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

Adams, Rozanne C. M.; Smith, Carine

doi:10.3389/fimmu.2020.00048

Cited by 9 publications

(8 citation statements)

References 41 publications

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“…In line with this result, maternal LPS-stimulated inflammation in rodents determined a proinflammatory macrophage phenotype and enhanced IL-1 β production in adult progeny under immune challenge [ 84 ]. Moreover, a recent animal model of chronic LPS-induced maternal inflammation found sex-specific leukocyte glucocorticoid hypersensitivity and exaggerated inflammatory cytokine responses in two generations of progeny [ 91 , 92 ]. In a mouse model, despite a comparable birth weight, a maternal high-fat diet and normal diet were shown to be associated with inflammatory changes in the adipose tissue of the offspring, including increased chemokine and cytokine expression [ 85 ].…”

Section: Maternal Obesity-related Inflammation and Developmental Pmentioning

confidence: 99%

Maternal Low-Grade Chronic Inflammation and Intrauterine Programming of Health and Disease

Parisi

Milazzo

Savasi

et al. 2021

IJMS

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Overweight and obesity during pregnancy have been associated with increased birth weight, childhood obesity, and noncommunicable diseases in the offspring, leading to a vicious transgenerational perpetuating of metabolic derangements. Key components in intrauterine developmental programming still remain to be identified. Obesity involves chronic low-grade systemic inflammation that, in addition to physiological adaptations to pregnancy, may potentially expand to the placental interface and lead to intrauterine derangements with a threshold effect. Animal models, where maternal inflammation is mimicked by single injections with lipopolysaccharide (LPS) resembling the obesity-induced immune profile, showed increased adiposity and impaired metabolic homeostasis in the offspring, similar to the phenotype observed after exposure to maternal obesity. Cytokine levels might be specifically important for the metabolic imprinting, as cytokines are transferable from maternal to fetal circulation and have the capability to modulate placental nutrient transfer. Maternal inflammation may induce metabolic reprogramming at several levels, starting from the periconceptional period with effects on the oocyte going through early stages of embryonic and placental development. Given the potential to reduce inflammation through inexpensive, widely available therapies, examinations of the impact of chronic inflammation on reproductive and pregnancy outcomes, as well as preventive interventions, are now needed.

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Section: Maternal Obesity-related Inflammation and Developmental Pmentioning

confidence: 99%

Maternal Low-Grade Chronic Inflammation and Intrauterine Programming of Health and Disease

Parisi

Milazzo

Savasi

et al. 2021

IJMS

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“…In this regard, food, exercise, and an enriched environment are considered as positive modulators [20,[43][44][45], while neuroinflammation, infections, and ageing have been proposed as negative regulators [15,[46][47][48]. Several studies have reported a characteristic age-associated decrease in Gdnf gene expression patterns in different rodent strains [49][50][51]. Consistent with these findings, the current results showed that ageing significantly affected the expression of both Gdnf and GFRα1 genes in CD-1 mice, with lower expression detected in 15-months-old relative to 3-months-old mice.…”

Section: Accelerated Age-associated Decline In Hippocampal Gdnf/gfrα1...mentioning

confidence: 99%

Effects of gestational inflammation on age-related cognitive decline and hippocampal Gdnf-GFRα1 levels in F1 and F2 generations of CD-1 Mice

