Susceptibility Of Offspring Research Articles

Effects of the loss of maternal gut microbiota before pregnancy on gut microbiota, food allergy susceptibility, and epigenetic modification on subsequent generations

Maternal environments affect the health of offspring in later life. Changes in epigenetic modifications may partially explain this phenomenon. The gut microbiota is a critical environmental factor that influences epigenetic modifications of host immune cells and the development of food allergies. However, whether changes in the maternal gut microbiota affect the development of food allergies and related epigenetic modifications in subsequent generations remains unclear. Here, we investigated the effects of antibiotic treatment before pregnancy on the development of the gut microbiota, food allergies, and epigenetic modifications in F1 and F2 mice. We found that pre-conception antibiotic treatment affected the gut microbiota composition in F1 but not F2 offspring. F1 mice born to antibiotic-treated mothers had a lower proportion of butyric acid-producing bacteria and, consequently, a lower butyric acid concentration in their cecal contents. The methylation level in the DNA of intestinal lamina propria lymphocytes, food allergy susceptibility, and production of antigen-specific IgE in the F1 and F2 mice were not different between those born to control and antibiotic-treated mothers. In addition, F1 mice born to antibiotic-treated mothers showed increased fecal excretion related to the stress response in a novel environment. These results suggest that the maternal gut microbiota is effectively passed onto F1 offspring but has little effect on food allergy susceptibility or DNA methylation levels in offspring.

Histological Studies of the Heart and Biochemical Changes Due to the Perinatal Consumption of Hibiscus sabdariffa (Flavonoid-rich Extract) to Feed-restricted Rats on Offspring

Background: Experiments using animal models have indicated that maternal diet during the perinatal period can drastically impact the life-long susceptibility of offspring to chronic disease. Objectives: This study aims to determine the impact of perinatal consumption of Hibiscus sabdariffa to feed restriction on offspring heart development. Methods: In this study, we used 25 pregnant rats. They were grouped as follows: group 1 (normal control), group 2 (70% feed restriction), group 3 (70% feed restriction and 5mg/kg body weight of H. sabdariffa administration), group 4 (70% feed restriction, and 10mg/kg body weight of H. sabdariffa administration), and group 5 (70% feed restriction and 20mg/kg body weight of H. sabdariffa administration). Dams were only allowed to nurse 8 pups. Pups were weaned and observed daily for puberty onset. Blood samples were collected to determine serum levels of creatine kinase, hydrogen peroxide, and malondialdehyde. The hearts were excised, weighed, and prepared for histological examination. Results: The result showed a significant increase in absolute and relative weights of the heart with alterations in the histology of the heart. There was a significant change in serum levels of creatine kinase and malondialdehyde. Conclusion: Maternal consumption of H. sabdariffa during pregnancy and lactation may increase the development of cardiovascular diseases in offspring during postnatal growth.

Valproic acid exposure decreases neurogenic potential of outer radial glia in human brain organoids.

Valproic acid (VPA) exposure during pregnancy leads to a higher risk of autism spectrum disorder (ASD) susceptibility in offspring. Human dorsal forebrain organoids were used to recapitulate course of cortical neurogenesis in the developing human brain. Combining morphological characterization with massive parallel RNA sequencing (RNA-seq) on organoids to analyze the pathogenic effects caused by VPA exposure and critical signaling pathway. We found that VPA exposure in organoids caused a reduction in the size and impairment in the proliferation and expansion of neural progenitor cells (NPCs) in a dose-dependent manner. VPA exposure typically decreased the production of outer radial glia-like cells (oRGs), a subtype of NPCs contributing to mammalian neocortical expansion and delayed their fate toward upper-layer neurons. Transcriptomics analysis revealed that VPA exposure influenced ASD risk gene expression in organoids, which markedly overlapped with irregulated genes in brains or organoids originating from ASD patients. We also identified that VPA-mediated Wnt/β-catenin signaling pathway activation is essential for sustaining cortical neurogenesis and oRGs output. Taken together, our study establishes the use of dorsal forebrain organoids as an effective platform for modeling VPA-induced teratogenic pathways involved in the cortical neurogenesis and oRGs output, which might contribute to ASD pathogenesis in the developing brain.

