Inflammation In Offspring Research Articles

Unraveling the long-term gastrointestinal impact of perinatal perfluorobutane sulfonate exposure on rat offspring: Intestinal barrier dysfunction and Th17/Treg imbalance

Per- and polyfluoroalkyl substances (PFAS), especially long-chain perfluorooctanoic acid (PFOA) and perfluorooctane sulfonate (PFOS), are increasingly acknowledged as a potential inflammatory bowel diseases (IBD) risk factor. Perfluorobutane sulfonate (PFBS), one kind of shorter chain alternative, has been reported to exhibit similar health hazards to those long-chain PFAS. However, the underlying mechanism underpinning PFBS-induced colonic inflammation has not been sufficiently elucidated. The T-helper-17 (Th17)/regulatory T (Treg) imbalance is a crucial event for the pathogenesis of colonic inflammation. In this study, we aimed to reveal whether and how perinatal PFBS exposure leads to the Th17/Treg imbalance and colonic inflammation in offspring. We firstly demonstrated in vivo that early-life PFBS exposure (0.5 mg/kg, 5 mg/kg) led to increased intestinal permeability and colonic inflammation accompanied by decreased expressions of tight junction protein 1 (Tjp1) and claudin-4 (Cldn4) and increased expressions of interleukin 17A (IL-17A) in colon of rat offspring. Further results indicated that PFBS exposure induces the Th17/Treg imbalance through upregulating the expression of retinoic acid receptor-related orphan receptor gamma t (Ror-γt) and transforming growth factor beta (TGF-β) and downregulating of forkhead box protein 3 (Foxp3) and IL-10 in colon. Moreover, metabolomics analyses indicated that bile secretion metabolism was significantly altered under PFBS exposure. The reduction of lithocholic acid and deoxycholic acid was closely related to the changes of TGF-β and IL-10 in colon, and may contribute to the perturbation of Th17/Treg balance and colonic inflammation. These results provide evidences for the immunotoxicity of PFBS and reveal the potential contribution to colonic inflammation, which raises concern on the health effects and risk assessment of short-chain PFAS.

Dendritic cell-specific deletion of PKCδ in offspring of allergic mothers prevents the predisposition for development of allergic lung inflammation in offspring.

In humans and in mice, maternal allergy predisposes offspring to development of allergy. In murine models, increased levels of maternal β-glucosylceramides are both necessary and sufficient for the development of allergic predisposition in offspring. Furthermore, increased numbers of CD11b+ dendritic cell subsets in the offspring of allergic mothers are associated with allergic predisposition. In vitro, β-glucosylceramides increase CD11b+ dendritic cell subset numbers through increased PKCδ signaling but it is not known if enhanced PKCδ signaling in dendritic cells is required in vivo. We demonstrate that dendritic cell-specific deletion of PKCδ prevents the β-glucosylceramide-induced increase in CD11b+ dendritic cell subset numbers both in vitro as well as in vivo in the fetal liver of offspring of mothers injected with β-glucosylceramides. Furthermore, dendritic cell-specific deletion of PKCδ in offspring prevents the maternal allergy-induced increase in CD11b+ dendritic cell subsets and decreases allergen-induced IL-5 and eosinophilia in lungs of offspring. However, loss of PKCδ in dendritic cells did not prevent development of allergen-specific IgE. Our study provides mechanistic insight into the function of PKCδ in the origins of allergic disease beginning in utero as well as the development of postnatal allergic lung inflammation.

Maternal Dietary Deficiency in Choline Reduced Levels of MMP-2 Levels in Blood and Brain Tissue of Male Offspring Mice.

