Elsevier

Brain, Behavior, and Immunity

Volume 83, January 2020, Pages 44-55
Brain, Behavior, and Immunity

Environmental influences on placental programming and offspring outcomes following maternal immune activation

https://doi.org/10.1016/j.bbi.2019.08.192Get rights and content

Highlights

  • We test if environmental enrichment mitigates maternal, placental and fetal responses to inflammation.

  • Maternal plasma corticosterone and interleukin-1β were elevated 3 h following LPS challenge.

  • LPS-induced decreases in placental Hsd11b2 suggest disturbances in glucocorticoid metabolism.

  • Enrichment mitigated placental, but not maternal, glucocorticoid implications of inflammation.

  • Social discrimination ability was impaired in LPS exposed offspring. Enrichment attenuated this.

  • Placental epigenetic machinery were affected as a consequence of environmental experience and sex.

Abstract

Adverse experiences during pregnancy induce placental programming, affecting the fetus and its developmental trajectory. However, the influence of ‘positive’ maternal experiences on the placenta and fetus remain unclear. In animal models of early life stress, environmental enrichment (EE) has ameliorated and even prevented associated impairments in brain and behavior. Here, using a maternal immune activation (MIA) model in rats, we test whether EE attenuates maternal, placental and/or fetal responses to an inflammatory challenge, thereby offering a mechanism by which fetal programming may be prevented. Moreover, we evaluate life-long EE exposure on offspring development and examine a constellation of genes and epigenetic writers that may protect against MIA challenges. In our model, maternal plasma corticosterone and interleukin-1β were elevated 3 h after MIA, validating the maternal inflammatory response. Evidence for developmental programming was demonstrated by a simultaneous decrease in the placental enzymes Hsd11b2 and Hsd11b2/Hsd11b1, suggesting disturbances in glucocorticoid metabolism. Reductions of Hsd11b2 in response to challenge is thought to result in excess glucocorticoid exposure to the fetus and altered glucocorticoid receptor expression, increasing susceptibility to behavioral impairments later in life. The placental, but not maternal, glucocorticoid implications of MIA were attenuated by EE. There were also sustained changes in epigenetic writers in both placenta and fetal brain as a consequence of environmental experience and sex. Following MIA, both male and female juvenile animals were impaired in social discrimination ability. Life-long EE mitigated these impairments, in addition to the sex specific MIA associated disruptions in central Fkbp5 and Oprm1. These data provide the first evidence that EE protects placental functioning during stressor exposure, underscoring the importance of addressing maternal health and well-being throughout pregnancy. Future work must evaluate critical periods of EE use to determine if postnatal EE experience is necessary, or if prenatal exposure alone is sufficient to confer protection.

Introduction

While epidemiological evidence supports an association between maternal infection during pregnancy and risk for central nervous system disorders in offspring (Knuesel et al., 2014), preclinical studies are well poised to inform our mechanistic understanding of these inflammatory mediated outcomes. Indeed, these models have clearly implicated maternal immune activation (MIA) to several neurobiological disruptions that mimic clinical psychiatric pathology (Gumudoglu and Stevens, 2018). For example, MIA is associated with the manifestation of a heterogeneous set of symptoms, including social and cognitive impairments in the offspring later in life, many of which reportedly occur in a sex-dependent manner (CDC, 2014, Kim et al., 2015, Meyer, 2014; Reisinger et al., 2015, Zhang et al., 2012).

Although the detrimental effects of prenatal infection are likely due to the maternal, fetal, and/or placental immune and endocrine responses to the infection (Gayle et al., 2004, Patterson, 2009, Shi et al., 2005), the specific factors or mechanisms by which the detrimental effects are conferred have yet to be fully elucidated. In rodents, we find that life-long exposure to environmental enrichment (EE), a translationally relevant intervention (Woo and Leon, 2013, Woo et al., 2015, Aronoff et al., 2016, Downs et al., 2018, Morgan et al., 2013, Morgan et al., 2015, Purpura et al., 2014), starting prior to breeding and extending through gestation until study’s end protects offspring against some effects of MIA (Connors et al., 2014). However, it is important to determine when during development this intervention is most beneficial and the mechanisms that underlie its positive influence.