Maternal diet disrupts the placenta-brain axis in a sex-specific manner.

High maternal weight is associated with detrimental outcomes in offspring, including increased susceptibility to neurological disorders such as anxiety, depression and communicative disorders. Despite widespread acknowledgement of sex biases in the development of these disorders, few studies have investigated potential sex-biased mechanisms underlying disorder susceptibility. Here, we show that a maternal high-fat diet causes endotoxin accumulation in fetal tissue, and subsequent perinatal inflammation contributes to sex-specific behavioural outcomes in offspring. In male offspring exposed to a maternal high-fat diet, increased macrophage Toll-like receptor 4 signalling results in excess microglial phagocytosis of serotonin (5-HT) neurons in the developing dorsal raphe nucleus, decreasing 5-HT bioavailability in the fetal and adult brains. Bulk sequencing from a large cohort of matched first-trimester human samples reveals sex-specific transcriptome-wide changes in placental and brain tissue in response to maternal triglyceride accumulation (a proxy for dietary fat content). Further, fetal brain 5-HT levels decrease as placental triglycerides increase in male mice and male human samples. These findings uncover a microglia-dependent mechanism through which maternal diet can impact offspring susceptibility for neuropsychiatric disorder development in a sex-specific manner.

MiR-133a-3p/Sirt1 epigenetic programming mediates hypercholesterolemia susceptibility in female offspring induced by prenatal dexamethasone exposure

Mounting evidence indicates that adverse intrauterine conditions increase offspring’s hypercholesterolemia susceptibility in adulthood. This study aimed to confirm prenatal dexamethasone exposure (PDE)-induced hypercholesterolemia susceptibility in female adult offspring rats, and elucidate its intrauterine programming mechanism. Pregnant Wistar rats were injected with dexamethasone subcutaneously (0, 0.1 and 0.2 mg/kg·d) from gestational day (GD) 9 to 20. Serum and liver of the female offspring were collected at GD21 and postnatal week (PW) 12 and 28. PDE offspring showed elevated serum total cholesterol (TCH) levels and a cholesterol phenotype of high cardiovascular disease risk at PW12 and PW28. The histone acetylation levels of 3-hydroxy-3-methylglutaryl-coenzyme A reductase (Hmgcr) and its expression were consistently increased in the PDE offspring both in utero and after birth. Moreover, PDE promoted glucocorticoid receptor (GR) nuclear translocation and miR-133a-3p expression and inhibited sirtuin-1 (Sirt1) expression in the fetal liver. In vitro, dexamethasone increased intracellular and supernatant TCH levels and miR-133a-3p expression, decreased SIRT1 expression, and promoted HMGCR histone acetylation and expression in bone marrow mesenchymal stem cells (BMSCs) hepatoid differentiated cells and HepG2 cell line. GR siRNA, miR-133a-3p inhibitor or SIRT1 overexpression reversed dexamethasone-induced downstream molecular and phenotypic changes. Furthermore, elevated TCH levels in umbilical cord blood and increased HMGCR expression in peripheral blood mononuclear cells (PBMCs) were observed in human female neonates who had received dexamethasone treatment during pregnancy. In conclusion, PDE can cause persistent enhancement of hepatic cholesterol synthesis function before and after birth through GR/miR-133a-3p/Sirt1 pathway, eventually leading to increased hypercholesterolemia susceptibility in female offspring rats.

