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Environmentally Induced Sperm RNAs Transmit Cancer Susceptibility to Offspring in a Mouse Model [RNA-seq II]

ABSTRACT: DNA sequence accounts for the majority of disease heritability, including cancer. Yet, not all familial cancer cases can be explained by genetic factors. It is becoming clear that environmentally induced epigenetic inheritance occurs and that the progeny’s traits can be shaped by parental environmental experiences. In humans, epidemiological studies have implicated environmental toxicants, such as the pesticide DDT, in intergenerational cancer development, including breast and childhood tumors. Here, we show that the female progeny of males exposed to DDT in the pre-conception period have higher susceptibility to developing aggressive tumors in mouse models of breast cancer. Sperm of DDT-exposed males exhibited distinct patterns of small non-coding RNAs, with an increase in miRNAs and a specific surge in miRNA-10b levels. Remarkably, embryonic injection of the entire sperm RNA load of DDT-exposed males, or synthetic miRNA-10b, recapitulated the tumor phenotypes observed in DDT offspring. Mechanistically, miR-10b injection altered the transcriptional profile in early embryos with enrichment of genes associated with cell differentiation, tissue and immune system development. In adult DDT-derived progeny, transcriptional and protein analysis of mammary tumors revealed alterations in stromal and in immune system compartments. Our findings reveal a causal role for sperm RNAs in environmentally induced inheritance of cancer predisposition and, if confirmed in humans, this could help partially explain some of the “missing heritability” of breast, and other, malignancies.

ORGANISM(S): Mus musculus

PROVIDER: GSE222357 | GEO | 2023/06/01

REPOSITORIES: GEO

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Project description:Environmental challenges experienced by an organism can have multiple effects at an individual level, with recent work also suggesting these challenges may affect their unexposed offspring. In a time of rapid environmental change, understanding whether environmental challenges experienced by organisms could increase the fitness of future generations to survive these same stressors, is critically needed. Low dissolved oxygen is a common environmental challenge that aquatic organisms encounter, resulting in numerous physiological, phenotypic, and epigenetic changes. In this study, we use zebrafish (Danio rerio) as a model to investigate how paternal hypoxia experience impacts subsequent progeny. Males were exposed to moderate hypoxia (11-13 kPA) for 2 weeks, bred to create an F1 generation, and progeny underwent an acute hypoxia (0-1 kPA) tolerance assay. Using time to loss of equilibrium and loss of equilibrium frequency as measured of hypoxia resistance, we show that paternal exposure to hypoxia endow offspring with a greater tolerance to acute hypoxia, compared to offspring of unexposed males, though there are strong family x treatment effects. In addition to phenotypic alternations, we also investigated changes in gene expression in offspring. We conducted RNA-Seq on whole fry and detected 91 differentially expressed genes, including two hemoglobin genes that are significantly upregulated by more than 4-fold in the offspring of hypoxia exposed males. Moreover, the offspring which maintained equilibrium the longest showed the greatest upregulation in hemoglobin expression. Paternal exposures to physiological challenges are thus able to impact the phenotype and gene expression of their unexposed progeny. We conducted whole genome bisulfite sequencing (WGBS) on the sperm of parental males to assess whether changes in progeny phenotype and gene expression are underpinned by changes in DNA methylation. While we observed coupling of methylation levels in the parental sperm and gene expression in progeny overall, we did not detect differential methylation at any of the differentially expressed genes, suggesting that another epigenetic mechanism is responsible for the observed changes in gene expression. Overall, our findings suggest that a ‘memory’ of past hypoxia exposure is maintained and that this environmentally induced information is transferred to subsequent generations, pre-acclimating progeny to cope with hypoxic conditions.

Project description:Environmental compounds including fungicides, plastics, pesticides, dioxin and hydrocarbons can promote the epigenetic transgenerational inheritance of adult-onset disease in future generation progeny following ancestral exposure during the critical period of fetal gonadal sex determination. This study examined the actions of the pesticide methoxychlor to promote the epigenetic transgenerational inheritance of adult-onset disease and associated differential DNA methylation regions (i.e. epimutations) in sperm. Gestating F0 generation female rats were transiently exposed to methoxychlor during fetal gonadal development (gestation days 8 to 14) and then adult-onset disease was evaluated in adult F1 and F3 (great-grand offspring) generation progeny for control (vehicle exposed) and methoxychlor lineage offspring. There were increases in the incidence of kidney disease, ovary disease, and obesity in the methoxychlor lineage animals. In females and males the incidence of disease increased in both the F1 and the F3 generations and the incidence of multiple disease increased in the F3 generation. There was increased disease incidence in F4 generation reverse outcross (female) offspring indicating disease transmission was primarily transmitted through the female germline. Analysis of the F3 generation sperm epigenome of the methoxychlor lineage males identified differentially DNA methylated regions (DMR) termed epimutations in a genome-wide gene promoters analysis. These epimutations were found to be methoxychlor exposure specific in comparison with other exposure specific sperm epimutation signatures. Observations indicate that the pesticide methoxychlor has the potential to promote the epigenetic transgenerational inheritance of disease and the sperm epimutations appear to provide exposure specific epigenetic biomarkers for transgenerational disease and ancestral environmental exposures. Methylated sperm DNA was isolated from rats ancestrally exposed to methoxychlor. Three independent samples from each treatment group were obtained. Differential DNA methylation between treatment groups was determined using Nimblegen microarrays. Treated samples were paired with control samples and hybridized together on arrays, resulting in three arrays for the treatment.

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Environmentally Induced Sperm RNAs Transmit Cancer Susceptibility to Offspring in a Mouse Model [RNA-seq II]

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