Ischemic stroke is one of the leading causes of disability and death globally, with a rising incidence in younger age groups. It is well known that maternal diet during pregnancy and lactation is vital for the early neurodevelopment of offspring. One-carbon (1C) metabolism, including folic acid and choline, plays a vital role in closure of the neural tube in utero. However, the impact of maternal dietary deficiencies in 1C on offspring neurological function following ischemic stroke later in life remains undefined. The aim of this study was to investigate inflammation in the blood and brain tissue of offspring from mothers deficient in dietary folic acid or choline. Female mice were maintained on either a control or deficient diet prior to and during pregnancy and lactation. When offspring were 3 months of age, ischemic stroke was induced. One and a half months later, blood and brain tissue were collected. We measured levels of matrix metalloproteases (MMP)-2 and 9 in both plasma and brain tissue, and reported reduced levels of MMP-2 in ChDD male offspring in both tissue types. No changes were observed in MMP-9. This observation supports our working hypothesis that maternal dietary deficiencies in folic acid or choline during early neurodevelopment impact the levels of inflammation in offspring after ischemic stroke.

Associations between prenatal stress with offspring inflammation, depression and anxiety

PurposeFew longitudinal studies have investigated the mediating role of inflammation during childhood in associations between prenatal maternal stress and adolescent mental health. The objective of this study was to examine the associations between prenatal maternal stress, concentrations of immune markers at age 9, and symptoms of generalized anxiety disorder (GAD) and depression during adolescence. MethodsThis study included 3723 mother-child pairs from the Avon Longitudinal Study of Parents and Children (ALSPAC). Prenatal maternal stress was examined using 55 items measured during pregnancy. Inflammation was assessed using serum concentrations of interleukin-6 (IL-6) and C-reactive protein (CRP) when children were 9 years old. GAD and depression were assessed when children were 16 and 18 years of age, respectively. Analyses comprised of structural equation models. ResultsPrenatal maternal stress was associated with higher concentrations of IL-6 in childhood, and with greater symptoms of depression and GAD in adolescence. However, we did not observe associations between prenatal maternal stress and CRP; also, CRP and IL-6 were not associated with depression and GAD. There was no evidence that CRP and IL-6 mediated the associations between prenatal maternal stress and either GAD or depression. ConclusionsPrenatal maternal stress is associated with IL-6 levels in childhood, and with GAD and depression during adolescence. Future studies should examine immune activity at multiple points during development in relation to mental health into adulthood to determine whether inflammation at different points during development could increase risk for mental health problems among children whose mothers experienced significant stressors during pregnancy.

Maternal dietary deficiency in choline reduced levels of MMP-2 levels in blood and brain tissue of male offspring mice.

Ischemic stroke is one of the leading causes of disability and death globally, with a rising incidence in younger age groups. It's well known that maternal diet during pregnancy and lactation is vital for the early neurodevelopment of offspring. One-carbon (1C) metabolism, including folic acid and choline, plays a vital role in closure of the neural tube in utero. However, the impact of maternal dietary deficiencies in 1C on offspring neurological function following ischemic stroke later in life remains undefined. The aim of this study was to investigate inflammation in blood and brain tissue of offspring from mothers deficient in dietary folic acid or choline. Female mice were maintained on either a control or deficient diets prior to and during pregnancy and lactation. When offspring were 3-months of age, ischemic stroke was induced. One and half months later blood and brain tissue were collected. We measured levels of matrix-metalloproteases (MMP)-2 and 9 in both plasma and brain tissue, and report reduced levels of MMP-2 in both, with no changes observed in MMP-9. This observation supports our working hypothesis that maternal dietary deficiencies in folic acid or choline during early neurodevelopment impact the levels of inflammation in offspring after ischemic stroke.

Exacerbated lung inflammation in offspring with high maternal antibody levels following secondary RSV exposure.

