Maternal LPS induces cytokines in the amniotic fluid and corticotropin releasing hormone in the fetal rat brain

Gayle, Dave; Beloosesky, Ron; Desai, Mina; Amidi, Fataneh; Nuñez, Sonia; Ross, Michael G.

doi:10.1152/ajpregu.00664.2003

Cited by 194 publications

(123 citation statements)

References 49 publications

(38 reference statements)

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“…MIA can result in increased levels of inflammatory cytokines in the fetal environment and can activate the fetal HPA axis (47). Upon activation of the HPA axis, the paraventricular nucleus of the hypothalamus releases CRH, which leads to release of adrenocorticotropic hormone (ACTH) by the anterior pituitary, which in turn leads again to release of cortisol by the cortex of the adrenal glands.…”

Section: Resultsmentioning

confidence: 99%

Sex-specific gene–environment interactions underlying ASD-like behaviors

Schaafsma

Gagnidze

Reyes

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

104

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The male bias in the incidence of autism spectrum disorders (ASDs) is one of the most notable characteristics of this group of neurodevelopmental disorders. The etiology of this sex bias is far from known, but pivotal for understanding the etiology of ASDs in general. Here we investigate whether a "three-hit" (genetic load × environmental factor × sex) theory of autism may help explain the male predominance. We found that LPS-induced maternal immune activation caused male-specific deficits in certain social responses in the contactin-associated protein-like 2 (Cntnap2) mouse model for ASD. The three "hits" had cumulative effects on ultrasonic vocalizations at postnatal day 3. Hits synergistically affected social recognition in adulthood: only mice exposed to all three hits showed deficits in this aspect of social behavior. In brains of the same mice we found a significant three-way interaction on corticotropin-releasing hormone receptor-1 (Crhr1) gene expression, in the left hippocampus specifically, which co-occurred with epigenetic alterations in histone H3 N-terminal lysine 4 trimethylation (H3K4me3) over the Crhr1 promoter. Although it is highly likely that multiple (synergistic) interactions may be at work, change in the expression of genes in the hypothalamic-pituitary-adrenal/ stress system (e.g., Crhr1) is one of them. The data provide proof-of-principle that genetic and environmental factors interact to cause sex-specific effects that may help explain the male bias in ASD incidence.maternal immune activation | prenatal stress | sex differences | Cntnap2 | autism A utism spectrum disorders (ASDs) comprise a heterogeneous group of neurodevelopmental disorders. The core symptoms of ASD are deficits in social communication and social interactions (Diagnostic and Statistical Manual of Mental Disorders V) and one of the most noticeable biological constants in this group of disorders is the sex difference: ∼80% of the children diagnosed with an ASD are boys (1). Many genes have been implicated in the etiologies underlying ASD in humans and ASD-like behavior in animal models. Some of these genes are located on the sex chromosomes and many of these genes may be able to affect other sex-chromosomal genes or may otherwise indirectly lead to sex-specific effects (reviewed in ref.2). However, it seems unlikely that these genes can account for the full sex bias in incidence and it is becoming increasingly clear that environmental factors play a very important role as well (3), and that these factors can interact with one another (2, 4). Moreover, prenatal testosterone (an indirect genetic factor) affects human behavior (5, 6) and may increase the risk to develop an ASD (7).Although today it is commonly proposed that many neurodevelopmental disorders result from interactions between "nature" and "nurture," studies investigating the gene-environment interaction in the development of ASD are scarce.In this study we tested whether an interaction between an ASD-related genetic mutation and an environmental factor may be a...

