Pitfalls and potential: Translating the two-hit model of early life stress from pre-clinical non-human experiments to human samples

Exposure to early life stress (ELS) has been linked to at least double the risk of psychopathology as well as higher morbidity and earlier mortality across the lifespan. For this reason, the field of developmental psychopathology has spent decades identifying factors that explain which individuals are at risk for negative health outcomes. Preclinical experiments in this field commonly test the "two-hit hypothesis", which explores how ELS potentiates vulnerability to pathogenic physiological and behavioral outcomes when an individual is exposed to a stressor later in development. Yet, translation of the two-hit hypothesis to humans is conceptually and practically challenging, thus impeding progress in the field. This review summarizes the two-hit hypothesis used in preclinical experiments as it pertains to two putative pathways linking ELS to psychopathology: the innate immune and neuroendocrine systems. This review also identifies important considerations when translating this model to humans and provides several recommendations. Specifically, attention to the "biological salience" of different forms of ELA and the concordance of that salience with later probes of the system are needed. Further, the consequences of ELS may be context-specific rather than ubiquitous, at least among young people. Within this conceptualization, "second hits" may be best operationalized using standardized acute challenges to the innate immune and neuroendocrine systems (e.g., psychosocial stress). Third, more explicit reporting of sex differences in the human literature is needed. Finally, preclinical experimental designs that more accurately reflect the natural occurrence of ELS in community samples will more effectively advance the understanding of developmental mechanisms that occur as a consequence of ELS.