Effect of a maternal inflammatory challenge during the preimplantation period on offspring development and phenotype

Abstract

The preimplantation mammalian embryo is sensitive to its immediate surroundings: alterations to its in vitro or in vivo environment can affect not only the immediate events of blastocyst formation, but can also give rise to long-term phenotypic consequences during fetal and/or postnatal life. For example, rodent studies have shown that maternal under-nutrition during preimplantation gestation can lead to increased risk of cardiovascular, metabolic and behavioural abnormalities in the adult offspring.
Do other types of maternal challenge similarly impact on the developmental programme with long-lasting consequences? Infection and injury are common in everyday life and normally result in altered homeostasis and generation of an inflammatory response. The aim of my thesis was to study the effects of an inflammatory environment during preimplantation development on the phenotype of the blastocyst, fetus and offspring postnatally. In the first part of the study mouse embryos were cultured in vitro in the presence of medium only (control) or increasing concentrations (1-1000 pg/ml) of the inflammatory cytokine, interferon ? (IFN-?). The second part of the study focused on an in vivo model of maternal systemic inflammation where saline (control), 10, 50 or 150 ?g/kg lipopolysaccharide (LPS) was administered intraperitoneally (i.p.) to female mice on gestational day 0.5 (GD 0.5).
In vitro culture of mouse embryos with select higher concentrations of IFN-? resulted in a greater proportion of cavitated embryos (1000 pg/ml) and reduced inner cell mass (ICM) cell number (10 and 1000 pg/ml) without affecting trophectoderm (TE) cell number. In vivo, generation of a maternal systemic inflammatory response to LPS administration was confirmed initially. LPS treatment induced sickness behaviour, weight loss and increased the serum concentration of several cytokines, e.g. interleukin-1? (IL-1?) and tumour necrosis factor-? (TNF-?). Prenatally, the maternal inflammatory challenge resulted in reduced ICM cell number and reduced ICM:TE cell ratio in GD 3.5 blastocysts, but did not affect the number of embryos generated or GD 17 litter size. Furthermore, the GD 17 conceptus was normal in terms of weight of the extra-embryonic tissues and fetal organs. Postnatally, the systemic maternal inflammatory challenge did not alter litter size, birth weight or growth, but did result in altered behaviour, organ/body weight ratios and immune status of adult offspring. In particular, male offspring from 150 ?g/kg LPS treated mothers displayed reduced levels of locomotor and exploratory related activity, increased mass of specific fat-pads and increased body mass index (BMI). Furthermore, male offspring from 150 ?g/kg LPS treated mothers displayed altered splenic T and B lymphocyte populations with the percentage of B lymphocytes reduced and the percentage of T lymphocytes increased. Both male and female offspring from LPS treated mothers had lower concentrations of 3 a number of serum cytokines and chemokines, either basally or after directly receiving their own LPS challenge.
My work using a mouse model has shown that maternal inflammation during preimplantation gestation can permanently change the developmental programme, leading to altered adult phenotype, affecting diverse physiological systems. This study implicates maternal immune status during very early gestation as critical in the health of the next generation.

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