Ancestral vinclozolin exposure alters the epigenetic transgenerational inheritance of sperm small noncoding RNAs

Abstract

Exposure to the agricultural fungicide vinclozolin during gestation promotes a higher incidence of various diseases in the subsequent unexposed F3 and F4 generations. This phenomenon is termed epigenetic transgenerational inheritance and has been shown to in part involve alterations in DNA methylation, but the role of other epigenetic mechanisms remains unknown. The current study investigated the alterations in small noncoding RNA (sncRNA) in the sperm from F3 generation control and vinclozolin lineage rats. Over 200 differentially expressed sncRNAs were identified and the tRNA-derived sncRNAs, namely 5′ halves of mature tRNAs (5′ halves), displayed the most dramatic changes. Gene targets of the altered miRNAs and tRNA 5′ halves revealed associations between the altered sncRNAs and differentially DNA methylated regions. Dysregulated sncRNAs appear to correlate with mRNA profiles associated with the previously observed vinclozolin-induced disease phenotypes. Data suggest potential connections between sperm-borne RNAs and the vinclozolin-induced epigenetic transgenerational inheritance phenomenon.

Epigenetic Mechanisms of Transmission of Metabolic Disease across Generations

“…This pattern, in turn, results in decreased expression of miR-466-3p, encoded by the Smbt2 gene; this alters post-transcriptional regulation of the PEPCK gene and increases PEPCK protein, a rate-limiting step for gluconeogenesis (Wu et al, 2016). Similar to what has been demonstrated in other models, in the transgenerational model of male vinclozin exposure, sperm sncRNAs are also altered, the latter being a potential mechanism of transgenerational transmission of epigenetic markers (Schuster et al, 2016). …”

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SpermBase: A Database for Sperm-Borne RNA Contents

“…5A) [51]. The predominance of 5′ halves in sperm-borne small RNA populations, in addition to speculation that they may play an important role in epigenetic inheritance, led us to focus our attention on this particular class of tsRNAs [16, 17, 51, 80–82]. …”

“…It is therefore possible that changes in sperm-borne 5′ half levels can have an effect on the early embryo; this is in agreement with the results of our analyses of the predicted gene targets of the 5′ tRNA halves, suggesting that 5′ tRNA halves interact with genes related to development. Recently, in three separate epigenetic inheritance models, expression of sperm-borne 5′ tRNA halves was observed to be affected by an altered diet (i.e., high fat or low protein) or vinclozolin (a common agricultural fungicide) exposure [16, 17, 82]. Future investigations into other examples of epigenetic inheritance could potentially benefit from the tsRNA expression data and consensus sequences housed in SpermBase.…”

Tertiary Epimutations – A Novel Aspect of Epigenetic Transgenerational Inheritance Promoting Genome Instability

“…Specific characteristics of vinclozolin-induced transgenerational differential DNA methylation regions (DMRs) in sperm included the nonrandom occurrence of unique consensus DNA sequences including zinc finger motifs and G-quadruplex sequences [44,45]. A recent report also documented alterations in small noncoding RNAs (sncRNAs) in the sperm from F3 generation control and vinclozolin lineage rats [46]. …”