Effect of early embryonic exposure to morphine on defects in the GABAergic system of day-old chicks

Embryonic morphine exposure (EME) leads to abnormal brain development and behavior in the offspring, and the functional alteration of γ-aminobutyric acid (GABA) system is considered to be one of the important mechanisms. To mimic the problem of susceptibility of human gestational drug abuse on addictive drugs in offspring, we administered morphine exposure on days 5–8 and 13–16 of chicken embryo development and examined the functions of GABA neurons and their receptors in postnatal chicks by neuroelectrophysiology, immunohistochemistry and behavioral methods. We found that morphine exposure during embryonic stages 5–8 (MorphineE5–8) significantly reduced the incidence of spontaneous inhibitory postsynaptic potentiation (IPSP) and the induction of evoked IPSP and the mean amplitude of GABAA agonist muscimol-induced response in the intermediate medial interstitial (IMM) region, compared to naïve controls or saline-exposed chicks. The results of immunocytochemistry further suggest that MorphineE5–8 decreased the synaptic density of GAD-expressing sites in the IMM, while increased the expression of the GABAA receptor subtype γ2 isoform. Behavioral results found that Morphine5–8 treatment de-inhibited morphine-induced psychomotor responses in postnatal chicks. Morphine exposure at embryonic stages 13–16 (MorphineE13–16) showed no significant changes in the above indicators compared to the saline group. Evidence suggests that early embryonic morphine exposure leads to defects in GABAergic function in the IMM, which in turn alters the responsiveness of postnatal chicks to addictive drugs. These results will help to understand the GABA mechanisms by which embryonic addictive drug exposure contributes to offspring susceptibility to addiction.

Positive programming of the GC-IGF1 axis mediates adult osteoporosis susceptibility in male offspring rats induced by prenatal dexamethasone exposure

Prenatal dexamethasone exposure (PDE) can lead to offspring long bone dysplasia and continue to postnatal, and this is an important cause of fetal-derived osteoporosis. Studies have confirmed that intrauterine endogenous GC overexposure mediates multiple organ dysplasia and adult-related disease susceptibility in offspring through the glucocorticoid-insulin-like growth factor1 (GC-IGF1) axis. However, it remains unknown if exogenous dexamethasone can regulate bone development in offspring through the GC-IGF1 axis. We determined that the PDE fetal rats exhibited poor osteogenic differentiation, decreased bone mass that continued to adolescence, and increased susceptibility to osteoporosis in adulthood. Concurrently, PDE decreased the serum corticosterone concentration and IGF1 expression in offspring before and after birth, while the increased serum corticosterone concentration induced by chronic stress reversed the inhibition of IGF1 expression induced by PDE. Furthermore, PDE decreased the expression of GRα and miR-130a-5p, increased HDAC4, and decreased H3K27 acetylation in the IGF1 promoter region in bone tissue, and the above changes were negatively compensated after chronic stress. In vitro, a low concentration of corticosterone inhibited the expression of GRα and miR130a-5p, upregulated the expression of HDAC4, inhibited the promoter region H3K27 acetylation, and expression of IGF1 in bone marrow mesenchymal stem cell (BMSCs) osteoblast differentiated cells and inhibited osteogenic differentiation of BMSCs. GRα overexpression, miR-130a-5p mimic treatment, or HDAC4 siRNA exposure reversed the downstream molecular alterations caused by low corticosterone concentrations. In conclusion, PDE-induced intrauterine hypoglucocorticoid exposure could positively program IGF1 expression in bone tissue through the GRα/miR-130a-5p/HDAC4 pathways, thus mediating osteogenic dysdifferentiation and adult osteoporosis susceptibility in male offspring rats.

Early life dietary emulsifier exposure predisposes the offspring to obesity through gut microbiota-FXR axis