Respiratory syncytial virus (RSV) is the primary cause of bronchiolitis-related hospitalizations among children under 5 years of age, with reinfection being common throughout life. Maternal vaccination has emerged as a promising strategy, delivering elevated antibody levels to newborns for immediate protection. However, limited research has explored the protective efficacy of maternal antibodies (matAbs) against secondary RSV infections in offspring. To address this gap, we employed a mouse model of maternal RSV vaccination and secondary infection of offspring to evaluate lung pathology following RSV reinfection in mice with varying levels of maternal antibody (matAb). Additionally, we aimed to investigate the potential causes of exacerbated lung inflammation in offspring with high matAb levels following secondary RSV exposure. Our findings revealed that offspring with elevated levels of maternal pre-F antibody demonstrated effective protection against lung pathology following the initial RSV infection. However, this protection was compromised upon reinfection, manifesting as heightened weight loss, exacerbated lung pathology, increased expression of RSV-A N genes, eosinophilia, enhanced IL-5, IL-13, MUC5AC, and eosinophils Major Basic Protein (MBP) production in lung tissue compared to offspring lacking matAbs. Importantly, these unexpected outcomes were not attributed to antibody-dependent enhancement (ADE) resulting from declining matAb levels over time. Notably, our findings showed a decline in secretory IgA (sIgA), mucosal IgA, and mucosal IgG levels in offspring with high matAb levels post-primary RSV challenge. We propose that this decline may be a critical factor contributing to the ineffective protection observed during secondary RSV exposure. Overall, these findings offer valuable insights into maternal vaccination against RSV, contributing to a comprehensive understanding and mitigation of potential risks associated with maternal RSV vaccination.

The potential of intervening on childhood adversity to reduce socioeconomic inequities in body mass index and inflammation among Australian and UK children: A causal mediation analysis

BackgroundLower maternal education is associated with higher body mass index (BMI) and higher chronic inflammation in offspring. Childhood adversity potentially mediates these associations. We examined the extent to which addressing...

MIA-reprogramed ILC2s promote enhanced lung allergic inflammation in offspring postnatally and into adulthood

Abstract Innate lymphoid cells (ILCs) are a relatively recently identified class of specialized innate-like lymphocytes that are the topic of intense investigation for their role in immune function during homeostasis and disease states. Accumulating evidence suggests that dysregulation of ILC2s and ILC2-derived Type II cytokines plays a critical role in the development of allergic airway hyper-responsiveness and asthma. To test how prenatal inflammation impacts ILC2 establishment, I profiled changes to a committed progenitor to all ILC lineages in the fetal liver (FL). MIA induction during mid-gestation expanded FL Common helper Innate Lymphoid Progenitors, resulting in robustly expanded and hyper-proliferative neonatal ILC2s exhibiting a greater inflammatory phenotype, producing more IL-5 and IL-13 cytokine on a per-cell basis. Hyper-activated ILC2s drove remodeling of the lung immune landscape, with multiple immune cell compartments, including eosinophils and alveolar macrophages, exhibiting expansion during the first two weeks of life in MIA-treated offspring. Surprisingly, levels of IL-33, a potent ILC2 activator, significantly decreased after MIA, and ILC2s were hyper-responsive to IL-33 in ex vivoculture. Single-cell RNA sequencing of neonatal lung ILC2s revealed extensive heterogeneity between MIA and saline litters, including clusters unique to MIA-exposed litters, and transcriptional similar to ILC2 signatures in human asthma patients. Altogether, my data suggests prenatal inflammation imparts lasting changes to lung immunity by perturbing the establishment of committed ILC progenitors in the FL, affecting the generation of neonatal lung ILC2s poised to hyperactively respond to secondary immune activation. NIH/NICHD training grant T32HD007491 The Pew Biomedical Scholars Award

Early life exposure to low-dose perfluorooctane sulfonate disturbs gut barrier homeostasis and increases the risk of intestinal inflammation in offspring

