Mouse maternal systemic inflammation at the zygote stage causes blunted cytokine responsiveness in lipopolysaccharide-challenged adult offspring

Abstract

BackgroundThe preimplantation embryo is sensitive to culture conditions in vitro and poor maternal diet in vivo. Such environmental perturbations can have long-lasting detrimental consequences for offspring health and physiology. However, early embryo susceptibility to other aspects of maternal health and their potential long-term influence into adulthood is relatively unexplored. In this study, we established an in vivo mouse model of maternal periconceptional systemic inflammation by intraperitoneal lipopolysaccharide (LPS) administration on the day of zygote formation and investigated the consequences into adulthood.ResultsIn the short term, maternal LPS challenge induced a transient and typical maternal sickness response (elevated serum proinflammatory cytokines and hypoactive behaviour). Maternal LPS challenge altered preimplantation embryo morphogenesis and cell lineage allocation, resulting in reduced blastocyst inner cell mass (ICM) cell number and a reduced ICM:trophectoderm cell ratio. In the long term, diverse aspects of offspring physiology were affected by maternal LPS treatment. Whilst birthweight, growth and adult blood pressure were unaltered, reduced activity in an open-field behaviour test, increased fat pad:body weight ratio and increased body mass index were observed in male, but not female, offspring. Most importantly, the maternal LPS challenge caused corticosterone-independent blunting of the serum proinflammatory cytokine response to innate immune challenge in both male and female offspring. The suppressed state of innate immunity in challenged offspring was dose-dependent with respect to the maternal LPS concentration administered.ConclusionsThese results demonstrate for the first time that the preimplantation embryo in vivo is sensitive to maternal systemic inflammation, with effects on blastocyst cell lineage allocation and consequences for behaviour, adiposity and innate immune response in adult offspring. Critically, we identify a novel mechanism mediated through maternal-embryonic interactions that confers plasticity in the development of the innate immune system, which is potentially important in setting postnatal tolerance to environmental pathogens. Our study extends the concept of developmental programming of health and disease to include maternal health at the time of conception.

Female Tract Cytokines and Developmental Programming in Embryos

“…This early phase is a highly susceptible period for influencing later fetal and infant health (Thompson et al 2005;Kwong et al 2000;Sjoblom et al 2005;Williams et al 2011). Several stressors can act in the peri-conception period including immunological, infectious, nutritional, metabolic, physiochemical or even psychosocial perturbations-all of which exert similar subtle but permanent alterations in fetal development and the life-course trajectory of offspring.…”

A Summary of Pathways or Mechanisms Linking Preconception Maternal Nutrition with Birth Outcomes

“…Maternal inflammation, which may be an indirect marker of maternal nutrition, also influences the offspringÕs phenotype as an adult (36). For example, the exposure of mice to bacterial LPS on day 1 of pregnancy induced increased body fat in the pups and a reduced cytokine response to an LPS challenge as adults (42). Thus, maternal health at conception appears to alter the immune function of the child.…”

In utero Programming of Allergic Susceptibility

“…LPS given to pregnant mice on the day after conception altered the capacity of their adult offspring to secrete cytokines after LPS challenge [44]. A blunted cytokine response to innate immune challenge was evident in both male and female offspring, and was dose-dependent with respect to the concentration of LPS administered to the mother.…”