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Section: Resultsmentioning

confidence: 99%

Sex-specific gene–environment interactions underlying ASD-like behaviors

Schaafsma

Gagnidze

Reyes

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

104

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“…However, a number of studies report that neither immune molecules (e.g., LPS) nor maternal cytokines enter fetal circulation suggesting that fetal cytokine levels are elevated due to exposure to placental cytokines or self-production (e.g., Cai et al, 2000;Gayle et al, 2004;Gilmore et al, 2005;Urakubo et al, 2001). The mechanism by which cytokines, once induced in the fetal brain, cause their effects is not yet known, however they have been found to regulate cell growth and differentiation (Heinrich et al, 1998).…”

Section: Animal Models Of Pathogenic Immune Activationmentioning

confidence: 99%

Sex effects on neurodevelopmental outcomes of innate immune activation during prenatal and neonatal life

Rana

Aavani

Pittman

2012

Hormones and Behavior

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Humans are exposed to potentially harmful agents (bacteria, viruses, toxins) throughout our lifespan; the consequences of such exposure can alter central nervous system development. Exposure to immunogens during pregnancy increases the risk of developing neurological disorders such as schizophrenia and autism. Further, sex hormones, such as estrogen, have strong modulatory effects on immune function and have also been implicated in the development of neuropathologies (e.g., schizophrenia and depression). Similarly, animal studies have demonstrated that immunogen exposure in utero or during the neonatal period, at a time when the brain is undergoing maturation, can induce changes in learning and memory, as well as dopaminemediated behaviors in a sex-specific manner. Literature that covers the effects of immunogens on innate immune activation and ultimately the development of the adult brain and behavior is riddled with contradictory findings, and the addition of sex as a factor only adds to the complexity. This review provides evidence that innate immune activation during critical periods of development may have effects on the adult brain in a sex-specific manner. Issues regarding sex bias in research as well as variability in animal models of immune function are discussed.

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“…Annealing temperatures and primer sequences for all the cytokines, excepted for TGF-b1, were obtained from Peinnequin et al (2004) and Gayle et al (2004) (Gayle et al, 2004;Peinnequin et al, 2004). Primers for TGFb1 were designed by using Beacon Designer software.…”

Section: Rna Extraction and Real Time Pcrmentioning

confidence: 99%

In vitro neuronal and glial differentiation from embryonic or adult neural precursor cells are differently affected by chronic or acute activation of microglia

Cacci

Ajmone‐Cat

Anelli

et al. 2008

Glia

205

188

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The contribution of microglia to the modulation of neurogenesis under pathological conditions is unclear. Both proand anti-neurogenic effects have been reported, likely reflecting the complexity of microglial activation process. We previously demonstrated that prolonged (72 hr) in vitro exposure to lipopolysaccharide (LPS) endows microglia with a potentially neuroprotective phenotype, here referred as to ''chronic''. In the present study we further characterized the chronic phenotype and investigated whether it might differently regulate the properties of embryonic and adult neural precursor cells (NPC) with respect to the ''acute'' phenotype acquired following a single (24 hr) LPS stimulation. We show that the LPS-dependent induction of the proinflammatory cytokines interleukin (IL)-1a, IL-1b, IL-6, and tumor necrosis factor (TNF)-a was strongly reduced after chronic stimulation of microglia, as compared with acute stimulation. Conversely, the synthesis of the anti-inflammatory cytokine IL-10 and the immunomodulatory prostaglandin E 2 (PGE 2 ) was still elevated or further increased, after chronic LPS exposure, as revealed by real time PCR and ELISA techniques. Acutely activated microglia, or their conditioned medium, reduced NPC survival, prevented neuronal differentiation and strongly increased glial differentiation, likely through the release of proinflammatory cytokines, whereas chronically activated microglia were permissive to neuronal differentiation and cell survival, and still supported glial differentiation. Our data suggest that, in a chronically altered environment, persistently activated microglia can display protective functions that favor rather than hinder brain repair processes. V V C

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Maternal LPS induces cytokines in the amniotic fluid and corticotropin releasing hormone in the fetal rat brain

Cited by 194 publications

References 49 publications

Sex-specific gene–environment interactions underlying ASD-like behaviors

Sex-specific gene–environment interactions underlying ASD-like behaviors

Sex effects on neurodevelopmental outcomes of innate immune activation during prenatal and neonatal life

In vitro neuronal and glial differentiation from embryonic or adult neural precursor cells are differently affected by chronic or acute activation of microglia

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