The idea that parents can transmit environmentally acquired traits to their offspring has been intuitively attractive ever since Lamarck proposed it in 1801. It had to go underground as evidence continuously piled up supporting Darwin's theory of natural selection, but it seems to be enjoying a popular resurgence with the discovery of epigenetics. Epigenetics explains how information can be transmitted between generations without the involvement of DNA sequences.

A number of recent studies have suggested that stress levels and the nutritional status of parents (and even grandparents) can influence the health of their offspring. But these studies have been somewhat murky on the details on how this transmission could occur. Now scientists who had previously shown that paternal stress impacts the next generation of mice have zeroed in on how it happens: males pack their sperm with RNA that influences gene activity in their offspring.

Through the uterine environment, mothers can pass their environmental exposures on to the fetuses they are nurturing. Thus, studies looking at mechanisms of epigenetic inheritance tend to focus on fathers—pretty much all they give to the fetus is genetic material. And male mice don't need to help in rearing the young, so this genetic material can be their only contribution to the next generation.

In earlier work, these scientists exposed male mice to six weeks of alternating stressors like 36 hours of constant light, a 15-minute exposure to fox odor, exposure to a novel object (marbles) overnight, 15 minutes of restraint in a 50 mL conical tube, multiple cage changes, white noise all night long, or saturated bedding.

Poor little guys.

Then the scientists allowed the mice to breed. Adult offspring of these chronically stressed dads had reduced hypothalamic-pituitary-adrenal stress axis reactivity; when they themselves were restrained for 15 minutes, they did not make as much corticosterone as mice sired by relaxed dads. This is relevant, and problematic, because blunted stress responses in humans are associated with neuropsychiatric disorders like depression, schizophrenia, and autism.

The offspring also had decreased expression of genes involved in building complex tissues (collagen and extracellular matrix proteins) in the stress-regulating regions of the hypothalamus. They didn't really behave differently from control mice when stressed, though, and their gross brain morphology was unaffected.

The researchers found that stressed dads have increased levels of nine microRNAs in their sperm. The scientists obviously hypothesized that these miRNAs were responsible for the reduced corticosterone response in the kids, and they set out to test it by injecting a similar cocktail of RNA into single-cell mouse zygotes. After these zygotes divided into two cells, one of the cells was allowed to develop into a full-grown mouse and the other was taken for genetic analysis. The mice that got these miRNAs looked exactly the same as those born to the stressed dads; as adults, they had the same blunted stress response and transcriptional changes in their brains. So the miRNAs are responsible for transmitting this effect.

Genetic analysis of the other zygotic cell—the one that didn't get to grow up into a mouse—revealed how this happens. The paternal miRNAs knocked down stores of total maternal mRNA and dramatically decreased the mRNA of a number of genes important in controlling the structure of chromosomes. The researchers think that this altered level of maternal mRNA in the zygote initiates a cascade of altered gene expression that ultimately ends up by downregulating genes responsible for stress regulation in adult mice.

This type of mRNA knock down was known to occur post-fertilization but had only been attributed to maternal miRNAs before this study.

So by knocking down these maternal stores of mRNA in the zygotes, these nine paternal miRNAs—the molecular consequence of their exposure to chronic stress—altered gene expression patterns in the brains of their offspring. As a result, the offspring are less responsive to stress than they should be.

PNAS, 2015. DOI: 10.1073/pnas.1508347112 (About DOIs).