Chronic Gestational Inflammation: Transfer of Maternal Adaptation over Two Generations of Progeny

Abstract

Changes in the in utero environment result in generational transfer of maladapted physiology in the context of conditions such as stress, obesity, and anxiety. Given the significant contribution of noncommunicable diseases—which are characterised by chronic inflammation—to population mortality, the potential for chronic maternal inflammation mediating foetal programming is a growing concern. The extent of generational transfer in terms of immune functionality and leukocyte glucocorticoid sensitivity was investigated over two generations of offspring (F1 and F2) in a model of chronic LPS-induced maternal inflammation in C57/BL/6 mice. Maternal inflammation resulted in glucocorticoid hypersensitivity (increased glucocorticoid receptor expression levels) in the majority of leukocyte subpopulations in both F1 and F2 offspring. Furthermore, splenocytes stimulated with LPS in vitro exhibited exacerbated inflammatory cytokine responses, which were even more prominent in F2 than F1; this effect could be ascribed to NLRP3 inflammasome hyperactivity in F1 but not F2. Current data illustrates that parental chronic inflammation may mediate the inflammatory profile in offspring, potentially propagating a maladapted proinflammatory phenotype in subsequent generations.

In utero Exposure to Maternal Chronic Inflammation Transfers a Pro-Inflammatory Profile to Generation F2 via Sex-Specific Mechanisms

“…F1 offspring is not indicative of generational inheritance because of the potential confounding influence of the in utero microenvironment (e.g., LPS-associated damage to the placenta) (14,15). By employing a model capable of reflecting maternal generational transfer, we recently reported in mice that experimentally induced chronic maternal gestational inflammation resulted in altered inflammatory profiles in at least two generations of offspring (16), which is consistent with an interpretation of multigenerational inheritance. Importantly, in terms of preventative treatment, in line with the "fetal origins of adult disease" hypothesis by Barker (17), recent publications described successful in utero treatment of inherited diseases, such as brittle bone disease (18), hemophilia (19), and Gaucher's disease (20).…”

“…The current gap, in terms of the sex dependence on these inherited inflammatory maladaptations, is a major obstacle in the development of strategies such as the in utero corrective intervention just mentioned and also in terms of preventative medicine practices. Our previously published study reflected the transgenerational adaptations that occur in chronic gestational LPS administration and its effect on two subsequent generations of offspring (16). In an attempt to bridge this gap in literature, we here expand on our previous study in two ways to determine potential sex differences in the pro-inflammatory maladaptation previously reported and potentially delineate sexspecific heritability.…”

“…The current study explored the generational transfer of HPAaxis-and immune adaptations across two generations of offspring, with the aim of delineating their possible sexspecific inheritance into subsequent generations. We expand on a previous report from our group (16) with the aim of by Williams et al (12)-our protocol entails weekly (every 7 days, starting immediately following plug-positive confirmation) LPS injections throughout the gestational period, to achieve consistent maternal exposure to the affecting agent during gestation. LPS administered intraperitoneally during gestation is known to not cross the placental barrier.…”

“…Relative glucocorticoid receptor (NR3C1) expression was assessed in T-lymphocytes (TCRβ+ NK1.1-), NKT lymphocytes (TCRβ+ NK1.1+) NK cells (TCRβ-CD11b+ NK1.1+), neutrophils (TCRβ-CD11b+ Ly6G+), monocytes (TCRβ-CD11b+ F4/80-), and macrophages (TCRβ-CD11b+ F4/80+), as identified by their specific marker expression. The gating strategy was previously described in more detail (16).…”

“…In an attempt to bridge this gap in literature, we here expand on our previous study in two ways to determine potential sex differences in the pro-inflammatory maladaptation previously reported and potentially delineate sexspecific heritability. First, we present a reanalysis of a portion of the data previously published (16) to reflect sex specificity of maladaptive inheritance. Second, we report novel data of cumulative inheritance in F2 offspring born from two LPSaffected (F1) parents.…”