Transgenerational inheritance of behavioral and metabolic effects of paternal exposure to traumatic stress in early postnatal life: evidence in the 4th generation

Abstract

In the past decades, evidence supporting the transmission of acquired traits across generations has reshaped the field of genetics and the understanding of disease susceptibility. In humans, pioneer studies showed that exposure to famine, endocrine disruptors or trauma can affect descendants, and has led to a paradigm shift in thinking about heredity. Studies in humans have however been limited by the low number of successive generations, the different conditions that can be examined, and the lack of mechanistic insight they can provide. Animal models have been instrumental to circumvent these limitations and allowed studies on the mechanisms of inheritance of environmentally induced traits across generations in controlled and reproducible settings. However, most models available today are only intergenerational and do not demonstrate transmission beyond the direct offspring of exposed individuals. Here, we report transgenerational transmission of behavioral and metabolic phenotypes up to the 4th generation in a mouse model of paternal postnatal trauma (MSUS). Based on large animal numbers (up to 124 per group) from several independent breedings conducted 10 years apart by different experimenters, we show that depressive-like behaviors are transmitted to the offspring until the third generation, and risk-taking and glucose dysregulation until the fourth generation via males. The symptoms are consistent and reproducible, and persist with similar severity across generations. These results provide strong evidence that adverse conditions in early postnatal life can have transgenerational effects, and highlight the validity of MSUS as a solid model of transgenerational epigenetic inheritance.

The active role of spermatozoa in transgenerational inheritance

“…Soma-to-sperm RNA delivery is an unprecedented dynamic, well-regulated process, mediated by extracellular vesicles occurring during the epididymal maturation of sperm cells in mice [14,18,19]. These RNAs comprise mostly regulatory miRNAs and tRNA fragments [11,12,14,20] that are delivered to oocytes at fertilization, are essential to early embryonic development [17] and have been demonstrated to affect the fate of the progeny [21][22][23][24][25][26] up to the fourth generation [27,28]. The effect on embryonic development is a consequence of spermatozoa delivering their RNA cargos to oocytes at fertilization [29].…”

Intermittent hypoxia promotes functional neuroprotection from retinal ischemia in untreated first-generation offspring

“…Evidence supporting the nongenetic inheritance of disease susceptibility as a result of environmentally-induced epigenetic modifications to the parental germline continues to grow (6)(7)(8)(9)(10)(11). conversely, passing the resilient phenotype to the F2 generation and beyond would be unnecessary if the potential for these subsequent generations to experience this injury is no longer present.…”

“…In fact, epigenetic modifications secondary to stress and environmental change can not only affect phenotypes across the lifespan, but can also affect phenotypes in progeny. Accumulating evidence documents the intergenerational and transgenerational passage of epigenetically-induced phenotypes in a number of species (6)(7)(8), including mammals (9)(10)(11). That this also occurs in humans, beyond imprinting, is strongly suggested by a broad set of elegantly curated epidemiological data (12,13).…”

Inter- and transgenerational inheritance of behavioral phenotypes

“…One of the most notable animal models is based on unpredictable maternal separation combined with unpredictable maternal stress (MSUS), an early postnatal paradigm of chronic trauma that leads to depressive-like symptoms, increased risk-taking, and antisocial behaviors up to the third or even the fourth generation [8,11,12]. In this model, hippocampus-dependent object recognition memory and synaptic plasticity are also impaired in exposed mice and their offspring [13].…”