Life’s full of experiences that often seem like a coin toss. Should you go the gym or feast on some sushi? While the epigenetic mechanisms behind the outcomes of these two events may seem quite different at first, when considering the epigenetics of sperm, it turns out they’re two-sides of the same coin.
Intergenerational Effect vs. Transgenerational Epigenetic Inheritance
Before we transmit ourselves over to these exciting findings, let’s take a quick refresher on how environmental experiences shape the epigenomes of generations. The most critical aspect here is the distinction between an intergenerational effect, which is the result of a direct exposure, from transgenerational epigenetic inheritance, the true transmission.
When you’re exposed to an environmental stressor, not only are you (F0) directly exposed but so are your germ cells (F1). So, your grandchildren must be examined (F2) in order to distinguish an intergenerational effect (F1) from transgenerational epigenetic inheritance (F2). However, if you’re a pregnant mother, then you (F0), your embryo (F1), and the developing germ cells within the embryo (F2) are all directly exposed. Thus, your great-grandchildren (F3) must also be examined. With that in mind, let’s run over to the first story.
Sperm ncRNAs and the Integrational Effect of Paternal Exercise
We all know that exercise is great for your physical and mental health, but now it seems that it’s also a great way for fathers to create resilient male offspring. Here’s what went down when a joint study from the labs of Terence Pang and Anthony Hannan at the University of Melbourne (Australia) examined the effect of voluntary wheel-running in future father mice (F0):
- The offspring (F1) underwent a battery of behavior work, which revealed effects specific to males but not females:
- Juveniles were not as scared of past traumatic memories, as revealed by fear conditioning
- Adults were less anxious on light–dark apparatus
- Small RNA sequencing of the fathers (F0) sperm uncovered the differential expression of:
- Three miRNAs: miR-19b, miR-455, and miR-133a
- Two tRNA fragments: tRNA-Gly and tRNA-Pro
- Interestingly, the predicted target genes of the miRNAs and tRNA fragments share no overlap although they have similar functions related to the brain and behavior
Overall, these findings deepen our understanding of the environmentally responsive nature of sperm ncRNAs, which include past observations of tRNAs fragments and diet as well miRNAs and stress. While these findings highlight a positive protective effect, there’s also the other side of the coin.
In Utero Mercury Exposure and Transgenerational Epigenetic Inheritance via Sperm
This next study comes at you from the transgenerational pioneers in the lab of Michael Skinner at Washington State University and shows how in utero exposures can transmit through the sperm of exposed individuals. The team exposed zebrafish embryos to varying concentrations of methylmercury (MeHg) for 24 hours ex vivo. Since they exposed the embryos directly and bypassed the mother, the embryos are still termed F0, but correspond to the F1 in mammals. Thus, only the F2 needed to be looked at to establish transgenerational epigenetic inheritance.
Here’s what their phenotypic analysis of the F2 generation revealed that:
- The visual startle assay and retinal electrophysiology bring impaired vision into sight
- The spontaneous locomotion assay jogs up hyperactivity
- The frequency of behavioral phenotypes increases with increasing ancestral exposure concentration
- The two behavioral phenotypes appear to be inherited independently
The team then used methylated DNA immunoprecipitation with sequencing (MeDIP-seq) to compare F0 and F2 sperm, where they found that:
- The F2 generation shows more differentially methylated regions (DMRs) than the F0 generation
- The DMRs in the F2 generation also tend to cluster together more so than the DMRs of the F0 generation
- The DMRs typically occur in regions of low CpG density, which matches their previous studies
- The vast majority of DMRs are unique between generations
- Gene-specific analysis revealed that translation was the primary function for the F0 generation, due to the only DMR cluster (which disappears in the F2), and that the F2 generation genes are associated with the neurobehavioral phenotypes seen
Skinner concludes, “Effects previously observed and suspected now have been shown to be passed to future generations, not simply the individual exposed. This dramatically impacts the health hazards of mercury exposure.” Although this effect was seen in zebrafish, the exposure was at a level similar to a human who likes to eat a lot fish. So, while there’s always the potential dual interest of zebrafish looking out for their other fishy relatives, it looks like pregnant mothers have one more reason to turn down sushi.
Taken together, these two studies add to the growing evidence that environmental experiences can be transmitted epigenetically through the male germline to shape behavior across generations.