Traces of Trauma in Sperm RNA

A mouse study shows that molecular remnants of early-life stress can be passed on to future generations.

By | April 13, 2014

WIKIMEDIA, RAMAThe offspring of mice that suffered early-life stress show signs of the disturbance their parent experienced, researchers from the University of Zurich in Switzerland and their colleagues have found, pointing to a potential RNA-based mechanism by which trauma may be epigenetically inherited. The team’s work was published today (April 13) in Nature Neuroscience.

Zurich’s Isabelle Mansuy and her collaborators sought to evaluate the environmental and genetic factors behind complex neurological diseases associated with childhood trauma, such as borderline personality disorder. The team used a mouse model of “unpredictable maternal separation combined with unpredictable maternal stress,” or MSUS. The MSUS mothers were separated from their young at different times once daily for two weeks. While the unpredictability of this event traumatized the pups, the mothers, too, were stressed during these separation periods, for instance, by being confined to a narrow tube.

When the MSUS young became adults, the researchers found that they were generally more likely to take risks than control adult mice. The MSUS mice were less hesitant to enter wide-open spaces or brightly lit areas than animals that had not been separated from their mothers, for instance. They also exhibited altered glucose metabolism, implying that early developmental trauma had caused permanent behavioral and metabolic changes.

And those changes were not confined to the once-traumatized adults. When the researchers bred those MSUS mice mated with control animals, they found that the progeny, too, were less risk-averse and showed more signs of depression than control animals. Even the offspring’s offspring exhibited altered glucose metabolism.

“This paradigm induced behavioral changes across generations,” said Mansuy.

To discern how such stress could be passed on, the researchers isolated RNA from MSUS animals’ sperm, sera, and hippocampi, and compared it with control animals. They detected changes in the abundance of several noncoding microRNAs (miRNAs) and PIWI-interacting miRNAs (piRNAs) in sperm, including some that were previously implicated in epigenetic regulation. These molecular changes typically carried over to the F2 generation, where differences in RNA abundance were seen in the hippocampus and serum, but were largely gone by F3. The behavioral changes remained in both generations.

Then, to solidify the observed link between RNA and behavior, Mansuy and her colleagues isolated RNA from sperm of MSUS mice, injected it into fertilized eggs, and reimplanted the eggs into pseudopregnant females. When the resulting pups became adults, they exhibited the same metabolic and behavioral traits as the MSUS mice.

“That was the best and most causal evidence we could provide,” said Mansuy.

The study represents “quite an exciting piece of work,” said Stephen Krawetz, the associate director of the C.S. Mott Center for Human Growth and Development at Wayne State University School of Medicine in Detroit, Michigan, who studies sperm RNA but was not involved in the research.

“What it’s doing is building on the notion that dad’s contribution is actually more than just his genes when he fertilizes the oocyte,” Krawetz continued. “[It] really adds a new dimension in terms of what impact dad can have.”

The mechanisms that mediate such impact, however, remain unclear, said Minoo Rassoulzadegan of the University of Nice in France, who advised Mansuy’s team on how to isolate RNA from sperm. The microinjection experiments demonstrated that stress-associated RNA can induce phenotype, she said, “but we don’t know how. This is the question for the future, to find out what [the RNA] is doing to the genome.”

Mansuy’s team is now focusing on pinning down how stress alters the germ cells’ RNA profiles, and what, exactly, those altered RNAs target.

K. Gapp et al., “Implication of sperm RNAs in transgenerational inheritance of the effects of early trauma in mice,” Nature Neuroscience, doi:10.1038/nn.3695, 2014.

Correction (April 13): This article has been updated to reflect that when examining RNA from mouse sperm, serum, and hippocampus, Mansuy’s team detected changes in the abundance of miRNAs and piRNAs only in spem, not in “all three sources” as originally stated. The Scientist regrets the error.

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Avatar of: James V. Kohl

James V. Kohl

Posts: 492

April 14, 2014

Re: "The mechanisms that mediate such impact, however, remain unclear..."

Nutrient stress and social stress link alterations in the microRNA/messenger RNA balance from the epigenetic landscape to the physical landscape of DNA in species from microbes to man via conserved molecular mechanisms.

I integrated experimental evidence of olfactory/pheromonal cause and effect in an invited review, which is a follow up to reviews I've published during the past two decades. For example, see: Nutrient-dependent/pheromone-controlled adaptive evolution: a model. However, soon after its publication, it became clear that 'adaptive evolution' is an incorrect term. 

Nutrient-dependent alterations in the microRNA/messenger RNA balance lead to pheromone-controlled species diversity via ecological adaptations, not via evolution. Therefore, I attempted to move forward via the incorporation of what is currently known about physics, chemistry, and molecular biology. I hoped to publish this article on nutritional epigenetics. See: Nutrient-dependent pheromone-controlled ecological adaptations: from atoms to ecosystems. However, no one would review the invited subsmission, which was rejected.

Nevertheless, the atoms to ecosystems approach is a clear representation of how nutrient-dependent changes in microRNAs lead to alterations in the microRNA/messenger RNA balance, SNPs, alternative splicings of pre-mRNA, amino acid substitutions and thus to the de novo creation of genes, which are required for the differentiation of cell types and the increasing organismal complexity that is manifested in the plasticity of morphological and behavioral phenotypes during their development.

Kudos to Gapp et al., for their experimental designs that clearly link microRNAs to transgenerational epigenetic effects on behaviors. Obviously, the behaviors do not evolve, but they must change in the context of species-specific nutrient-dependent ecological adaptations to ecological variation in the availability of nutrients (i.e., nutrient stress and social stress).


Avatar of: Alexandru


Posts: 92

April 15, 2014

It is un important step in genetic data transmission observation.

I advanced wireless data transmission link between DNA and behavior seven years ago in "Paternal mitochondria DNA (Adam mtDNA) data transmission theory" (ISBN 978-606-92107-1-0).

Abstract: Brain and soul storming - The necessary and sufficient processes to a well function of the human body are meticulous arranged by specific organizational cells, so called process bio-managers, using inter-conditioned procedures, transmitted through three ways of communication: chemical or “protein channel”, electrical or “ion channel” and mitochondrial or “Electro Magnetic Field wireless channel”. The third type is out of the visible and measurable spectrum and raises a new challenge to the scientist. For this type of bio communication, we bring a new theoretical hypothesis, based on the managerial multidisciplinary analysis of a cybernetic model proposed by us, by simulating the human body function with the virtual computerized system based on the management of its total knowledge and its perfect quality way of function. The main bricks used for this virtual construction are: the brain, as main bio-processor, and Eve mtDNA and Adam mtDNA, as bio-antennas. We call this assembly of the total knowledge, build with brain reasoning, biological feeling, and unlimited spirit feeling, Main Decision Triangle: reason IQ- feeling EQ-conformance of harmony CQ. The main principle of the management of the total knowledge imposes us to not neglect the information produced by man during the time, even if it seems creasy at the beginning (see brainstorming definition). Because in the natural fertilisation the spermatozoids are naturally equipped with the paternal mtDNA (it looks like reflex klystron power amplifier, a veritable main bio-GPS), we consider that the paternal mitochondria DNA have a very important role in the evolution of the human being life quality and we have developed a new hypothesis, "Adam mtDNA theory", in addition to "Eve mtDNA theory". (Keywords: brain, mitochondria, maternal, paternal)

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Avatar of:

Posts: 23

November 19, 2014

Impressive. I would like to see this study repeated with fostered pups and foster mothers.

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