Prenatal caffeine exposure induces a poor quality of articular cartilage in male adult offspring rats via cholesterol accumulation in cartilage.
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ABSTRACT:
SUBMITTER: Luo H
PROVIDER: S-EPMC4671025 | biostudies-other | 2015 Dec
REPOSITORIES: biostudies-other
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Project description:Background and purposePrenatal caffeine exposure (PCE) can cause developmental toxicity of long bones in offspring, but the long-term effects and the underlying mechanism have not been fully clarified. Here, we investigated the effects of PCE peak bone mass accumulation and osteoporosis susceptibility in offspring and its intrauterine programming mechanism.Experimental approachPregnant Wistar rats were administrated intragastrically with saline or caffeine (120 mg·kg-1 ·day-1 ) on gestational days 9-20. The serum and bone samples were collected from the fetal and postnatal offspring for bone mass, genes expression and corticosterone analysis. Then, rat bone marrow mesenchymal stem cells (BMSCs) were treated with corticosterone in vitro to confirm the molecular mechanism.Key resultsPCE caused fetal bone dysplasia in male and female offspring. In adulthood, PCE reduced peak bone mass and increased osteoporosis susceptibility in male offspring but not in females. Meanwhile, PCE only decreased the H3K9ac and expression levels of 11β-hydroxysteroid dehydrogenase 2 (11β-HSD2) before and after birth in the male offspring but not in the females. Moreover, the high level of corticosterone induced by PCE down-regulated the H3K9ac and expression levels of 11β-HSD2 through promoting glucocorticoid receptor (GR; NR3C1) into the nucleus of bone marrow mesenchymal stem cells (BMSCs) and recruiting histone deacetylase 11 (HDAC11) binding to 11β-HSD2 promoter region, which further enhanced the effect of corticosterone on suppressing osteogenic function of BMSCs.Conclusion and implicationsPCE caused osteoporosis susceptibility in male adult offspring, which attributed to the low-functional programming of 11β-HSD2 induced by corticosterone via GR/HDAC11 signalling.
| S-EPMC7520449 | biostudies-literature
Project description:Inflammation is critical to the pathogenesis of cardiovascular diseases (CVDs). We have uncovered intrauterine inflammation induced by lipopolysaccharide (LPS) increases CVDs in adult offspring rats. The present study aimed to explore the role of prenatal exposure to LPS on the lipid profiles in male offspring rats and to further assess their susceptibility to high fat diet (HFD). Maternal LPS (0.79 mg/kg) exposure produced a significant increase in serum and hepatic levels of total cholesterol, triglycerides, low-density lipoprotein cholesterol, aspartate amino transferase as well as liver morphological abnormalities in 8-week-old offspring rats. Meanwhile, disturbed gene expressions involved in hepatic lipid metabolism and related signaling pathways were found, especially the up-regulated very-low density lipoprotein receptor (VLDLR) and down-regulated transmembrane 7 superfamily member 2 (TM7SF2). Following HFD treatment, however, the lipid profile shifts and liver dysfunction were exacerbated compared to the offsprings treated with prenatal LPS exposure alone. Compared with that in control offsprings, the hepatic mitochondria (Mt) in offspring rats solely treated with HFD exhibited remarkably higher ATP level, enforced Complex IV expression and a sharp reduction of its activity, whereas the offsprings from LPS-treated dams showed the loss of ATP content, diminished membrane potential, decline in protein expression and activity of mitochondrial respiratory complex IV, increased level of MtDNA deletion as well. Furthermore, treatment with HFD deteriorated these mitochondrial disorders in the prenatally LPS-exposed offspring rats. Taken together, maternal LPS exposure reinforces dyslipidemia in response to a HFD in adult offsprings, which should be associated with mitochondrial abnormalities and disturbed gene expressions of cholesterol metabolism.
