Doctoral Degrees (Physiological Sciences)

Permanent URI for this collection

https://scholar.sun.ac.za/handle/10019.1/3773

Browse

Browsing Doctoral Degrees (Physiological Sciences) by Author "Adams, Rozanne Charlene McChary"

Now showing 1 - 1 of 1
  • Thumbnail Image
    Item
    Influence of maternal inflammation on immune modulation
    (Stellenbosch : Stellenbosch University, 2020-03) Adams, Rozanne Charlene McChary; Smith, Carine; Stellenbosch University. Faculty of Science. Dept. of Physiological Sciences.
    ENGLISH ABSTRACT: Perturbations within intrauterine microenvironment, due to maternal stressors such as chronic inflammation, metabolic dysfunction and psychological stress, can result in lifelong detrimental consequences in affected offspring. Given the substantial contribution of noncommunicable diseases to the global morbidity and mortality rate, the potential impact of maternal prenatal chronic disease on foetal development is of increasing concern. Additionally, inheritance of these developmental defects, such as behavioural, neurological, glucocorticoid and immune maladaptations, can persist for multiple generations in offspring. Although inflammation that forms part of the aetiology of chronic diseases, very few studies have reported on the immunological and glucocorticoid maladaptations in offspring exposed to maternal inflammation. Moreover, even less is known about the extent of this generational transfer, the sex-specific inheritance or the transgenerational plasticity of these maladaptations in the F1 and F2 generations. Thus, we aimed to delineate the immune functionality and glucocorticoid sensitivity in leukocytes in two generations of offspring in a mouse model of chronic induced maternal inflammation. Pregnant C57/BL/6 (F0) dams were exposed to either 10µg/kg lipopolysaccharide (LPS) or 0.9% saline (control) every seven days for the duration of gestation, with no further intervention after gestation. At 8 weeks of age, the F1 offspring were crossed with either a wild-type untreated C57/BL/6 mate or F1 LPS-affected non-sibling mate to create the second generation of offspring, F2. For experimental analyses, F0, F1 and F2 mice were profiled to assess the changes in differential splenic and circulatory leukocyte populations, corticosterone concentrations, splenic leukocyte glucocorticoid sensitivity and ex vivo cytokine responses. LPS-treated F0 dams displayed augmented glucocorticoid receptor expression in splenic leukocytes, which transferred to both F1 and F2 offspring, as well as elevated inflammatory cytokine responses in LPS-stimulated splenocytes. Both male and female F1 offspring displayed glucocorticoid hypersensitivity, indicated by elevated corticosterone and leukocyte glucocorticoid receptor levels, as well as a heightened inflammatory phenotype, which was transferred to F2. However, no sex-specific traits were observed. Interestingly, F1 LPS-affected offspring displayed sex-specific transfer of inflammatory effects to F2. The glucocorticoid dysregulation and the resultant pro-inflammatory phenotype appeared to be transferred in the F1 maternal lineage to her F2 offspring, affecting the male offspring to a greater extent. In contrast, F1 LPS males only transferred a pro-inflammatory phenotype to their offspring. The cumulative inheritance of maladaptation in F2 offspring, from F1 maternal and paternal lineages being LPS-affected, displayed blunted functional immune responses, and dampened glucocorticoid levels, but unchanged leukocyte numbers and may be suggestive of immune senescence. This study contributes to the knowledge of inheritance of susceptibility to noncommunicable chronic diseases. Our findings illustrate that parental chronic inflammation may cause lifelong reprogramming to a maladapted pro-inflammatory phenotype, persisting to at least two subsequent generations of offspring. Moreover, divergent adverse outcomes are seen in F2 offspring, in terms of sex-differences and cumulative inheritance of inflammatory effects. Given the potential impact of these findings, more focussed research in this context is required to confirm and further characterise the mechanisms underlying this paradigm, to facilitate the development of future interventions.