The prevalence of obesity is increasing rapidly around the world, and there is growing evidence that obesity is closely related to diet and gut microbiota. Early life adverse exposures have profound effects on gut microbiota. However, the effects of maternal emulsifier polysorbate 80 (P80) exposure in early life on obesity of offspring remains unclear. Female C57BL/6 mice were free access to water containing 1 % P80 during pregnancy and lactation to investigate the effects of maternal P80 exposure on gut microbiota and obesity susceptibility of offspring, while bile acid composition and the FGF15-FXR axis were also analyzed. Maternal P80 exposure significantly impaired intestinal development and barrier function and increased intestinal low-grade inflammation in offspring mice. Maternal P80 exposure led to gut dysbiosis in offspring at 3 weeks of age, which was characterized by increased potentially harmful bacteria, Prevotella, Helicobacter and Ruminococcus and Mucin degrading bacteria, Akkermansia. Interestingly, mice transplanted with the fecal microbiota of offspring exposed to maternal P80 showed more serious intestinal barrier impairment and increased low-grade inflammation than that received microbiota of offspring fed with normal diet. After a high-fat diet, Maternal P80 exposed offspring showed more severe in gut dysbiosis and obesity, accompanied by alternation in bile acid profile and up regulation of the FXR-FGF15 axis. Conclusively, early life emulsifier exposure predisposes the offspring to obesity through gut microbiota-FXR axis. The findings will provide new insights into effects of P80 on health.

Generating a Reproducible Model of Mid-Gestational Maternal Immune Activation using Poly(I:C) to Study Susceptibility and Resilience in Offspring.

Maternal immune activation (MIA) during pregnancy is consistently linked to increased risk of neurodevelopmental and neuropsychiatric disorders in offspring. Animal models of MIA are used to test causality, investigate mechanisms, and develop diagnostics and treatments for these disorders. Despite their widespread use, many MIA models suffer from a lack of reproducibility and almost all ignore two important aspects of this risk factor: (i) many offspring are resilient to MIA, and (ii) susceptible offspring can exhibit distinct combinations of phenotypes. To increase reproducibility and model both susceptibility and resilience to MIA, the baseline immunoreactivity (BIR) of female mice before pregnancy is used to predict which pregnancies will result in either resilient offspring or offspring with defined behavioral and molecular abnormalities after exposure to MIA. Here, a detailed method of inducing MIA via intraperitoneal (i.p.) injection of the double stranded RNA (dsRNA) viral mimic poly(I:C) at 12.5 days of gestation is provided. This method induces an acute inflammatory response in the dam, which results in perturbations in brain development in mice that map onto similarly impacted domains in human psychiatric and neurodevelopmental disorders (NDDs).

Generating a Reproducible Model of Mid-Gestational Maternal Immune Activation using Poly(I:C) to Study Susceptibility and Resilience in Offspring

Generating a Reproducible Model of Mid-Gestational Maternal Immune Activation using Poly(I:C) to Study Susceptibility and Resilience in Offspring

A maternal high-fat diet induces fetal origins of NASH-HCC in mice

Maternal overnutrition affects offspring susceptibility to nonalcoholic steatohepatitis (NASH). Male offspring from high-fat diet (HFD)-fed dams developed a severe form of NASH, leading to highly vascular tumor formation. The cancer/testis antigen HORMA domain containing protein 1 (HORMAD1), one of 146 upregulated differentially expressed genes in fetal livers from HFD-fed dams, was overexpressed with hypoxia-inducible factor 1 alpha (HIF-1alpha) in hepatoblasts and in NASH-based hepatocellular carcinoma (HCC) in offspring from HFD-fed dams at 15 weeks old. Hypoxia substantially increased Hormad1 expression in primary mouse hepatocytes. Despite the presence of three putative hypoxia response elements within the mouse Hormad1 gene, the Hif-1alpha siRNA only slightly decreased hypoxia-induced Hormad1 mRNA expression. In contrast, N-acetylcysteine, but not rotenone, inhibited hypoxia-induced Hormad1 expression, indicating its dependency on nonmitochondrial reactive oxygen species production. Synchrotron-based phase-contrast micro-CT of the fetuses from HFD-fed dams showed significant enlargement of the liver accompanied by a consistent size of the umbilical vein, which may cause hypoxia in the fetal liver. Based on these findings, a maternal HFD induces fetal origins of NASH/HCC via hypoxia, and HORMAD1 is a potential therapeutic target for NASH/HCC.

