Transgenerational Transmission of Drug Exposure and Stress in Rodents

January 28, 2015 · Posted in Genetics 

baby rats

New data suggest that there can be transgenerational transmission of the effects of drug exposure and stress from a paternal rat to its offspring. The father mates with a female who was not exposed to drugs or stress and never has any contact with the offspring.  Consensus is now building that this transmission occurs via epigenetic alterations in sperm.

Epigenetic alterations are those that are mediated by chemical changes in the structure of DNA and of the histones around which DNA is wrapped. These changes do not alter the inherited gene sequences but only alter how easy it is for genes encoded in the DNA to be activated (transcribed) or suppressed (inhibited).

There are three common types of epigenetic modifications. One involves the attachment of a methyl or acetyl group to the N-terminals of histones. Methylation typically inhibits transcription while acetylation activates transcription. Histones can also be altered by the addition of other compounds. The second major type of epigenetic change is when the DNA itself is methylated. This usually results in inhibition of the transcription of genes in that area. The third epigenetic mechanism is when microRNA (miRNA) binds to active RNA and changes the degree to which proteins are synthesized.

At a recent scientific meeting, researchers described the various ways epigenetic changes can be passed on to future generations.

Researcher Chris Pierce reported that chronic cocaine administration increased brain-derived neurotrophic factor (BDNF) in the medial prefrontal cortex of rats. (BDNF is important for learning and memory.) The cocaine administration led to acetylation of the promoter for BDNF.

This exposure to cocaine in male rats who then fathered offspring led to two changes in the offspring, presumably conveyed by epigenetic changes to the fathers’ sperm. The first change was a decrease in cocaine reinforcement. The offspring took longer to acquire a cocaine self-administration habit. The second change was long-lasting learning deficits in the male offspring, specifically recognition of novel objects. The deficit was associated with a reduction in long-term potentiation in the offspring. Long-term potentiation is the strengthening of synapses that occurs through repeated patterns of activity. Surprisingly, the following generation also showed deficits in learning and memory, but did not show a loss of long-term potentiation.

Editor’s Note: These data indicate that alterations in sensitivity to cocaine (in this case slower acquisition of cocaine self-administration) can be transferred to a later generation, as can learning deficits in males. These data suggest that fathers’ experience of drugs can influence cocaine responsiveness and learning via epigenetic mechanisms likely mediated via epigenetic changes to the father’s sperm.

This research suggests the possibility that, in a human clinical situation, there would be three ways that a father’s drug abuse could affect his child’s DNA. First, there is the traditional genetic inheritance, where, for example, an increased risk for drug abuse is passed on to the child via the father’s genetic code. Next, drug abuse brings about epigenetic changes to the father’s sperm. (His genetic code remains the same, but acetyl groups attach to the BDNF promoter section of his DNA, changing how those proteins get produced.) Lastly, if the father’s drug abuse added stress to the family environment, this stress could have epigenetic effects on the child’s DNA.

Researcher Alison Rodgers described how epigenetic changes involving miRNA in paternal rats influence endocrine responsivity to stress in their offspring. Rodgers put rats under stress and observed a decrease in hormonal corticosterone response to stress. When a father rat was stressed, nine different miRNAs were altered in its sperm. To prove that this stress response could be passed on transgenerationally via miRNAs, the researchers took sperm from an unstressed father, loaded it with one or all nine miRNAs from the stressed animal, and artificially inseminated female rats. Rodgers found that the sperm containing all nine miRNAs, but not the sperm carrying one randomly selected miRNA, resulted in offspring with a blunted corticosterone response to stress.

Researcher Eric Nestler showed that when a rodent goes through 10 days of defeat stress (being defeated repeatedly by a larger animal), they begin to exhibit behaviors resembling those seen in depression. Social avoidance was the most robust change, and continued for the rest of the animal’s life. Animals did not have to be physically attacked by the bigger animal to show the depression-like effects of defeat stress. Just witnessing the repeated defeats of another rat was sufficient to produce the syndrome. Again, father rats that experienced defeat stress or witnessed it passed this susceptibility to defeat stress on to their offspring (with whom they never had any contact), likely by epigenetic changes to sperm.

Editor’s Note: People take genetic vulnerability seriously, and doctors counsel families with bipolar disorder to be on the lookout for symptoms and engage in preventive measures as necessary (just as a family with a history of heart disease or breast cancer might increase vigilance and preventative measures). The risks of psychiatric illness through epigenetic mechanisms should be taken equally seriously, and families should consider preventive interventions as needed.

The evidence for epigenetic inheritance has profound clinical implications, if it is found that similar epigenetic mechanisms occur in humans. Earlier research indicates that maternal behavior can bring about long-term changes in offspring behavior and biology. Anxiety and stressors in a mother can bring about epigenetic changes to eggs, and can also affect a fetus in utero. Now it appears that a father’s sperm can also convey information about the fathers’ drug use or experience of stress to subsequent generations.

Now we know that life experiences of parents can also affect their offspring through epigenetic changes to genetic material.

In the US, the parents and grandparents of patients with bipolar disorder are more ill than the parents and grandparents of patients with bipolar disorder from the Netherlands and Germany. Family histories in the US include more unipolar depression, bipolar disorder, alcohol and substance abuse, suicide attempts, and other psychiatric illnesses, and a family history that includes these illnesses is associated with an earlier age of onset of bipolar disorder and a more difficult course of illness. Patients with bipolar illness in the US also reported more of these difficulties (excepting suicide attempts) in their children than patients with bipolar disorder in the Netherlands and Germany reported about their children.

Thus, we have seen four generations (patients plus their grandparents, parents, and children) with more cases of bipolar illness and more severe illness in those from the US compared to the Netherlands and Germany. It is likely that that this illness burden is conveyed through both genetic and epigenetic mechanisms.

These data also suggest that future generations in the US are at increased risk for illness complexity, and that we should take these clinical findings seriously and try to head off the early development of bipolar disorder with new approaches to treatment and prevention. This is a clinical and public health necessity, and one with a sense of immediacy.

On a more speculative and preliminary note, the conveyance of information transgenerationally via epigenetic marks in sperm raises a potential ameliorative approach for consideration. Should people consider harvesting and freezing their sperm when they are young adults?

The offspring of older fathers are at greater risk for some illnesses such as autism and bipolar disorder. It has long been though that mutations in sperm increase as a result of the aging process, but the current data raise the possibility that an accumulation of environmental factors (such as stressors) causing epigenetic alterations could also play a role.

Women who want to delay childbearing sometimes freeze their eggs when they are young (and eggs are more plentiful and likely to be viable). Perhaps younger men should also consider storage of their sperm for later use. In this way, the number of mutations from aging would be reduced, but so might the influence of epigenetic alterations. This might also be particularly appropriate for consideration in men who will undergo the pernicious effects of chemotherapy for cancer or even in those who will be deployed to high risk war zones where they could be exposed to traumatic experiences resulting in PTSD (which also conveys an increased risk for alcohol and substance abuse). Preserving sperm for later use might help prevent not only mutations that occur with aging, but also adverse epigenetic marks that could accumulate over time.


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