Paternal transmission of behavioural and metabolic traits induced by postnatal stress to the 5th generation in mice

Abstract

Life experiences and environmental conditions in childhood can change the physiology and behaviour of exposed individuals and in some cases, of their offspring. In rodent models, stress/trauma, poor diet and endocrine disruptors in a parent have been shown to cause phenotypes in the direct progeny, suggesting intergenerational inheritance. A few models also examined transmission to further offspring and suggested transgenerational inheritance, but such multi-generations inheritance is not well characterized. Our previous work in a mouse model of early postnatal stress showed that behaviour and metabolism are altered in the offspring of exposed males up to the 4th generation in the patriline and up to the 2nd generation in the matriline. The present study examined if in the patriline, symptoms can be transmitted beyond the 4th generation. Analyses of the 5th and 6th generation of mice revealed that altered risk-taking and glucose regulation caused by postnatal stress are still manifested in the 5th generation but are attenuated in the 6th generation. Some of the symptoms are expressed in both males and females, but some are sex-dependent and sometimes opposite. These results indicate that postnatal trauma can affect behaviour and metabolism over many generations, suggesting epigenetic mechanisms of transmission.

Inter- and transgenerational heritability of preconception chronic stress or alcohol exposure: Translational outcomes in brain and behavior

“…F4 and F5 effects were specific to males. Interestingly, F4 males showed decreased EPM open arm time, but increased EPM open arm time was restored in F5 males ( Boscardin et al, 2022 ). While many of the above phenotypes ( i.e., increased EPM open arm time, decreased latency to enter EPM open arm or OFT center time) may appear to suggest that the parental exposure resulted in reduced anxiety-like behaviors in the progeny, there have been other interpretations of these effects.…”

“…Sex- and generation-dependent behavioral phenotypes have been observed in the progeny of sires exposed to maternal separation with unpredictable stress (MSUS). The MSUS paradigm of PPS can produce transgenerational alterations in behavior up to the fifth generation in male mice ( Boscardin et al, 2022 ). Interpretation of these effects requires a synthesis of multiple studies ( Table 2 ).…”

“…All studies used C57BL/6JRj mice and performed MSUS from postnatal days 1–14. Franklin et al (2010) van Steenwyk et al (2018) Boscardin et al (2022) F1 Males: did not examine Females: ↓ EPM open arm entry latency ( Gapp et al, 2014a ) ↑ FST floating time ↓ latency to enter unfamiliar area in free exploratory paradigm ↓ OFT center entry latency Males: ↑ EPM open arm time ↓ EPM open arm entry latency – F2 Males: ↑ FST floating time Females: ↓ latency to enter unfamiliar area in free exploratory paradigm ↓ OFT center entry latency Males: ↓ EPM open arm entry latency ↑ FST floating time – F3 – Males: ↑ EPM open arm time ↓ EPM open arm entry latency Females: ↑ EPM open arm time ↓ EPM open arm entry latency – F4 – – Males: ↓ EPM open arm time F5 – – Males: ↑ EPM open arm time -: not applicable or not specified. EPM: elevated plus maze.…”

The Logic of Transgenerational Inheritance: Timescales of Adaptation

“…This nomenclature issue extends to the lack of consistent phenotypes in multiple generations; if inherited effects are observed in one of the sexes in specific progeny generations, and if opposite effects are observed between generations, further investigation should be done to address the biological significance of those observations. For example, if a phenotype is only reported in males of the one generation and females of another generation, or a new phenotype is seen in a much later generation (Boscardin et al 2022, Franklin et al 2010, and all show low statistical significance, then whether this is truly a transgenerational effect should be evaluated. It is important to determine not only what is a TEI phenotype but also whether these effects are reproducible and significant in order to understand what we might do to interrupt maladaptive TEI effects.…”