A High-Sugar Diet Consumption, Metabolism and Health Impacts with a Focus on the Development of Substance Use Disorder: A Narrative Review.

Carbohydrates are important macronutrients in human and rodent diet patterns that play a key role in crucial metabolic pathways and provide the necessary energy for proper body functioning. Sugar homeostasis and intake require complex hormonal and nervous control to proper body energy balance. Added sugar in processed food results in metabolic, cardiovascular, and nervous disorders. Epidemiological reports have shown enhanced consumption of sweet products in children and adults, especially in reproductive age and in pregnant women, which can lead to the susceptibility of offspring’s health to diseases in early life or in adulthood and proneness to mental disorders. In this review, we discuss the impacts of high-sugar diet (HSD) or sugar intake during the perinatal and/or postnatal periods on neural and behavioural disturbances as well as on the development of substance use disorder (SUD). Since several emotional behavioural disturbances are recognized as predictors of SUD, we also present how HSD enhances impulsive behaviour, stress, anxiety and depression. Apart from the influence of HSD on these mood disturbances, added sugar can render food addiction. Both food and addictive substances change the sensitivity of the brain rewarding neurotransmission signalling. The results of the collected studies could be important in assessing sugar intake, especially via maternal dietary patterns, from the clinical perspective of SUD prevention or pre-existing emotional disorders. Methodology: This narrative review focuses on the roles of a high-sugar diet (HSD) and added sugar in foods and on the impacts of glucose and fructose on the development of substance use disorder (SUD) and on the behavioural predictors of drugs abuse. The literature was reviewed by two authors independently according to the topic of the review. We searched the PubMed and Scopus databases and Multidisciplinary Digital Publishing Institute open access scientific journals using the following keyword search strategy depending on the theme of the chapter: “high-sugar diet” OR “high-carbohydrate diet” OR “sugar” OR “glucose” OR “fructose” OR “added sugar” AND keywords. We excluded inaccessible or pay-walled articles, abstracts, conference papers, editorials, letters, commentary, and short notes. Reviews, experimental studies, and epidemiological data, published since 1990s, were searched and collected depending on the chapter structure. After the search, all duplicates are thrown out and full texts were read, and findings were rescreened. After the selection process, appropriate papers were included to present in this review.

Paternal knockdown of tRNA(cytosine-5-)-methyltransferase (Dnmt2) increases offspring susceptibility to infection in red flour beetles.

Intergenerational effects from fathers to offspring are increasingly reported from diverse organisms, but the underlying mechanisms remain speculative. Paternal trans-generational immune priming (TGIP) was demonstrated in the red flour beetle Tribolium castaneum: non-infectious bacterial exposure of fathers protects their offspring against an infectious challenge for at least two generations. Epigenetic processes, such as cytosine methylation of nucleic acids, have been proposed to enable transfer of information from fathers to offspring. Here we studied a potential role in TGIP of the Dnmt2 gene (renamed as Trdmt1 in humans), which encodes a highly conserved enzyme that methylates different RNAs, including specific cytosines of a set of tRNAs. Dnmt2 has previously been reported to be involved in intergenerational epigenetic inheritance in mice and protection against viruses in fruit flies. We first studied gene expression and found that Dnmt2 is expressed in various life history stages and tissues of T.castaneum, with high expression in the reproductive organs. RNAi-mediated knockdown of Dnmt2 in fathers was systemic, slowed down offspring larval development and increased mortality of the adult offspring upon bacterial infection. However, these effects were independent of bacterial exposure of the fathers. In conclusion, our results point towards a role of Dnmt2 for paternal effects, while elucidation of the mechanisms behind paternal TGIP needs further studies.

Intrahepatic Cholestasis of Pregnancy Increases Inflammatory Susceptibility in Neonatal Offspring by Modulating Gut Microbiota.