et al. 2023

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Background It has been reported that age-associated cognitive decline (AACD) accelerated by maternal lipopolysaccharide (LPS) insult during late pregnancy can be transmitted to the second generation in a sex-specificity manner. In turn, recent studies indicated that glial cell line‐derived neurotrophic factor (GDNF) and its cognate receptor (GFRα1) are critical for normal cognitive function. Based on this evidence, we aimed to explore whether Gdnf-GFRα1 expression contributes to cognitive decline in the F1 and F2 generations of mouse dams exposed to lipopolysaccharide (LPS) during late gestation, and to evaluate also the potential interference effect of pro-inflammatory cytokines. Methods During gestational days 15–17, pregnant CD-1 mice (8–10 weeks old) received a daily intraperitoneal injection of LPS (50 μg/kg) or saline (control). In utero LPS-exposed F1 generation mice were selectively mated to produce F2 generation mice. In F1 and F2 mice aged 3 and 15 months, the Morris water maze (MWM) was used to evaluated the spatial learning and memory ability, the western blotting and RT-PCR were used for analyses of hippocampal Gdnf and GFRα1 expression, and ELISA was used to analyse IL-1β, IL-6 and TNF-α levels in serum. Results Middle-aged F1 offspring from LPS-treated mothers exhibited longer swimming latency and distance during the learning phase, lower percentage swimming time and distance in targe quadrant during memory phase, and lower hippocampal levels of Gdnf and GFRα1 gene products compared to age-matched controls. Similarly, the middle-aged F2 offspring from the Parents-LPS group had longer swimming latency and distance in the learning phase, and lower percentage swimming time and distance in memory phase than the F2-CON group. Moreover, the 3-month-old Parents-LPS and 15-month-old Parents- and Father-LPS groups had lower GDNF and GFRα1 protein and mRNAs levels compared to the age-matched F2-CON group. Furthermore, hippocampal levels of Gdnf and GFRα1 were correlated with impaired cognitive performance in the Morris water maze after controlling for circulating pro-inflammatory cytokine levels. Conclusions Our findings indicate that accelerated AACD by maternal LPS exposure can be transmitted across at least two generations through declined Gdnf and GFRα1 expression, mainly via paternal linage.

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“…In animal models, adverse conditions in the uterus during germline programming may be transmitted through both paternal and maternal lines to induce disease phenotypes in offspring or even be inherited in multiple generations (Constantinof et al, 2016 ; Coley et al, 2019 ). Studies have revealed that the effects of chronic gestational inflammation on proinflammatory phenotype could be transmitted to F1 offspring and, to some extent, F2 offspring (Adams and Smith, 2019 , 2020 ). Anxiety-like behaviors increase with age in rodents, for instance in Kunming, C57BL, and SAMP8 mice and rats (Chen et al, 2004 ; Schulz et al, 2007 ; Penteado et al, 2014 ).…”

Section: Introductionmentioning

confidence: 99%

Prenatal exposure to inflammation increases anxiety-like behaviors in F1 and F2 generations: possible links to decreased FABP7 in hippocampus

Chen

Zhang

Luo

et al. 2022

Front. Behav. Neurosci.

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Anxiety disorder has a high prevalence, and the risk of anxiety increases with age. Prenatal inflammation during key developmental timepoints can result in long-term changes in anxiety phenotype, even over a lifetime and across generations. However, whether maternal inflammation exposure during late gestation has intergenerational transmission effects on age-related anxiety-like behaviors and the possible underlying mechanisms are largely unknown. Fatty acid binding protein 7 (FABP7) is critical in hippocampal neurogenesis and is closely related to neuropsychiatric diseases, including anxiety disorder. The current study investigated the effects of maternal (F0 generation) lipopolysaccharide administration (50 μg/kg, i.p.) during late gestation on anxiety-like behaviors and FABP7 expression in F1 and F2 offspring, as well as the potential sex-specificity of intergenerational effects. Anxiety-like behaviors were evaluated using open field (OF), elevated plus maze, and black–white alley (BWA) tests at 3 and 13 months of age. The protein and messenger RNA levels of FABP7 in the hippocampus were measured using Western blot and real-time quantitative polymerase chain reaction (PCR), respectively. Overall, gestational LPS exposure in the F0 generation increased anxiety levels and decreased FABP7 expression levels in the F1 generation, which carried over to the F2 generation, and the intergenerational effects were mainly transferred via the maternal lineage. Moreover, hippocampal FABP7 expression was significantly correlated with performance in the battery of anxiety tests. The present study suggested that prenatal inflammation could increase age-related anxiety-like behaviors both in F1 and F2 offspring, and these effects possibly link to the FABP7 expression.

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

Cited by 9 publications

References 41 publications

Maternal Low-Grade Chronic Inflammation and Intrauterine Programming of Health and Disease

Maternal Low-Grade Chronic Inflammation and Intrauterine Programming of Health and Disease

Effects of gestational inflammation on age-related cognitive decline and hippocampal Gdnf-GFRα1 levels in F1 and F2 generations of CD-1 Mice

Prenatal exposure to inflammation increases anxiety-like behaviors in F1 and F2 generations: possible links to decreased FABP7 in hippocampus

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