Epigenetic mechanisms and the transgenerational effects of maternal care

Abstract

The transmission of traits across generations has typically been attributed to the inheritance by offspring of genomic information from parental generations. However, recent evidence suggests that epigenetic mechanisms are capable of mediating this type of transmission. In the case of maternal care, there is evidence for the behavioral transmission of postpartum behavior from mothers to female offspring. The neuroendocrine and molecular mediators of this transmission have been explored in rats and implicate estrogen-oxytocin interactions and the differential methylation of hypothalamic estrogen receptors. These maternal effects can influence multiple aspects of neurobiology and behavior of offspring and this particular mode of inheritance is dynamic in response to environmental variation. In this review, evidence for the generational transmission of maternal care and the mechanisms underlying this transmission will be discussed as will the implications of this inheritance system for offspring development and for the transmission of environmental information from parents to offspring. Keywords maternal; epigenetic; DNA methylation; estrogen receptor α; oxytocin; environment; cross-fostering Maternal effects have been demonstrated across many species and serve as an important cue to offspring development. In mammals, the lengthy period of prenatal and postnatal motherinfant interaction provides an opportunity for mothers to influence offspring through a variety of mechanisms. During gestation, interactions between mother and fetus are critical for growth and development and variations in these interactions can have long-term consequences for offspring physiological and psychological health. These effects have best been demonstrated through study of prenatal stress [1] and maternal malnutrition [2;3] in which changes to the mother's neuroendocrine system and physiology produces a shift in fetal neurodevelopment. Likewise, the care received by an infant early in life can produce changes in the development of neural systems regulating response to novelty and social behavior [4]. Thus, the maternal environment experienced by a developing organism can play a critical role in shaping adult patterns of behavior. Moreover, there can be transmission of these effects to subsequent generations through alterations in the reproductive behavior of offspring. Thus maternal care can be transmitted from mothers to daughters and grand-daughters. The mechanisms mediating Correspondence should be addressed to: Dr. Frances A. Champagne, Department of Psychology, Columbia University, Room 406 Schermerhorn Hall, 1190 Amsterdam Avenue, New York, NY 10017, Phone: (212) 854-2589, Fax: (212) 854-3609, Email: E-mail: fac2105@columbia.edu. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is ...

Oxytocin pathways in the intergenerational transmission of maternal early life stress

“…Finally, OT modulates the activity of stress-sensitive biological systems, such as the HPA-axis (Cardoso et al, 2014) and the immune system (Wang et al, 2015), which have been previously proposed to affect fetal development (Entringer et al, 2015). Taken together, these findings suggest OT signaling to be an exquisite target for pre- and postnatal pathways of intergenerational transmission of maternal ELS, which is further substantiated by findings in rodents (Champagne, 2008). …”

“…These epigenetic modifications occur without sequential variation. Epigenetic control of gene expression is highly responsive to environmental influences such as ELS, especially during developmentally sensitive periods in early life, as has been shown in rodents (Champagne, 2008; Meaney, 2001; Weaver et al, 2004) and humans (McGowan et al, 2009). DNA methylation, i.e., the attachment of methyl groups (CH 3 ) to the 5-carbon position of cytosine, which typically occurs at so-called CpG dinucleotides where a cytosine base is followed by a guanine base, generally results in gene silencing and is the only epigenetic modification of the human OXTR gene studied to date.…”

“…The effects of ELS on key regions of the neural circuits that underlie parenting have been most rigorously studied in animal models (Champagne, 2008; Champagne et al, 2001; Pena et al, 2014). In female offspring of rats, a low level of maternal care (LG) is associated with lower OTR expression in the MPOA, PVN, the central nucleus of the amygdala, and the lateral septum (Champagne et al, 2001).…”

“…These experience-induced differences in OT-DA neural circuits that underlie parenting correspond to observable parenting behaviors. Lower levels of OTR expression are associated with less maternal responsiveness towards pups (Champagne, 2008; Champagne et al, 2001). This intergenerational transmission of maternal behavior in rats is partly mediated by epigenetic modifications of the estrogen receptor α with downstream effects on OTR expression regulation in the brain, which will be further described below (see section 3.2.2).…”

“…In animal models of non-genetic intergenerational transmission of maternal parenting behaviors (Champagne, 2008), experience-dependent differential methylation of the estrogen receptor α gene has been shown to be associated with observable differences in maternal parenting. The E-activated ERα acts as a transcription factor at an estrogen-response element in the rat Oxtr gene, thereby upregulating OTR mRNA expression in brain regions that are critically involved in maternal behavior such as the MPOA.…”