Intrahepatic cholestasis of pregnancy (ICP) is a liver disease of pregnancy that is characterized by increased bile acid levels in maternal serum. Studies have shown that cholestatic pregnancy can result in long-term metabolic disturbances in the offspring. However, how ICP shapes the offspring’s immunity and predisposition to inflammatory disorders at an early stage is unknown. In this study, we investigated the effect of maternal cholestasis on neonatal offspring metabolism and immune function. We compared 71 neonates with ICP mothers and 63 neonates with healthy mothers and found that the incidence of jaundice and infection was significantly higher in ICP offspring. Maternal serum total bile acid level was associated with blood cell counts in full-term ICP offspring. In animal experiments, a compensatory activation of hepatic and ileal farnesoid X receptor (FXR) and altered gut microbiota in the first week were found in ICP offspring. We also investigated lipopolysaccharide (LPS)-induced inflammatory responses in neonatal rats and found that ICP offspring were more susceptible to inflammation. To understand the correlation between congenital abnormal FXR activation and tissue immunity dysregulation, we assessed the effects of the FXR agonist GW4064 and FXR antagonist E/Z-GS in ICP offspring after LPS exposure. The expression of several pro-inflammatory cytokines significantly decreased after treatment with E/Z-GS but increased after treatment with GW4064. Treatment with the probiotic Lactobacillus rhamnosus LRX01 that inhibits FXR expression in the ileum reduced susceptibility to LPS exposure in ICP offspring. The current study indicated that cholestatic pregnancy may increase the susceptibility of the offspring to inflammation by altering bile acid metabolism and gut microbiota at an early stage. We suggest that supplementation with Lactobacillus rhamnosus LRX01, which inhibits FXR expression in the ileum, may improve intestinal immunity in ICP offspring.

Impact of Maternal High-Fat Induced Obesity on Offspring’s Liver Transcriptome

Abstract Objectives Epidemiological studies suggest that parental obesity is associated with an increased risk of childhood obesity. We previously demonstrated that maternal obesity had a transgenerational impact on offspring body weight; however, this effect was sex specific, with male offspring being more susceptible to weight gain in comparison to their female counterparts. To elucidate the potential underlying mechanisms for this observation we characterized the offspring's liver transcriptome. Methods To determine the potential mechanisms by which maternal obesity could differentially impact the offspring's susceptibility to weight gain we characterized the offspring's liver transcriptome (n = 6–8/sex). The quality of the liver transcriptome was assessed by FastQC. The reads were aligned and mapped using the Bowtie R package. Gene expression was normalized by FPKM using the Cufflinks R package. Differential gene expression and gene set enrichment analyses (GSEA) were performed using the DEseq and Limma R packages, respectively. An FDR adjusted p-value (q-value) < 0.05 was considered statistically significant. Results Differential analysis demonstrated that 2275 transcripts were differentially expressed between male and female offspring (q < 0.05). Of those 2275,265 mRNAs were had a 1.5-fold higher (154) or lower (111) level of expression in the male offspring in comparison to the female offspring. Using the Gene Ontology and KEGG database, GSEA was performed using a set of 237 mRNAs that met our pre-selected criteria (q < 0.05, ±1.5-fold difference in gene expression level, had an Entrezgene ID). GSEA revealed that the top molecular function and biological process enriched in our unique gene set was, unsurprisingly, steroid hormone synthesis. Notably, GSEA further revealed significant differences in lipid/lipid oxidation metabolism, arachidonic and eicosanoid metabolism, cytochrome P450 metabolism, and immune system responses. Conclusions Our study suggests that the expression of genes involved in a variety of biological processes differ between male and female offspring born to obese mothers. Differences in these pathways may underlie the sex-driven difference in body weight gain. Funding Sources This material is based upon work supported by the U.S. Department of Agriculture – Agricultural Research Service, Agreement No. 58-1950-4-003.

Maternal Prenatal Inflammation Increases Brain Damage Susceptibility of Lipopolysaccharide in Adult Rat Offspring via COX-2/PGD-2/DPs Pathway Activation.