Perfluorooctane sulfonate (PFOS), one of the legacy per- and poly-fluoroalkyl substances (PFAS), is associated with multiple adverse health effects on children. However, much remains to be known about its potential impacts on intestinal immune homeostasis during early life. Our study found that PFOS exposure during pregnancy in rats significantly increased the maternal serum levels of interleukin-6 (IL-6) and zonulin, a gut permeability biomarker, and decreased gene expressions of Tight junction protein 1 (Tjp1) and Claudin-4 (Cldn4), the tight junction proteins, in maternal colons on gestation day 20 (GD20). Being exposed to PFOS during pregnancy and lactation in rats significantly decreased the body weight of pups and increased the offspring's serum levels of IL-6 and tumor necrosis factor-α (TNF-α) on postnatal day 14 (PND14), and induced a disrupted gut tight junction, manifested by decreased expressions of Tjp1 in pup's colons on PND14 and increased pup's serum concentrations of zonulin on PND28. By integrating high-throughput 16S rRNA sequencing and metabolomics, we demonstrated that early-life PFOS exposure altered the diversity and composition of gut microbiota that were correlated with the changed metabolites in serum. The altered blood metabolome was associated with increased proinflammatory cytokines in offspring. These changes and correlations were divergent at each developmental stage, and pathways underlying immune homeostasis imbalance were significantly enriched in the PFOS-exposed gut. Our findings provide new evidence for the developmental toxicity of PFOS and its underlying mechanism and explain in part the epidemiological observation of its immunotoxicity.

Impact of Gestational Diabetes on the Thymus Gland of Rat's Offspring and the Possible Ameliorating Effect of Thymoquinone: Biochemical, Histological, and Immunohistochemical Study.

Gestational diabetes mellitus (GDM) not only has short-term side effects on offspring but also has an increased risk of developing chronic diseases in adulthood. The thymus gland is a vital organ of immune system and thymoquinone (TQ) has an immunomodulatory effect. This study aimed to investigate the long-term adverse effects of GDM on offspring's thymus gland and the ameliorating effect of TQ. Pregnant rats were divided into four groups: C-group, T-group, GD-group, and GD + T-group. Offspring of all groups were subdivided into two subgroups, one sacrificed on day 21 and the other on day 42. The thymus of the offspring in the GD-group at both time points revealed a significant decrease in thymic weight, superoxide dismutase (SOD), and reduced glutathione (GSH) levels with a significant increase in malondialdehyde (MDA), interleukin-8 (IL-8), and tumor necrosis factor-alpha (TNF-α) levels. Moreover, there were microscopic degenerative changes, a significant decrease in C/M ratio, CD3, CD4, and CD8 immune expression, and a significant increase in activated caspase-3 immune expression. Interestingly, TQ administration revealed a significant increase in thymic weight, thymic SOD and GSH, C/M ratio, and CD3, CD4, and CD8 immune expression with a significant decrease in MDA, IL-8, TNF-α and activated caspase-3. For the first time, this study has shown that GDM causes long-term oxidative stress, apoptosis, and inflammation in offspring's thymus and these changes could be attenuated by TQ.

Prenatal LPS Exposure Promotes Allergic Airway Inflammation via Long Coding RNA NONMMUT033452.2, and Protein Binding Partner, Eef1D.

Epidemiological surveys indicate that intrauterine inflammation increases the risk of asthma in offspring. However, the underlying mechanisms remain largely unknown. Previous studies in BALB/c and C57BL/6 mice showed that prenatal exposure to endotoxins prevented allergic airway inflammation in offspring, which is inconsistent with most clinical observations. In this study, we found that prenatal LPS exposure increased airway resistance and total exfoliated cell counts, eosinophils, and IL-4 concentrations in BAL fluid of ovalbumin-sensitized Institute of Cancer Research (ICR) mice. Importantly, long noncoding RNA (lncRNA) NONMMUT033452.2 was upregulated in the lungs of LPS-exposed ICR offspring. Fluorescence in situ hybridization and cytoplasmic and nuclear fraction analyses revealed that this lncRNA was distributed in both the nuclei and cytoplasm of lung and airway epithelial cells, smooth muscle cells, and fibroblasts. Intranasal administration of NONMMUT033452.2 siRNA markedly alleviated allergic airway inflammation in ovalbumin-sensitized ICR mice. In vitro functional experiments demonstrated that overexpression of NONMMUT033452.2 inhibited the proliferation of lung and bronchiolar epithelial cells and promoted oxidative stress. RNA pull-down assays proved that NONMMUT033452.2 could directly bind Eef1D (eukaryotic translation elongation factor 1 delta). Overexpression of NONMMUT033452.2 induced the redistribution of Eef1D and substantially inhibited the expression of its downstream heat shock genes. NONMMUT033452.2 was also involved in the modulation of IL-1, IL-12, and some key molecules related to asthma, including Npr3 (natriuretic peptide receptor 3), Rac1 (Rac family small GTPase 1), and Nr4a3 (nuclear receptor subfamily 4, group A, member 3). Furthermore, the human lncRNA NONHSAT078603.2 was identified as a functional homolog of NONMMUT033452.2. These findings provide new insight into the pathogenic mechanism underlying asthma development.

