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Epigenetic transgenerational inheritance of altered stress responses

A fantastic article on epigenetics. Please download the pdf file to read the full article.



Ancestral environmental exposures have previously been shown to promote epigenetic transgenerational inheritance and influence all aspects of an individual’s life history. In addition, proximate life events such as chronic stress have documented effects on the development of physiological, neural, and behavioral phenotypes in adulthood. We used a systems biology approach to investigate in male rats the interaction of the ancestral modifications carried transgenerationally in the germ line and the proximate modifications involving chronic restraint stress during adolescence. We find that a single exposure to a common-use fungicide (vinclozolin) three generations removed alters the physiology, behavior, metabolic activity, and transcriptome in discrete brain nuclei in descendant males, causing them to respond differently to chronic restraint stress. This alteration of baseline brain development promotes a change in neural genomic activity that correlates with changes in physiology and behavior, revealing the interaction of genetics, environment, and epigenetic transgenerational inheritance in the shaping of the adult phenotype. This is an important demonstration in an animal that ancestral exposure to an environmental compound modifies how descendants of these progenitor individuals perceive and respond to a stress challenge experienced during their own life history.

Phenotype is determined by both inherited and experienced factors. Traditionally, the former are regarded as a result of genetic inheritance, and the latter encompass events in the individual’s personal life history. Study of how the environment shapes the phenotype was initially referred to as “epigenesis” (1) and later termed “epigenetics” by Waddington (2). The current definition for epigenetics used in this study is “molecular factors or processes that regulate genome activity independent of DNA sequence and are mitotically stable” (3). The model used in the current study involves an epigenetic transgenerational inheritance of a behavioral phenotype (4) induced by an environmental toxicant (5) and transmitted through the germ line, involving a permanent alteration in the sperm epigenome (i.e., DNA methylation) (6). The epigenetic transgenerational inheritance of this altered sperm epigenome modifies the subsequent development and epigenomes of all cells and tissues, including the brain, to promote phenotypic variation (7). Although no direct epigenetic measurements were made in the current study, the epigenetic model and role of epigenetics in development provides the molecular basis of the observations presented.

The development of brain and behavior involves at least two distinct epigenetic programming mechanisms (38). “Germ line-dependent” epigenetic change occurs when the modified epigenome is permanently incorporated into the germ line to manifest each generation in the absence of the causative agent. “Context-dependent” epigenetic change occurs when the environmental factors that bring about the epigenetic modification persist in the environment. Most research in epigenetics today falls within this context-dependent category. Although both have been attributed with “generational” properties, only germ line-dependent epigenetic modification is epigenetic transgenerational inheritance (57). The life-history approach to the study of behavioral development emphasizes both the continuity and interplay between the internal and external environmental characteristic of the specific life stages. Most research on the effects of stress has focused on the earliest life stages (fetus and neonate) or adulthood, with relatively few studies on adolescence (9?11). It is during this period that adrenarche and pubarche occur and the individual graduates from dependence to independence, assuming the properties of maturity. Stress experienced during adolescence has enduring effects, including neural remodeling, sensitivity to drugs of abuse, impaired learning and memory, and altered emotional behaviors in adulthood (12??15). The current study shows that the effects of chronic restraint stress (CRS) during adolescence on the adult physiological, behavioral, and neural phenotypes become more profound when considered in the context of epigenetic transgenerational inheritance.

We investigated this complex phenotypic response with a unique statistical approach for multidimensional phenotype analysis (16). Systems biology attempts to understand how molecular- to organism-level processes are involved in the emergence of complex phenotypes. Emergence was originally formulated by Weiss (1718) to mean “phenotypes, and the mechanisms that underlie them, depend on, and subordinate to, the law which rules the complex as a unit.” Systems biology approaches have recently been used to examine the phenotype at the molecular level of genetics or epigenetics (19). The current study tests the hypothesis that a combination of an environmentally induced epigenetic transgenerational inheritance (lineage) and context-dependent stress (stress) interact and promote alterations in brain development and genome activity (gene networks) that alter the adult phenotype at all levels.


In social animals, the presence of conspecifics is another powerful force shaping how an individual responds to abiotic and biotic stimuli (Fig. S1A). When housed together individuals tend to be less sensitive to stressors that, if experienced alone, are debilitating or lethal (20). Social status also influences sensitivity to negative allostatic factors, with subordinate individuals often faring more poorly than dominant individuals. Social housing also modulates both the stress response (21) and the behavior of transgenerationally epigenetically modified individuals (22). Thus, individuals from each lineage were housed together in dyads; half of the dyads were exposed to CRS.

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