A growing body of research suggests that inflammatory insult contributes to the etiology of central nervous system diseases, such as depression, Alzheimer’s disease, and so forth. However, the effect of prenatal systemic inflammation exposure on offspring brain development and cerebral susceptibility to inflammatory insult remains unknown. In this study, we utilized the prenatal inflammatory insult model in vivo and the neuronal damage model in vitro. The results obtained show that prenatal maternal inflammation exacerbates LPS-induced memory impairment, neuronal necrosis, brain inflammatory response, and significantly increases protein expressions of COX-2, DP2, APP, and Aβ, while obviously decreasing that of DP1 and the exploratory behaviors of offspring rats. Meloxicam significantly inhibited memory impairment, neuronal necrosis, oxidative stress, and inflammatory response, and down-regulated the expressions of APP, Aβ, COX-2, and DP2, whereas significantly increased exploring behaviors and the expression of DP1 in vivo. Collectively, these findings suggested that maternal inflammation could cause offspring suffering from inflammatory and behavioral disorders and increase the susceptibility of offspring to cerebral pathological factors, accompanied by COX-2/PGD-2/DPs pathway activation, which could be ameliorated significantly by COX-2 inhibitor meloxicam treatment.

Prenatal caffeine exposure induced renal developmental toxicity and transgenerational effect in rat offspring

Epidemiological studies revealed that prenatal caffeine exposure (PCE) is associated with adverse gestational outcomes and susceptibility to chronic diseases in offspring, yet the effects of PCE on glomerulosclerosis susceptibility in adult female offspring and its intergenerational transmission remain to be further investigated. Here, we found that PCE caused fetal kidney dysplasia and glomerulosclerosis of the female offspring. Besides, the kidney of F1 offspring in PCE group exhibited the “low expressional programming of AT2R” and “GC-IGF1 programming” alteration. Intergenerational genetic studies revealed that the renal defect and GC-IGF1 programming alteration was inherited to F2 adult female offspring derived from the female germ line, but Low expression of AT2R did not extend to the F2 female offspring. Taken together, PCE caused renal dysplasia and adult glomerulosclerosis in the F1 female offspring, which might be mediated by renal AT2R low expressional programming and GC-IGF1 axis alteration. Furthermore, PCE induced transgenerational toxicity on kidney, and GC-IGF1 programming alteration might be the potential molecular mechanism. This study provided experimental evidence for the mechanism study of the intergenerational inheritance of kidney developmental toxicity caused by PCE.

Interaction between maternal killer immunoglobulin-like receptors and offspring HLAs and susceptibility of childhood ALL

AbstractAcute lymphoblastic leukemia (ALL) in children is associated with a distinct neonatal cytokine profile. The basis of this neonatal immune phenotype is unknown but potentially related to maternal-fetal immune receptor interactions. We conducted a case-control study of 226 case child-mother pairs and 404 control child-mother pairs to evaluate the role of interaction between HLA genotypes in the offspring and maternal killer immunoglobulin-like receptor (KIR) genotypes in the etiology of childhood ALL, while considering potential mediation by neonatal cytokines and the immune-modulating enzyme arginase-II (ARG-II). We observed different associations between offspring HLA-maternal KIR activating profiles and the risk of ALL in different predicted genetic ancestry groups. For instance, in Latino subjects who experience the highest risk of childhood leukemia, activating profiles were significantly associated with a lower risk of childhood ALL (odds ratio [OR] = 0.59; 95% confidence interval [CI], 0.49-0.71) and a higher level of ARG-II at birth (coefficient = 0.13; 95% CI, 0.04-0.22). HLA-KIR activating profiles were also associated with a lower risk of ALL in non-Latino Asians (OR = 0.63; 95% CI, 0.38-1.01), although they had a lower tumor necrosis factor-α level (coefficient = −0.27; 95% CI, −0.49 to −0.06). Among non-Latino White subjects, no significant association was observed between offspring HLA-maternal KIR interaction and ALL risk or cytokine levels. The current study reports the association between offspring HLA-maternal KIR interaction and the development of childhood ALL with variation by predicted genetic ancestry. We also observed some associations between activating profiles and immune factors related to cytokine control; however, cytokines did not demonstrate causal mediation of the activating profiles on ALL risk.

