Effects of stress across generations: why sex matters.

I n this issue of Biological Psychiatry, Saavedra-Rodrı́guez and Feig (1) demonstrated that the experience of social stress during a period spanning from adolescence to adulthood induces longterm increases in anxiety-like behavior and social deficits in mice. However, the consequences of stress are revealed to extend far beyond this initial effect. Using a breeding design in which stressexposed males and females are mated with stressed or nonexposed mice (Figure 1), with no subsequent stress exposure, the effects of stress across generations are explored. Offspring (F1), grandoffspring (F2), and great-grandoffspring (F3) were observed to inherit the effects of parental (F0) stress, with females but not males exhibiting anxiety-like behavior and social deficits. Although males do not inherit the behavioral characteristics associated with stress exposure, the breeding design suggested that it is through males (and not females) that these effects can be transmitted to the F3 generation. Both mothers and fathers are capable of the transmission of the effects of social stress to their daughters; however, beyond this F1 generation, it is through stress-exposed fathers that both anxiety and social deficits can be observed in subsequent generations. This study highlights the complex pathways through which males and females may potentially influence the development of future generations and may contribute to a growing literature on the transgenerational consequences of adversity (2). The notion that the experiences of one generation can have an impact on the development of subsequent generations, leading to vulnerability to psychopathology, has added a new level of complexity to the study of the origins of disease. The question raised by the persistence of environmentally induced effects across generations is regarding mechanism: What biologic and behavioral pathways can lead to the transgenerational continuity of phenotype? It is likely that there is no simple answer to this question, which will require a more in-depth understanding of the interaction between males and females during mating; the prenatal and postnatal interplay between mothers, fathers, and offspring; the molecular events characteristic of the maturation of gametes; and the potential heritability of biological information. Saavedra-Rodrı́guez and Feig (1) tackled the question of mechanism using a number of approaches. First, they demonstrated that postnatal cross-fostering of F1 offspring between stressed and control parents did not diminish the transmission of the effects of parental stress to offspring. Stress experienced at various times within the life span can result in decreased mother-infant interactions during the postnatal period. Thus, a possible route through which the effects of social stress become perpetuated across generations is through altered maternal care (3). However, it would appear that this behavioral mechanism of transmission does not account for the transgenerational impact of social instability in the current paradigm.