Aging, Environment, & DiseaseDNA Methylation and Hydroxymethylation

Epigenetic Programming of Stress

Epigenetic Programming of StressWritten by Patrick McGowan and Sophie St-Cyr – University of Toronto Scarborough

Maternal effects can lead to important changes in the long-term phenotype of their offspring. These changes are often associated to a stressful prenatal or early postnatal environment that lead offspring to display altered physical defenses (increased egg size in a fish species 1) or increased stress reactivity. The transmission of information about a stressful prenatal environment from a mother to her offspring is therefore thought to be highly relevant in optimally preparing the offspring for the environment they will face later in life2. This form of early life ‘programming’, mediated prenatally through the maternal physiology or postnatally via changes in maternal behavior, can have impacts on the offspring phenotype that persist throughout the lifespan. Accumulating evidence indicates that these effects are mediated in part by epigenetic changes through DNA methylation of stress axis related genes such as the glucocorticoid receptor3. In turn, these changes lead to prolonged and elevated levels of stress hormones.

We were interested in examining the long-term impacts of a prenatal stressor that is psychogenic, mild and ecologically relevant. In prey animals such as rodents, predator odor does not require learning to be alarming and yet does not cause physical discomfort. Animals exposed to predator odor in adulthood show a wide range of impacts, including a long-term increase in anxiety behaviors, increased levels of circulating stress hormones and altered transcript abundance of stress-related genes. A number of laboratory experiments using physical stress in the mother have found long-term impacts in offspring on stress-related behavior and neural circuitry. The long-term impacts and mechanism of transmission of maternal exposure to predator odor on offspring phenotypes are still mostly unknown.

To study the impact of prenatal predator odor exposure on adult mice offspring, we exposed pregnant dams to randomized predator odor daily over the second half of the pregnancy, when the hypothalamic-pituitary adrenal (HPA) axis is developing. Controls were exposed to distilled water. Adult mice offspring whose mothers were exposed to predator odor during pregnancy stayed further away and showed decreased locomotor activity when faced with a predator odor as adults. These behaviors can be associated to antipredatory behaviors that minimize detection from predators. The behaviors occurred in conjunction with increased corticosterone stress hormone levels after predator odor exposure that correlated with the corticotrophin releasing hormone receptor 1 (CRHR1) expression in the amygdala. Furthermore, in the hippocampus of females the expression of brain-derived neurotrophic factor (BDNF) correlated positively with decreased BDNF exon IV methylation at a specific CpG site.It is possible that these sex-specific differences play an adaptive role in stressful situations and could lead to differential risks for behaviors linked to psychopathology in humans, including an increased risk for behaviors linked to affective disorders among females4.

In conclusion, prenatal predator odor exposure alone, a psychological and ethologically-relevant stressor, appears to be sufficient to alter offspring phenotype in a manner that persists through adulthood. There is also a sex-specific difference in the impacts of prenatal predator odor exposure. To our knowledge, our study provides the first evidence of maternal transmission of behavioral, neural and endocrine sensitivity to predator odor exposure in adulthood, in part via epigenetic modifications to stress-sensitive genes.

 

Original Article:

St-Cyr S, & McGowan PO (2015). Programming of stress-related behavior and epigenetic neural gene regulation in mice offspring through maternal exposure to predator odor. Frontiers in behavioral neuroscience, 9 PMID: 26082698

 

References:

1. Giesing ER, Suski CD, Warner RE, & Bell AM (2011). Female sticklebacks transfer information via eggs: effects of maternal experience with predators on offspring. Proceedings. Biological sciences / The Royal Society, 278 (1712), 1753-9 PMID: 21068041

2. Meaney MJ (2001). Maternal care, gene expression, and the transmission of individual differences in stress reactivity across generations. Annual review of neuroscience, 24, 1161-92 PMID: 11520931

3. Weaver, I., Cervoni, N., Champagne, F., D’Alessio, A., Sharma, S., Seckl, J., Dymov, S., Szyf, M., & Meaney, M. (2004). Epigenetic programming by maternal behavior Nature Neuroscience, 7 (8), 847-854 DOI: 10.1038/nn1276

4. Glover V (2011). Annual Research Review: Prenatal stress and the origins of psychopathology: an evolutionary perspective. Journal of child psychology and psychiatry, and allied disciplines, 52 (4), 356-67 PMID: 21250994

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Patrick McGowan

Patrick McGowan