Supplementation of Methyl-Donor Nutrients to a High-Fat, High-Sucrose Diet during Pregnancy and Lactation Normalizes Circulating 25-Dihydroxycholecalciferol Levels and Alleviates Inflammation in Offspring.

A Western-style diet that is high in fat and sucrose has been shown to alter DNA methylation and epigenetically modify genes related to health risk in offspring. Here, we investigated the effect of a methyl-donor nutrient (MS) supplemented to a high-fat, high-sucrose (HFS) diet during pregnancy and lactation on vitamin D (VD) status and inflammatory response in offspring. After mating, 10-week-old female Sprague-Dawley (SD) rats (n = 10/group) were randomly assigned to one of the four dietary groups during pregnancy and lactation: (1) control diet (CON), (2) CON with MS (CON-MS), (3) HFS, and (4) HFS with MS (HFS-MS). Weanling offspring (three weeks old) were euthanized and sacrificed (n = 8-10/sex/group). The remaining offspring (n = 10/sex/group) were randomly assigned to either a CON or an HFS diet for 12 weeks and sacrificed at 15 weeks of age. Our results indicated that prenatal MS supplementation, but not postnatal diet, restored low vitamin D status and suppressed elevation of proinflammatory cytokine induced by maternal HFS in the offspring. Furthermore, both prenatal and postnatal diets modulated the abundance of Lactobacillus spp. and Bacteroides spp. in the offspring, a shift that was independent of vitamin D status. Collectively, our data support a role for MS in restoring the perturbation of VD status and normalizing maternal HFS-induced inflammation in the offspring. Further investigation is warranted to elucidate the methylation status of VD metabolism-related pathways in the offspring, as well as the immunomodulatory role of vitamin D during the progression of obesity.

Maternal programming by high-energy diets primes ghrelin sensitivity in the offspring of rats exposed to chronic immobilization stress

Maternal overnutrition during pregnancy leads to metabolic and immune alterations, including obesity, hyperphagia, and central and peripheral inflammation in offspring. Exposure to high-energy diets during pregnancy primes ghrelin sensitivity to overfeeding in the offspring at early stages of life. Overfeeding has also been partially related to the early stages of chronic stress. We hypothesized that maternal programming sensitizes ghrelin-induced overfeeding following a chronic stress schedule in the offspring. We used a nutritional programming model exposing female Wistar rats to a cafeteria (CAF) or control diet from prepregnancy to weaning. Male offspring were injected with ghrelin and then subjected to a chronic immobilization stress (CIS) schedule, after which food intake was determined. Hypothalamic and plasma accumulation of cytokines and cortisol were evaluated using BioPlex analysis and enzyme-linked immunosorbent assay, respectively. We found that rats exposed to the CAF diet exhibited overfeeding after fasting and peripheral ghrelin administration, which was exacerbated in rats exposed to chronic stress. Offspring exposed to the CAF diet accumulated pro-inflammatory interleukin-6 (IL-6), interferon-γ, and monocyte chemoattractant protein-1 cytokines in plasma, and IL-6 cytokine in the hypothalamus. Ghrelin-sensitive overfeeding in rats exposed to CAF diet + CIS display increased cortisol levels and decreased IL-6 accumulation in plasma. Together, our results suggest that maternal nutritional programming primes susceptibility to ghrelin response for overfeeding after a CIS schedule that mirrors plasma cortisol accumulation in male offspring.

