Environmental influences on placental programming and offspring outcomes following maternal immune activation
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.
References (97)
Trajectories of brain development: point of vulnerability or window of opportunity?
Neurosci. Biobehav. Rev.
(2003)The role of FKBP5, a co-chaperone of the glucocorticoid receptor in the pathogenesis and therapy of affective and anxiety disorders
Psychoneuroendocrinology
(2009)- et al.
Neuroendocrine control of maternal stress responses and fetal programming by stress in pregnancy
Prog. Neuro-Psychopharmacol. Biol. Psychiatry
(2011) - et al.
Prenatal immune activation in mice blocks the effects of environmental enrichment on exploratory behavior and microglia density
Prog. Neuro-Psychopharmacol. Biol. Psychiatry
(2016) - et al.
Discordant protein and mRNA expression in lung adenocarcinomas
Mol. Cell. Proteomics
(2002) - et al.
Maternal immune activation in rats blunts brain cytokine and kynurenine pathways responses to a second immune challenge in early adulthood
Prog. Neuropsychopharmacol. Biol. Psychiatry
(2019) - et al.
Environmental enrichment mitigates the sex-specific effects of gestational inflammation on social engagement and the hypothalamic pituitary adrenal axis-feedback system
Brain, Behav., Immun.
(2014) - et al.
Environmental enrichment models a naturalistic form of maternal separation and shapes the anxiety response patterns of offspring
Psychoneuroendocrinology
(2015) - et al.
Intrauterine inflammation, insufficient to induce parturition, still evokes fetal and neonatal brain injury
Int. J. Dev. Neurosci.
(2011) - et al.
Prenatal caloric restriction enhances DNA methylation and MeCP2 recruitment with reduced murine placental glucose transporter isoform 3 expression
J. Nutr. Biochem
(2014)
Species differences of 11beta-hydroxysteroid dehydrogenase type 2 function in human and rat term placenta determined via LC-MS/MS
Placenta
Altered object-in-place recognition memory, prepulse inhibition, and locomotor activity in the offspring of rats exposed to a viral mimetic during pregnancy
Neuroscience
Activation of the maternal immune system induces endocrine changes in the placenta via IL-6
Brain Behav. Immun.
Environmental enrichment rescues the effects of early life inflammation on markers of synaptic transmission and plasticity
Brain Behav. Immun.
Complex environmental rearing enhances social salience and affects hippocampal corticotropin releasing hormone receptor expression in a sex-specific manner
Neuroscience
Targeted sensory enrichment interventions protects against behavioral and neuroendocrine consequences of early life stress
Psychoneuroendocrinology
Tracing the trajectory of behavioral impairments and oxidative stress in an animal model of neonatal inflammation
Neuroscience
Understanding the molecular mechanisms underpinning gene by environment interactions in psychiatric disorders: the FKBP5 Model
Biol. Psychiatry
Environmental enrichment influences brain cytokine variations elicited by social defeat in mice
Psychoneuroendocrinology
Prenatal poly (I:C) exposure and other developmental immune activation models in rodent systems
Biol. Psychiatry
Adult brain and behavioral pathological markers of prenatal immune challenge during early/middle and later fetal development in mice
Brain Behav. Immun.
Evolution of a maternal immune activation (mIA) model in rats: early developmental effects
Brain Behav. Immun.
Maturation- and sex-sensitive depression of hippocampal excitatory transmission in a rat schizophrenia model
Brain Behav. Immun.
Immune involvement in schizophrenia and autism: etiology, pathology and animal models
Behav. Brain Res.
Effect of early multisensory massage intervention on visual functions in infants with Down Syndrome
Early Human Dev.
Genomewide DNA methylation changes in a mouse model of infection-mediated neurodevelopmental disorders
Biol. Psychiatry
Understanding the relationship between DNA methylation and histone lysine methylation
Biochim. Biophys. Acta
Behavioral effects of environmental enrichment during gestation in WKY and Wistar rats
Behav. Brain Res.
Enriched environment and acceleration of visual system development
Neuropharmacology
Maternal influenza infection is likely to alter fetal brain development indirectly: the virus is not detected in the fetus
Int. J. Dev. Neurosci.
Behavioral and physiological consequences of enrichment loss in rats
Psychoneuroendocrinology
LPS alters placental inflammatory and endocrine mediators and inhibits fetal neurite growth in affected offspring during late gestation
Placenta
Natural disaster-related prenatal maternal stress is associated with alteration in placental glucocorticoid system: the QF2011 Queesnsland Flood Study
Psychoneuroendocrinology
Effects of early prenatal dexamethasone on the cognitive and behavioral development of young children: results of a pilot study
Psychoneuroendocrinology
Combined pre- and postnatal environmental enrichment programs the HPA axis differentially in male and female rats
Psychoneuroendocrinology
Prenatal exposure to a viral mimetic alters behavioural flexibility in male, but not female, rats
Neuropharmacology
Epigenetic mechanisms for the early environmental regulation of hippocampal glucocorticoid receptor gene expression in rodents and humans
Neuropsychopharmacology
Maternal exposure to environmental enrichment before and during gestation influences behaviour of rat offspring in a sex-specific manner
Physiol. Behav.
Prenatal exposure to LPS leads to long-lasting physiological consequences in male offspring
Dev. Psychobiol.
Environmental enrichment therapy for autism: outcomes with increased access
Neural Plast.
Prenatal stress-induced increases in placental inflammation and offspring hyperactivity are male-specific and ameliorated by maternal antiinflammatory treatment
Endocrinology
Acceleration of visual system development by environmental enrichment
J. Neurosci.
Pre-reproductive maternal enrichment influences offspring developmental trajectories: motor behavior and neurotrophin expression
Front. Behav. Neurosci.
Prevalence of autism spectrum disorder—autism and developmental disability monitoring network, 11 sites, United States, 2010
Surveill Summ Mortal Wkly Rep.
Intrauterine microbiota: missing, or the missing link?
Trends Neurosci.
The maternal interleukin-17a pathway in mice promotes autism-like phenotypes in offspring
Science
Sex and gender bias in the experimental neurosciences: the case of the maternal immune activation model
Transl. Psychiatry
Social behavior tests for mice
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Authors contributed equally.