motivation. The critical question we have posed in this work is whether maternal protein malnutrition alters the offspring’s social cognition and if this were the case, if these behavioral deficits are transmitted to the following generation. We hypothesized that at the basis of such alterations in social cognition underlie changes in gene expression related to E/I signaling within the mPFC. Our results focus on damaging effects of maternal protein malnutrition even for generations that are not exposed to this environmental adversity.

Project description:BackgroundWhile many studies have shown that maternal factors in pregnancy affect the cancer risk for offspring, few studies have investigated the impact of paternal exposures on their progeny's risk of this disease. Population studies generally show a U-shaped association between birthweight and breast cancer risk, with both high and low birthweight increasing the risk compared with average birthweight. Here, we investigated whether paternal malnutrition would modulate the birthweight and later breast cancer risk of daughters.MethodsMale mice were fed AIN93G-based diets containing either 17.7% (control) or 8.9% (low-protein (LP)) energy from protein from 3 to 10 weeks of age. Males on either group were mated to females raised on a control diet. Female offspring from control and LP fathers were treated with 7,12-dimethylbenz[a]anthracene (DMBA) to initiate mammary carcinogenesis. Mature sperm from fathers and mammary tissue and tumors from female offspring were used for epigenetic and other molecular analyses.ResultsWe found that paternal malnutrition reduces the birthweight of daughters and leads to epigenetic and metabolic reprogramming of their mammary tissue and tumors. Daughters of LP fathers have higher rates of mammary cancer, with tumors arising earlier and growing faster than in controls. The energy sensor, the AMP-activated protein kinase (AMPK) pathway, is suppressed in both mammary glands and tumors of LP daughters, with consequent activation of mammalian target of rapamycin (mTOR) signaling. Furthermore, LP mammary tumors show altered amino-acid metabolism with increased glutamine utilization. These changes are linked to alterations in noncoding RNAs regulating those pathways in mammary glands and tumors. Importantly, we detect alterations in some of the same microRNAs/target genes found in our animal model in breast tumors of women from populations where low birthweight is prevalent.ConclusionsOur study suggests that ancestral paternal malnutrition plays a role in programming offspring cancer risk and phenotype by likely providing a metabolic advantage to cancer cells.

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Paternal malnutrition programs offspring’s breast cancer risk and tumor metabolism in a mouse model (MBD-seq)

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