Maternal consumption of a fermented diet protects offspring against intestinal inflammation by regulating the gut microbiota

ABSTRACT The neonatal intestinal tract is immature and can be easily infected by pathogens causing inflammation. Maternal diet manipulation is a promising nutritional strategy to enhance the gut health of offspring. A fermented diet is a gut microbiota targeting diet containing live probiotics and their metabolites, which benefit the gut and overall health host. However, it remains unclear how a maternal fermented diet (MFD) affects neonatal intestinal inflammation. Here, in vivo and in vitro models together with multi-omics analysis were applied to investigate the impacts and the underlying mechanism through which an MFD prevents from gut inflammation in neonates. An MFD remarkably improved the performance of both sows and piglets and significantly altered the gut microbiome and milk metabolome of sows. In addition, the MFD significantly accelerated the maturation of the gut microbiota of neonates and increased the abundance of gut Lactobacillus and the microbial functions of amino acid-related enzymes and glucose metabolism on the weaning day. Notably, the MFD reduced susceptibility to colonic inflammation in offspring. The fecal microbiota of sows was then transplanted into mouse dams and it was found that the mouse dams and pups in the MFD group alleviated the LPS-induced decrease in gut Lactobacillus abundance and barrier injury. Milk L-glutamine (GLN) and gut Lactobacillus reuteri (LR) were found as two of the main MFD-induced sow effectors that contributed to the gut health of piglets. The properties of LR and GLN in modulating gut microbiota and alleviating colonic inflammation by inhibiting the phosphorylation of p38 and JNK activation of Caspase 3 were further verified. These findings provide the first data revealing that an MFD drives neonate gut microbiota development and ameliorates the colonic inflammation by regulating the gut microbiota. This fundamental evidence might provide references for modulating maternal nutrition to enhance early-life gut health and prevent gut inflammation.

Maternal gut bacteria drive intestinal inflammation in offspring with neurodevelopmental disorders by altering the chromatin landscape of CD4+ T cells

Children with autism spectrum disorders often display dysregulated immune responses and related gastrointestinal symptoms. However, the underlying mechanisms leading to the development of both phenotypes have not been elucidated. Here, we show that mouse offspring exhibiting autism-like phenotypes due to prenatal exposure to maternal inflammation were more susceptible to developing intestinal inflammation following challenges later in life. In contrast to its prenatal role in neurodevelopmental phenotypes, interleukin-17A (IL-17A) generated immune-primed phenotypes in offspring through changes in the maternal gut microbiota that led to postnatal alterations in the chromatin landscape of naive CD4+ Tcells. The transfer of stool samples from pregnant mice with enhanced IL-17A responses into germ-free dams produced immune-primed phenotypes in offspring. Our study provides mechanistic insights into why children exposed to heightened inflammation in the womb might have an increased risk of developing inflammatory diseases in addition to neurodevelopmental disorders.

Association between parent work-family conflict and offspring inflammation

Association between parent work-family conflict and offspring inflammation

Prenatal maternal infection promotes tissue-specific immunity and inflammation in offspring.

The immune system has evolved in the face of microbial exposure. How maternal infection experienced at distinct developmental stages shapes the offspring immune system remains poorly understood. Here, we show that during pregnancy, maternally restricted infection can have permanent and tissue-specific impacts on offspring immunity. Mechanistically, maternal interleukin-6 produced in response to infection can directly impose epigenetic changes on fetal intestinal epithelial stem cells, leading to long-lasting impacts on intestinal immune homeostasis. As a result, offspring of previously infected dams develop enhanced protective immunity to gut infection and increased inflammation in the context of colitis. Thus, maternal infection can be coopted by the fetus to promote long-term, tissue-specific fitness, a phenomenon that may come at the cost of predisposition to inflammatory disorders.

Perinatal High-Fat Diet Influences Ozone-Induced Responses on Pulmonary Oxidant Status and the Molecular Control of Mitophagy in Female Rat Offspring.