MicroRNAs Regulate Hypothalamic AT2R Expression in Hypercaloric Diet‐Induced Epigenetic Programming of Male Mice Offspring

One in ten adults are living with diabetes worldwide and it is expected to be one in eight adults by the year 2045. Maternal epigenetic programming is one of the determinants of disease susceptibility in offspring. The renin‐angiotensin system contributes to metabolic homeostasis through the balance between Angiotensin II (Ang‐II) binding to Angiotensin II Type 1 receptor (AT1R) and Angiotensin II Type 2 receptor (AT2R). We have shown that maternal hypercaloric (HCD) diet leads to a pre‐diabetic state exclusively in adult male offspring. Additionally, we showed a paradoxical reversal of hyperglycemia in programmed males challenged with Ang‐II. Here, we hypothesize that this hypoglycemic response in programmed males is due to a shift in Ang‐II binding from AT1R towards the protective AT2R. To test this hypothesis, C57BL6/J dams were fed HCD or regular diet (RD) for 1 month and mated with RD‐fed males. After weaning, offspring were maintained on RD for 3 months resulting in two groups: HCD‐RD (programmed) and RD‐RD (control). Half of each group was implanted with a subcutaneous Ang‐II osmotic pump (200 ng/kg/min/2 weeks). Another osmotic pump filled with AT2R blocker, PD123319 (10 mg/kg/day) was implanted in a subgroup of Ang‐II programmed mice resulting in 5 groups: HCD‐RD, RD‐RD, HCD‐RD+Ang‐II, RD‐RD+Ang‐II and HCD‐RD+Ang‐II+PD123319 (n=7‐10/group). A glucose tolerance test was performed before and after drugs infusion. Following euthanasia, half of each hypothalamus was harvested for protein quantification using simple western while the other halves were processed for microRNA (miRNA) sequencing. Results show that HCD‐RD+Ang‐II+PD123319 had elevated glucose levels compared to HCD‐RD+Ang‐II mice at 15 min (355.7 ± 32 vs. 279.8 ± 19.66 mg/dL, p=0.04), 30 min (405 ± 18.54 vs. 263.5 ± 22.68mg/dL, p=0.0013) and 60 min (298.3 ± 19.75 vs.189.8 ± 21.35 mg/dL, p=0.0036). On the other hand, there was no difference in the glycemic levels of HCD‐RD+Ang‐II+PD123319 compared to RD‐RD+Ang‐II groups at 15 min (355.7 ± 32.97 vs. 349.0 ± 32.06 mg/dL, p=0.8), 30 min (405.0 ± 18.54 vs. 405.8 ± 44.28 mg/dL, p=0.9) and 60 min (298.3 ± 19.75 vs. 230.0 ± 35.52 mg/dL, p=0.1). AT2R protein expression was higher in the HCD‐RD compared to RD‐RD (p=0.04) and in HCD‐RD+Ang‐II compared to RD‐RD+Ang‐II (p=0.03). For miRNA sequencing, miRNA 124‐3p, targeting AT2R was differentially expressed in the HCD‐RD compared to RD‐RD (FC=1.4, p=0.04) as well as HCD‐RD compared to HCD‐RD+Ang‐II (FC=0.74, p=0.0001). Whereas, no change in the miRNA expression was depicted in the non‐programmed groups; RD‐RD vs RD‐RD+Ang‐II (FC=0.97, p=0.85). In conclusion, maternal hypercaloric diet epigenetic programming takes place probably through regulating the gene expression of AT2R via changing miRNA ‐124 levels that works on the post‐transcriptional modification level.

S06.3: Antibiotic use during pregnancy: Influence on the gut microbiome, immune system development and asthma susceptibility in murine offspring

S06.3: Antibiotic use during pregnancy: Influence on the gut microbiome, immune system development and asthma susceptibility in murine offspring