Prenatal two-hit stress affects maternal and offspring pregnancy outcomes and uterine gene expression in rats: match or mismatch?†

Abstract

Maternal stress and inflammation excesses can lead to adverse pregnancy outcomes and offspring development. We evaluated whether distinct prenatal stressors affect pregnancy, maternal and offspring outcomes and uterine gene expression differently when combined than either alone. Long-Evans dams were exposed to psychological or/and (two-hit) immune stress (interleukin-1 beta [IL-1β]), on gestational days 12-18 and 17-delivery respectively. Gestational length, maternal weight gain, glycaemia and corticosterone levels, offspring weight and gender effects were recorded. Maternal and offspring uteri were collected at weaning and on postnatal day 160 correspondingly. Uterine expression of genes involved in local progesterone metabolism, neuroendocrine and immune systems were analyzed using qRT-PCR. Maternal two-hit stress increased gestational length variation and the occurrence of adverse pregnancy outcomes while reducing gestational weight gain. Pup weight was negatively affected by prenatal stressors in a gender-specific way. In dams, IL-1β upregulated gene expression of neuroendocrine (Crh, Crhr1) and cytokine genes (Il1b, Il1rn, Il6 and Il10). Conversely, transcriptional patterns in offspring uteri were more variable with gene-specific up- or downregulation by each stressor separately, while exposure to both extensively reduced the expression of neuroendocrine (Hsd11b1), cytokine (Il1a, Il1rn, Il6) and IL-1 receptor genes. In conclusion, maternal stress affects physiological and molecular processes in dams and their offspring; two hits have different effects than single stressors. Outcomes appear generation-, gender- and stressor-specific. Dampening of offspring uterine gene expression after exposure to multiple stressors could fit within the match/mismatch hypothesis of perinatal programming, with offspring preparing for a stressful life.

Maternal immune activation generates anxiety in offspring: A translational meta-analysis

“…Considering that MIA might lead to altered behavior in offspring, an alternative model has emerged as an explanation for the etiology of psychiatric disorders: the two-hit model 4 – 6 . In this model, two “hits” are required for the emergence of disorders in offspring: a first “hit”, which occurs during prenatal life (such as MIA) and disrupts the offspring’s central nervous system (CNS) development, thereby increasing the vulnerability to a second “hit”, which might occur later in life and leads to the onset of the disorder 7 . In many cases, the second “hit” could be an environmental factor such as psychological stress 7 , 8 .…”

“…One of the common animal models used to study the two-hit model of psychiatric disorders is induced by MIA, which is achieved by exposing a dam to polyinosinic:polycytidylic acid (PolyI:C) or lipopolysaccharide (LPS), which mimic viral or bacterial insult, respectively, during pregnancy 7 . Both of these agents stimulate the production of many endogenous proinflammatory cytokines, including interleukin (IL)-1β, IL-6, and TNFα, which, along with other factors, recruit and stimulate the production of immune cells 9 .…”

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

“…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).…”

Ageing, Social Distancing, and COVID-19 Risk: Who is more Vulnerable?

“…Based on reports of non-communicable and communicable diseases, it is possible that COVID-19 vulnerability includes adverse childhood and lifetime experiences (Danese and McEwen, 2012), heritable epigenetic markers linked to ancestral stress (Ambeskovic et al, 2019;Faraji et al, 2017b;Yao et al, 2014), environmental pollution (Chau and Wang, 2020;Hoyt et al, 2020), poor diet (Mozaffarian et al, 2019), and poor social support (Ge et al, 2017;Malcolm et al, 2019;Menec et al, 2020). Each of these factors may be considered a stressor, or a "hit", with potentially cumulative impacts (Daskalakis et al, 2013;Verstraeten et al, 2019b) on COVID-19 vulnerability and complication. Across a single lifespan, the effects of recurrent stress may accumulate (Faraji et al, 2017a), thus increasing the body's "wear and tear" and allostatic load (AL), ultimately heightening the vulnerability to disease in an older individual (McEwen, 2002;McEwen and Wingfield, 2010).…”