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Method, degree and lineage of prenatal maternal stress: effects on inflammatory and stress marker profiles of reproductive tissues and pregnancy outcomes
- Author / Creator
- Lopes, Nayara Gabriela Antunes
Prenatal maternal stress (PNMS) is any type of stress that pregnant women and animals experience. It was reported that over 70% of pregnant women experience low to moderate stress, while 6% experience high stress. Growing evidence indicates that PNMS influences maternal and offspring health outcomes. PNMS alters the homeostatic milieu of pregnancy, impairs the maternal-fetal neuroendocrine axis, and increases systemic and gestational tissues' pro-inflammatory mediators. Such changes increase the risk of pregnancy complications, including preterm birth. Adversity during critical periods of embryonic and fetal development may alter the transcriptome and affect gene expression and phenotypes in adulthood. These stress-induced changes can be inherited through paternal and maternal lineages via transgenerational transmission of traits to the offspring and may cause low birth weight, cardio-metabolic dysfunction, cognitive, and behavioural adverse outcomes. However, the molecular mechanisms underlying stress-related adverse pregnancy outcomes and fetal programming are poorly understood.
In this dissertation, I investigated the effects of PNMS on reproductive tissues' inflammatory and endocrine programming of the offspring and the risk of preterm birth across generations. First, rats were subjected to preconceptional and gestational social isolation stress (SIS), and its effects were assessed across four generations. I found that SIS shortened F0 dams' pregnancy duration and reduced the birth weights of female and male offspring. In addition, SIS programmed the offspring's long-term metabolic outcomes and altered uterine inflammatory and stress markers, predominantly inducing an adaptive phenotype through the F1-F3 generations. Interestingly, the stress-induced changes were similar in the two stress paradigms used in the study, where the offspring exposed to ancestral stress (transgenerational group) or cumulative stress (multigenerational group) appeared to build resilience to counteract SIS.
Next, I showed that chronic variable stressors (CVS) - SIS and restraint stress - have immediate, long-term, and transgenerational effects on the offspring. F0 pregnant rats were subjected to CVS from gestational days (GD)12-18 while their F1-F3 offspring were undisturbed. The F1 female and male offspring gave rise to two cohorts: maternal transgenerational prenatal stress (MTPS) and paternal transgenerational prenatal stress (PTPS), respectively. The MTPS study revealed that transmission of stress occurs through the maternal lineage, altering uterine markers of inflammation and stress through generations without inducing preterm birth or low birth weight. I also observed signs of adaptation to stress in the offspring’s uterine biomarkers, suggesting that resilience is passed down to the offspring. Enriched environment intervention was implemented in the F1 generation from weaning until GD20 to dampen stress effects across generations. However, the enrichment intervention produced stress-like effects in the F1-F3 generations, possibly due to the involuntary and unexpected environmental change to a novel cage in which they were not programmed to live. This can be considered positive stress, in which novelty, larger spaces, and frequent exercise may be perceived as stress and cause uterine gene expression changes across generations. Still, it might not produce the adverse health consequences of chronic stress.
In the PTPS study, the effects of CVS were transmitted from F0-stressed mothers to sons and then to grandchildren through the paternal lineage. It was observed that stress altered uterine and testicular inflammatory and stress markers by primarily upregulating female gene expression and decreasing it in the male offspring. Yet, pregnancy lengths remained unchanged in the paternal lineage. CVS also programmed the F2 offspring to higher pre-pregnancy and gestational body weights in females and increased neonatal birth weights in males.
This work confirms that PNMS and resilience are passed on to later generations regardless of the stress type. Stress consistently altered inflammatory and metabolic markers in the reproductive tissues and blood of exposed mothers and their offspring - even in the F3 generation not directly exposed to the insult - suggesting genuine transgenerational inheritance. I also showed that enrichment therapy could be stressful for animals and that its outcomes vary based on the context of the analyzed variables. Additionally, I demonstrated through our three PNMS cohorts that generational programming of stress and housing types depend on the sex and generation of the offspring, stress method, degree, time of exposure, and animal individuality. Finally, I suggest that additional stress hits in future generations might exacerbate the prenatally programmed imbalance of uterine inflammatory and stress-related mediators, predisposing them to preterm birth and other pregnancy complications.
- Graduation date
- Spring 2023
- Type of Item
- Doctor of Philosophy
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