An immune challenge during mid-gestation can induce the release of pro-inflammatory immune molecules (i.e. interleukin (IL-1)-1β), the production of stress hormones, and disrupt the expression of placental 11-β hydroxysteroid dehydrogenase (11HSD) 1 and 2, both of which are enzymes critical for glucocorticoid metabolism and the passage of maternal glucocorticoids to the fetus (Diaz et al., 1996, Straley et al., 2014). While 11HSD2 protects the fetus from high maternal levels of glucocorticoids (e.g. cortisol, corticosterone), by rapidly inactivating them into inactive metabolites (e.g. cortisone, 11-dehydrocorticosterone), 11HSD1 converts the inactive glucocorticoids into cortisol/corticosterone (Waddell et al., 1998). Converging basic and clinical evidence suggests that disruptions of these placental enzymes in response to challenge result in excess glucocorticoid exposure to the fetus and altered glucocorticoid receptor expression, increasing susceptibility to behavioral changes later in life (Levitt et al., 1996, Räikkönen et al., 2015, Seckl and Meaney, 2004, Trautman et al., 1995).

One aim of the present study was to determine whether EE exerts its prophylactic effects by attenuating the maternal and/or placental stress and inflammatory responses directly, thereby preventing fetal programming in the offspring. We examined the influence of EE on the release of maternal plasma corticosterone and IL-1β at 3 h (peak of the proinflammatory response) and 24 h post treatment with the inflammatory mediator lipopolysaccharide (LPS) on gestational day (G)15. We also evaluated mRNA expression of proinflammatory and stress-associated molecules in the placenta (e.g. IL-1β; Hsd11b1, Hsd11b2) and fetal brain (e.g. Nr3c1, Nr3c2) of male and female offspring. Given that DNA methyltransferase (DNMT)3a and DNA methylation have been implicated in stress-induced downregulation of placental Hsd11b2 (Jensen Peña et al., 2012), we also evaluated differences in epigenetic machinery recognized to be developmentally important (e.g. DNMT1, DNMT3a, O-GlcNAcylation, methyl cPG binding protein 2; Rose and Klose, 2014, Howerton et al., 2013, Nugent et al., 2018). By evaluating maternal, placental, and fetal responses to prenatal LPS treatment, we aimed to identify the specific level at which EE may offer protection. For example, it is possible that EE may not counteract the maternal inflammatory response but that it instead a) prevents the release of placental cytokines such as IL-1β, or b) contributes to the maintenance of glucocorticoid metabolism via placental Hsd11b1 and Hsd11b2. If so, this would be the first report that EE could specifically protect placental function at the time of a maternal stressor, without affecting maternal responses to stress.

A second aim was to extend upon our previous findings that life-long EE can attenuate MIA induced social impairments in male offspring. While male, but not female, rats demonstrated impairments in the social interaction test (Connors et al., 2015), we hypothesized that the apparent resiliency of MIA exposed females may be dependent on the behavioral and central endpoints evaluated; indeed, males and females may present with differing phenotypes following early life challenges (Goldstein et al., 2019). We also tested whether exposure to complex housing environments could be beneficial for females following MIA.

Section snippets

Animals and housing

Sprague Dawley rats were acquired from Charles River Laboratories (Wilmington, MA), and housed at 20 °C on a 12 h light/dark cycle (0700–1900 light) with ad libitum access to food and water. A schematic timeline of experimental procedures is presented in Fig. 1A. Female rats were housed in pairs in one of two conditions: environmental enrichment (EE; 91.5 × 64 × 159 cm; see Fig. 1B), comprised of large multi-level cages with ramps and access to toys, tubes, chew bones, and Nestlets® (Ancare,

Validation of MIA

There was a significant effect of gestational treatment on maternal plasma corticosterone (F(1, 23) = 20.420, p = 0.0001; Fig. 2AB) and IL-1β (X2(1) = 13.906, p = 0.0001; Fig. 2AC) at 3 h, but not 24 h (p > 0.05; data not shown) following LPS challenge, validating both inflammation and high circulating levels of maternal glucocorticoids. Moreover, in the third cohort of dams (those permitted to give birth), LPS treated animals had significantly slowed body weight gain (-0.37 ± 1.02 g) between

Discussion

This study provides the first evidence that EE can impact placental functioning, potentially protecting the developing offspring from the consequences of stress-induced fetal programming. While there is a plethora of data demonstrating that gestational stressors affect placenta and fetal development (Brunton and Russell, 2011, Chen and Gur, 2019, Monk et al., 2012, St. Pierre et al., 2018), a stronger emphasis on identifying interventions to promote maternal/offspring protection from adverse

Funding and disclosure

This project was funded by NIMH under Award Number R15MH114035 (to ACK) and a MCPHS Summer Undergraduate Fellowship (SURF) awarded to JQTN. The authors would also like to thank the MCPHS University School of Pharmacy and School of Arts & Sciences for their continual support. The content is solely the responsibility of the authors and does not necessarily represent the official views of any of the financial supporters.

Declaration of Competing Interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Acknowledgments

The authors would like to extend their thanks to Antoine Khoury and Molly MacRae for technical assistance.

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