Germ Cell Drivers: Transmission of Preconception Stress Across Generations

Abstract

Exposure to stress can accelerate maturation and hasten reproduction. Although potentially adaptive, the trade-off is higher risk for morbidity and mortality. In humans, the intergenerational effects of stress have been demonstrated, but the precise mechanisms are unknown. Strikingly, even if parental stress occurs prior to conception, as adults, their offspring show worse mental and physical health. Emerging evidence primarily from preclinical models suggests that epigenetic programming may encode preconception stress exposures in germ cells, potentially impacting the phenotype of the offspring. In this narrative review, we evaluate the strength of the evidence for this mechanism across animals and humans in both males and females. The strongest evidence comes from studies of male mice, in which paternal preconception stress is associated with a host of phenotypic changes in the offspring and stress-induced changes in the small non-coding RNA content in sperm have been implicated. Two recent studies in men provide evidence that some small non-coding RNAs in sperm are responsive to past and current stress, including some of the same ones identified in mice. Although preliminary evidence suggests that findings from mice may map onto men, the next steps will be (1) considering whether stress type, severity, duration, and developmental timing affect germ cell epigenetic markers, (2) determining whether germ cell epigenetic markers contribute to disease risk in the offspring of stress-exposed parents, and (3) overcoming methodological challenges in order to extend this research to females.

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

“…In animal studies, these include chronic unpredictable stress ( Monteiro et al, 2015 ; Katz, 1982 ; Willner et al, 1987 ; D’Aquila et al, 1994 ; Tannenbaum et al, 2002 ) (CUS, also sometimes referred to as chronic variable stress), chronic social defeat stress (CSDS), ( Krishnan et al, 2007 ; Golden et al, 2011 ; Kudryavtseva et al, 1991 ) and early life stress specifically induced by maternal separation with unpredictable stress (MSUS) ( Mansuy et al, 2011 ; Franklin et al, 2010 ). For further reviews that investigate other forms of stress ( e.g., nutrient deficiencies or pathogen infections) and trauma exposure, we recommend the following: Chan et al (2018) ; Duffy et al (2021) ; Tan et al (2023) ; Batchelor and Pang (2019) ; Siddeek et al (2018) . For clarity and consistency both within the literature and across paradigms discussed, this review will refer to the directly stressed animal as the parental/founder generation (F0), and following mating, the initial generation of offspring produced will be referred to as the first filial generation (F1).…”

“…While most epigenetic marks such as DNA and histone modifications are erased during gametogenesis, some persist ( Kovalchuk and Migicovsky, 2011 ; Ben Maamar et al, 2021 ) and could be partially responsible for preconception stress phenotypes in offspring. An increasing number of studies have also implicated noncoding RNAs in cross-generational regulation of molecular and behavioral phenotypes ( Duffy et al, 2021 ; Yin et al, 2021 ; Skvortsova et al, 2018 ; Rompala and Homanics, 2019 ). The following section discusses germline mechanisms of cross-generational preconception stress inheritance.…”

Animal Foetal Models of Obesity and Diabetes – From Laboratory to Clinical Settings

“…However, in epigenetic studies on humans it is a challenge to select relevant tissues accessible to examination such as peripheral blood cells (PBC), buccal epithelial cells (BEC), or hair follicles. As both maternal and paternal history and experiences exert influence through the epigenomic information which is not contained in the DNA sequence, including variations in sperm and oocyte cytosine methylation and chromatin patterning, the influence of noncoding RNAs and mitochondria of both maternal and paternal lines should be considered (287,288). Currently, very little is known about the effects of the paternal metabolic status on the outcomes of offspring.…”

Cross Talk proposal: The kids will be fine: parental stress rodent models are good for assessing influences on human neurobiology

“…In other words, epigenetic mark ‘A’ is not itself inherited by daughter cells after conception, but rather A affects B affects C until the detectable phenotypic change being measured is produced. Often, the environmental insult producing epigenetic mark A begins in parental somatic cells, not germ cells, and may be long‐lived and able to continuously send signals to germ cells long after the insult has ended (Alshanbayeva et al., 2021; Chan et al., 2020; Duffy et al., 2021; Eaton et al., 2015). While changes in the same detectable epigenetic marks can occur at each stage (A, B, C, etc.)…”

“…For example, twin studies and GWAS of families with schizophrenia demonstrate that genetic risk only accounts for 7-52% of heritability (Hilker et al, 2018;Ripke et al, 2013Ripke et al, , 2014. Environmental factors are similarly complex and include parental exposures to nutritional challenges, stress and trauma, substance use, etc., including well-described effects on human germ cells (Chan et al, 2020;Dickson et al, 2018;Donkin et al, 2016;Duffy et al, 2021;Morgan et al, 2019;Nätt et al, 2019), and animal models have replicated such environmental effects on specific germ cell epigenetic marks (Chan et al, 2020;Chen, Yan, Cao et al, 2016;Gapp et al, 2014;Grandjean et al, 2015;Rodgers et al, 2013;Rompala et al, 2018;Sharma et al, 2016;Short et al, 2016;Vassoler et al, 2013). However, additional animal studies are needed to fill current gaps in our understanding of the mechanistic processes underlying germline epigenetic effects.…”