Previous research has shown that a perinatal obesogenic, high-fat diet (HFD) is able to exacerbate ozone-induced adverse effects on lung function, injury, and inflammation in offspring, and it has been suggested that mitochondrial dysfunction is implicated herein. The aim of this study was to investigate whether a perinatal obesogenic HFD affects ozone-induced changes in offspring pulmonary oxidant status and the molecular control of mitochondrial function. For this purpose, female Long-Evans rats were fed a control diet or HFD before and during gestation, and during lactation, after which the offspring were acutely exposed to filtered air or ozone at a young-adult age (forty days). Directly following this exposure, the offspring lungs were examined for markers related to oxidative stress; oxidative phosphorylation; and mitochondrial fusion, fission, biogenesis, and mitophagy. Acute ozone exposure significantly increased pulmonary oxidant status and upregulated the molecular machinery that controls receptor-mediated mitophagy. In female offspring, a perinatal HFD exacerbated these responses, whereas in male offspring, responses were similar for both diet groups. The expression of the genes and proteins involved in oxidative phosphorylation and mitochondrial biogenesis, fusion, and fission was not affected by ozone exposure or perinatal HFD. These findings suggest that a perinatal HFD influences ozone-induced responses on pulmonary oxidant status and the molecular control of mitophagy in female rat offspring.

Associations of maternal insulin resistance during pregnancy and offspring inflammation at birth and at 5 years of age: A prospective study in the Gen3G cohort

BackgroundMaternal insulin resistance is associated with greater maternal inflammation during pregnancy, but its relation to inflammation in offspring remains unclear. The goal of this study was to assess the relationship of gestational insulin resistance and other glycemic markers with offspring inflammation at birth and at 5 years of age. MethodsWe included 653 mother–child pairs from the prospective pre-birth Gen3G cohort. We examined maternal insulin and glucose levels measured during the second trimester of pregnancy, from which we derived the homeostatic model of assessment of insulin resistance (HOMA-IR) and the Matsuda index. We assessed offspring inflammation at birth and at 5 years of age by measuring plasma tumor necrosis factor-α (TNFα) concentrations. We conducted multivariable regression models to evaluate associations of each insulin and glucose marker with offspring inflammation adjusting for confounding variables. ResultsHigher levels of fasting insulin were associated with lower TNFα levels at birth (−0.78, 95% CI [−1.45, −0.11]), in the fully adjusted model. We observed similar associations with the HOMA-IR and opposite direction with the Matsuda index. We did not find persistence of the association between maternal fasting insulin and offspring TNFα at 5 years of age. ConclusionsGreater maternal insulin resistance during pregnancy was associated with lower cord blood TNFα levels in newborns. The mechanisms by which maternal insulin resistance may promote lower inflammatory levels in newborns are not fully understood and more research is needed to deepen our understanding of these mechanisms.

Perinatal exposure to silver nanoparticles reprograms immunometabolism and promotes pancreatic beta-cell death and kidney damage in mice

Silver nanoparticles (AgNPs) are extensively utilized in food, cosmetics, and healthcare products. Though the effects of AgNPs exposure on adults are well documented, the long-term effects of gestational/perinatal exposure upon the health of offspring have not been addressed. Herein, we show that only perinatal exposure to AgNPs through the mother could lead to chronic inflammation in offspring which persists till adulthood. Further, AgNPs exposure altered offspring’s immune responses against environmental stresses. AgNPs exposed offspring showed an altered response in splenocyte proliferation assay when challenged to lipopolysaccharide, concanavalin-A, AgNPs, or silver ions. Perinatal AgNPs exposure affected metabolic parameters (resistin, glucagon-like peptide-1, leptin, insulin) and upregulated JNK/P38/ERK signaling in the pancreas. We observed pancreatic damage, reduced insulin level, and increased blood glucose levels. Further, we observed renal damage, particularly to tubular and glomerular regions as indicated by histopathology and electron microscopy. Our study thus shows that only perinatal exposure to AgNPs could induce persistent inflammation, alter immune responses against foreign antigens and metabolism which may contribute to pancreatic and renal damage later in life.