Wednesday, November 20, 2013

Maternal Stress Prior to Conception May Influence Genetic Expression of Offspring

The most interesting field in neuroscience right now, to me, is epigenetics - in fact, it might be one of the most important new inquiries we have made in decades into understanding how our biopsychosocial surround impacts our physical health, our mental health, and even our sense of who are as human beings.

From Seminars in Reproductive Medicine: (via NIH)
Epigenetics has been defined and today is generally accepted as ‘‘the study of changes in gene function that are mitotically and/or meiotically heritable and that do not entail a change in DNA sequence.’’[3] The epigenetic modifications described in current literature generally comprise histone variants, posttranslational modifications of amino acids on the amino-terminal tail of histones, and covalent modifications of DNA bases. The validity of the current definition of epigenetics should be seriously questioned because the previously mentioned epigenetic modifications also have a crucial role in the silencing and expression of noncoding sequences.

We know, for example that the nutritional status of a man as he enters puberty will impact the health status of his son (lack of food led to lower-than-normal rates of heart disease, while too much food led to greater risk of diabetes). In animal models (murine), research confirms that "a male mammal’s nutritional past has a surprisingly strong effect on his offspring." Pre-reproduction starvation of male rats produce offspring with lower blood sugar and "altered levels of corticosterone (which protects against stress) and insulin-like growth factor 1 (which helps babies develop)."

In this new study, researchers have re-confirmed prior studies around the impact of pre-conception stress on "behavioral outcomes of offspring, even in adult life, independently of any interactions between the mother and her developing infant."

Maternal Stress Prior to Conception May Influence Genetic Expression of Offspring

November 18, 2013
Stephen I. Deutsch, MD, PhD - Ann Robinson Endowed Chair in Psychiatry, Professor and Chairman, Department of Psychiatry and Behavioral Sciences, Eastern Virginia Medical School; Attending Psychiatrist, Sentara Norfolk General Hospital, Norfolk, Va.

First published in Psychiatry Weekly, Volume 8, Issue 23, November 18, 2013

A recent study showed that maternal pre-reproductive stress in rats occurring before conception and pregnancy had transgenerational effects on both newborn and adult offspring.1 Exposing female adult rats (postnatal day 45-54) to chronic unpredictable stress 14 days before they were mated resulted in increased expression of mRNA for the corticotropin releasing factor type 1 receptor (CRF1) in frontal cortex and mature oocyte of the stressed adult female rats, as well as in the brain of newborn offspring on postnatal day 0.

The data suggest that the transgenerational transmission of effects of pre-reproductive maternal stress occurred via changes in epigenetic regulation of CRF1 expression in ova; there was an 18.5-fold enrichment of CRF1 mRNA expression in mature oocytes of stressed adult female rats, relative to oocytes of controls.1 Changes in epigenetic regulation of gene expression occur commonly as a result of changes in the methylation status of cytosine residues in CpG islands associated with promoter regions of genes. Changes in CRF1 expression may reflect alterations of function in the hypothalamic-pituitary-adrenal (HPA) axis, which responds to stress; also, CRF1 expression is enriched in areas of brain implicated in the stress response (eg, cerebral cortex, hippocampus, and amygdala), as well as in regions of the periphery (eg, GI tract, spleen and ova).

The effects of pre-reproductive maternal stress on behavior of adult offspring were influenced by both gender and the history of stress exposure of the adult offspring, and particularly by the intensity of stressful exposures in adulthood. Also, expression of CRF1 mRNA in brains of adult offspring was influenced by both maternal stress history and the stress history of the adult offspring. Exposure of the adult offspring to high stress, as opposed to low stress, led to the appreciation of differences in regional expression of CRF1 mRNA between adult offspring of maternal pre-reproductive stressed and nonstressed dams. Differences also emerged between male and female adult offspring of stressed dams and their appropriate same-sex controls. Therefore, in the high-stress condition, adult female offspring of maternal pre-reproductive stressed rats showed increased expression of CRF1 mRNA in frontal cortex, compared to adult female control offspring, whereas both male and female adult offspring of maternal pre-reproductive stressed rats showed decreased expression in the amygdala, relative to their same-sex controls.

The implications of this research suggest that the early maternal history before conception and delivery could affect behavioral outcomes of offspring, even in adult life, independently of any interactions between the mother and her developing infant.[1] The transgenerational transmission may occur through the germ line. However, transgenerational effects on outcomes may be influenced by the offspring’s gender and unique developmental history, including history of stressful exposures, and may not be dramatic. Epigenetic transmission may also include transmission of resiliency factors, and plasticity is a feature of the adult brain, so there may be reason to remain optimistic about therapeutic potential.

Disclosure: Dr. Deutsch has received grant support from the Commonwealth Health Research Board (State of Virginia).

Zaidan H, Leshem M, Gaisler-Salomon I. (2013, May 31). Prereproductive stress to female rats alters corticotropin releasing factor type 1 expression in ova and behavior and brain corticotropin releasing factor type 1 expression in offspring. Biological Psychiatry;74: 680-687.
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Here is the abstract for the original article:

Prereproductive Stress to Female Rats Alters Corticotropin Releasing Factor Type 1 Expression in Ova and Behavior and Brain Corticotropin Releasing Factor Type 1 Expression in Offspring

Hiba Zaidan, Micah Leshem, Inna Gaisler-Salomon


Human and animal studies indicate that vulnerability to stress may be heritable and that changes in germline may mediate some transgenerational effects. Corticotropin releasing factor type 1 (CRF1) is a key component in the stress response. We investigated changes in CRF1 expression in brain and ova of stressed female rats and in the brain of their neonate and adult offspring. Behavioral changes in adulthood were also assessed.


Adult female rats underwent chronic unpredictable stress. We extracted mature oocytes and brain regions from a subset of rats and mated the rest 2 weeks following the stress procedure. CRF1 expression was assessed using quantitative reverse-transcription polymerase chain reaction. Tests of anxiety and aversive learning were used to examine behavior of offspring in adulthood.


We show that chronic unpredictable stress leads to an increase in CRF1 messenger RNA expression in frontal cortex and mature oocytes. Neonatal offspring of stressed female rats show an increase in brain CRF1 expression. In adulthood, offspring of stressed female rats show sex differences in both CRF1 messenger RNA expression and behavior. Moreover, CRF1 expression patterns in frontal cortex of female offspring depend upon both maternal and individual adverse experience.

Our findings demonstrate that stress affects CRF1 expression in brain but also in ova, pointing to a possible mechanism of transgenerational transmission. In offspring, stress-induced changes are evident at birth and are thus unlikely to result from altered maternal nurturance. Finally, brain CRF1 expression in offspring depends upon gender and upon maternal and individual exposure to adverse environment.

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