Social Isolation Stress Modulates Pregnancy Outcomes and the Inflammatory Profile of Rat Uterus

Abstract

Prenatal stressors have been linked to adverse pregnancy outcomes; including preterm birth (PTB). Recent work demonstrates that social isolation in mothers represents a silent stressor contributing to PTB risk. Here; we investigate the association of inflammatory and stress markers with PTB risk in Long–Evans rats exposed to social isolation stress (SIS) during preconception and pregnancy across four generations (F0-F3). Gestational length; blood glucose; corticosterone levels; and maternal and offspring weights were assessed in two SIS paradigms: transgenerational (TG) and multigenerational (MG) exposure. Maternal uterine tissues were collected 21 days after the dams gave birth. Exposure to SIS reduced pregnancy lengths in the parental generation and neonatal birth weights in the F1 and F2 generations. Interleukin (IL)-1β (Il1b) mRNA levels increased in F0 animals but decreased in the offspring of both stress lineages. Protein levels of IL-1β decreased in the TG lineage. Corticotrophin-releasing hormone receptor 1 (Crhr1) expression decreased in SIS-exposed F0 animals and increased in the TG-F2 and MG-F1 offspring. Expression of enzyme 11-β hydroxysteroid dehydrogenase-2 (11bHSD2) was enhanced in F1 animals. These findings suggest SIS has adverse consequences on the F0 mothers; but their F1–F3 progeny may adapt to this chronic stress; thus supporting the fetal programming hypothesis.

Environmental Enrichment Promotes Transgenerational Programming of Uterine Inflammatory and Stress Markers Comparable to Gestational Chronic Variable Stress

“…Stress has known adverse effects on neonatal birth weights [ 3 , 17 , 28 ]. We measured female and male weights on postnatal day (P)1 to determine if a combination of psychological and psychosocial stressors impacted offspring weight.…”

“…Stress has been shown to alter proinflammatory cytokine expression in the uterus and levels in the blood [ 17 , 22 , 28 , 46 ]. Since proinflammatory cytokines are essential mediators of the inflammatory events leading to the activation of the birth cascade [ 21 ], we measured Il1a and Il1b gene expression in the uteri of rats that experienced gestational and ancestral stress.…”

“…Maternal stress may disrupt this sensitive immunological balance and lead to birth complications (i.e., preterm birth [ 4 , 49 , 50 ], preeclampsia [ 51 , 52 ]) and inflammation in the placenta and fetal brain [ 5 , 53 , 54 ]. Restraint and social isolation stressors have been associated with uterine inflammatory, endocrine, and epigenetic modifications in gestational tissues [ 3 , 17 ]. Other consequences of such stressors include metabolic, behavioural, and APOs in rats [ 43 , 55 , 56 ].…”

“…The hypothalamic–pituitary–adrenal (HPA) axis and the immune system are two of the most relevant systems affected by gestational stress [ 14 ]. Several studies have shown a link between prenatal stressors and altered endocrine and inflammatory mediators in the gestational tissues [ 3 , 5 , 15 , 16 , 17 ]. Excess maternal cortisol/corticosterone (CORT) is released during stress and may cross the placenta, directly affecting the fetal brain and HPA axis [ 18 ].…”

“…Further studies demonstrated that changes in the immune system and cytokine milieu during PNMS are associated with poor pregnancy outcomes, including preterm birth [ 4 , 25 , 26 , 27 ]. Similarly, prenatal exposure to social isolation and restraint stress in rats induced changes in the uterine expression of inflammatory markers [ 17 , 28 ].…”