Stress transgenerationally programs metabolic pathways linked to altered mental health

Kiss, Douglas; Ambeskovic, Mirela; Montina, Tony; Metz, Gerlinde A. S.

doi:10.1007/s00018-016-2272-4

Cited by 40 publications

(44 citation statements)

References 66 publications

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“…The effects observed on these tasks are robust, consistent and highly reproducible. MSUS is currently one of the few available mouse models of transgenerational epigenetic inheritance with transmission up to the 4th generation, a depth of inheritance previously demonstrated in rodents with prenatal stress [ 57 ], toxicants [ 9 , 24 ], drugs [ 30 , 58 ] or genetic mutation ( Mtrr hypomorphic) [ 59 ]. Studies of the mechanisms of transgenerational inheritance are expected to have important implications for public health in the future.…”

Section: Discussionmentioning

confidence: 99%

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

Steenwyk

Roszkowski

Manuella

et al. 2018

Environmental Epigenetics

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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.

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Section: Discussionmentioning

confidence: 99%

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

Steenwyk

Roszkowski

Manuella

et al. 2018

Environmental Epigenetics

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“…The deleterious consequences of prenatal maternal stress not only affect the first generation of newborns, but also may be transmitted across subsequent generations (24,25). In fact, recent animal studies have shown that gestational stress across generations has downstream effects on the endocrine and metabolic pathways (26,27). Importantly, intergenerational maternal stress gradually shortens the length of gestation (26) and affects physiological and molecular processes in both the mother and offspring (28).…”

Section: Introductionmentioning

confidence: 99%

Prenatal Maternal Stress Causes Preterm Birth and Affects Neonatal Adaptive Immunity in Mice

et al. 2020

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Maternal stress is a well-established risk factor for preterm birth and has been associated with adverse neonatal outcomes in the first and subsequent generations, including increased susceptibility to disease and lasting immunological changes. However, a causal link between prenatal maternal stress and preterm birth, as well as compromised neonatal immunity, has yet to be established. To fill this gap in knowledge, we used a murine model of prenatal maternal stress across three generations and high-dimensional flow cytometry to evaluate neonatal adaptive immunity. We report that recurrent prenatal maternal stress induced preterm birth in the first and second filial generations and negatively impacted early neonatal growth. Strikingly, prenatal maternal stress induced a systematic reduction in T cells and B cells, the former including regulatory CD4+ T cells as well as IL-4-and IL-17A-producing T cells, in the second generation. Yet, neonatal adaptive immunity gained resilience against prenatal maternal stress by the third generation. We also show that the rate of prenatal maternal stress-induced preterm birth can be reduced upon cessation of stress, though neonatal growth impairments persisted. These findings provide evidence that prenatal maternal stress causes preterm birth and affects neonatal immunity across generations, adverse effects that can be ameliorated upon cessation.

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“…In the human environment, PS may be particularly impactful in low socioeconomic status communities (Farah 2017), where such stress can occur across generations, consistent with the cyclical nature of poverty. A series of studies in rats (Kiss et al 2016;McCreary et al 2016) mimicked this feature of the human environment by imposing PS consisting of restraint stress and forced swimming in a semi-random sequence in an F0, F1, and F2 generation and subsequently examined multiple consequences in female F3 offspring. Under these conditions, increases in basal corticosterone levels were seen across generations, with almost 2-fold increases between the F2 and F3 generations.…”

Section: Introductionmentioning

confidence: 99%

Lineage- and Sex-Dependent Behavioral and Biochemical Transgenerational Consequences of Developmental Exposure to Lead, Prenatal Stress, and Combined Lead and Prenatal Stress in Mice

Sobolewski

Abston

Conrad

et al. 2020

Environ Health Perspect

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BACKGROUND: Lead (Pb) exposure and prenatal stress (PS) during development are co-occurring risk factors with shared biological substrates. PS has been associated with transgenerational passage of altered behavioral phenotypes, whereas the transgenerational behavioral or biochemical consequences of Pb exposure, and modification of any such effects by PS, is unknown. OBJECTIVES: The present study sought to determine whether Pb, PS, or combined Pb and PS exposures produced adverse transgenerational consequences on brain and behavior. METHODS: Maternal Pb and PS exposures were carried out in F0 mice. Outside breeders were used at each subsequent breeding, producing four F1-F2 lineages: [F1 female-F2 female (FF), FM (male), MF, and MM]. F3 offspring were generated from each of these lineages and examined for outcomes previously found to be altered by Pb, PS, or combined Pb and PS in F1 offspring: behavioral performance [fixed-interval (FI) schedule of food reward, locomotor activity, and anxiety-like behavior], dopamine function [striatal expression of tyrosine hydroxylase (Th)], glucocorticoid receptor (GR) and plasma corticosterone, as well as brain-derived neurotrophic factor (BDNF) and total percent DNA methylation of Th and Bdnf genes in the frontal cortex and hippocampus. RESULTS: Maternal F0 Pb exposure produced runting in F3 offspring. Considered across lineages, F3 females exhibited Pb-related alterations in behavior, striatal BDNF levels, frontal cortical Th total percentage DNA methylation levels and serum corticosterone levels, whereas F3 males showed Pb-and PS-related alterations in behavior and total percent DNA methylation of hippocampal Bdnf. However, numerous lineage-specific effects were observed, most of greater magnitude than those observed across lineages, with outcomes differing by F3 sex. DISCUSSION: These findings support the possibility that exposures of previous generations to Pb or PS may influence the brain and behavior of future generations. Observed changes were sex-dependent, with F3 females showing multiple changes through Pb-exposed lineages. Lineage effects may occur through maternal responses to pregnancy, altered maternal behavior, epigenetic modifications, or a combination of mechanisms, but they have significant public health ramifications regardless of mechanism. https://doi.

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Stress transgenerationally programs metabolic pathways linked to altered mental health

Cited by 40 publications

References 66 publications

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

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

Prenatal Maternal Stress Causes Preterm Birth and Affects Neonatal Adaptive Immunity in Mice

Lineage- and Sex-Dependent Behavioral and Biochemical Transgenerational Consequences of Developmental Exposure to Lead, Prenatal Stress, and Combined Lead and Prenatal Stress in Mice

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