| S-EPMC5964359 | biostudies-literature
Project description:Background and aimsSeveral studies have indicated an association between maternal prenatal substance use and offspring externalizing disorders; however, it is uncertain whether this relationship is causal. We conducted a systematic review to determine: (1) if the literature supports a causal role of maternal prenatal substance use on offspring externalizing disorders diagnosis and (2) whether these associations differ across externalizing disorders.MethodsWe searched Web of Science, Embase, PsycINFO and Medline databases. Risk of bias assessment was conducted using the Newcastle-Ottawa Scale (NOS), and where possible meta-analysis was conducted for studies classed as low risk of bias. We included studies of any design that examined prenatal smoking, alcohol or caffeine use. Studies in non-English language, fetal alcohol syndrome and comorbid autism spectrum disorders were excluded. Participants in the included studies were mothers and their offspring. Measurements included prenatal smoking, alcohol or caffeine use as an exposure, and diagnosis of attention-deficit hyperactivity disorder (ADHD), conduct disorder (CD) and oppositional defiant disorder (ODD) in offspring as an outcome.ResultsWe included 63 studies, 46 of which investigated smoking and ADHD. All studies were narratively synthesized, and seven studies on smoking and ADHD were meta-analysed. The largest meta-analysis based on genetically sensitive design included 1 011 546 participants and did not find evidence for an association [odds ratio (OR)1-9 cigarettes = 0.90, 95% confidence interval (CI) = 0.83-1.11; OR > 10 cigarettes = 1.04, 95% CI = 0.79-1.36). Studies on alcohol exposure in all the outcomes reported inconsistent findings and no strong conclusions on causality can be made. Studies on caffeine exposure were mainly limited to ADHD and these studies do not support a causal effect.ConclusionsThere appears to be no clear evidence to support a causal relationship between maternal prenatal smoking and offspring attention-deficit hyperactivity disorder. Findings with alcohol and caffeine exposures and conduct disorder and oppositional-defiant disorder need more research, using more genetically sensitive designs.
| S-EPMC10308447 | biostudies-literature
Project description:The main objective of the present study was to determine whether prenatal exposure to atrazine could affect testicle descent and penile masculinization. Atrazine has been demonstrated with a variety of endocrine disrupting activities and reproductive toxicities. However, the effects of prenatal atrazine exposure on male offspring's genital malformation, such as hypospadias and cryptorchidism, remain poorly understood. In this study, pregnant ICR mice were gavaged from gestational day 12.5-16.5 with different doses of atrazine. Although no sign of systemic toxicity was observed in F1 male pups, prenatal exposure to 100 mg/kg/day atrazine affected penile morphology, urethral meatus position and descent of testis, and reduced anogenital distance and penile size in postnatal day 21 F1 male pups. The comparative study with an androgen receptor (AR) antagonist vinclozolin suggested that these effects of atrazine on male genital development may not be through antagonism of AR. The results also revealed that atrazine exposure significantly reduced maternal serum testosterone levels, decreased AR nuclear translocation, and altered the expression levels of developmental gene networks in developing penis of mice. Atrazine exposure also affected the expression of insulin-like 3 (Insl3) and steroidogenic gene expression in developing reproductive tract. Therefore, our data indicate that prenatal atrazine exposure can induce hypospadias in F1 mice, likely through disruption of testosterone production, decreasing genomic androgen action, and then altering expression of developmental genes during sexual differentiation. Our data also suggest that prenatal atrazine exposure can induce cryptorchidism in F1 mice, possibly through down regulation of Insl3.
| S-EPMC7986601 | biostudies-literature
Project description:The current opioid epidemic has dramatically increased the number of children who are prenatally exposed to opioids, including oxycodone. A number of social and cognitive abnormalities have been documented in these children as they reach young adulthood. However, little is known about the mechanisms underlying developmental effects of prenatal opioid exposure. Microglia, the resident immune cells of the brain, respond to acute opioid exposure in adulthood. Moreover, microglia are known to sculpt neural circuits during typical development. Indeed, we recently found that microglial phagocytosis of dopamine D1 receptors (D1R) in the nucleus accumbens (NAc) is required for the natural developmental decline in NAc-D1R that occurs between adolescence and adulthood in rats. This microglial pruning occurs only in males, and is required for the normal developmental trajectory of social play behavior. However, virtually nothing is known as to whether this developmental program is altered by prenatal exposure to opioids. Here, we show in rats that maternal oxycodone self-administration during pregnancy leads to reduced adolescent microglial phagocytosis of D1R and subsequently higher D1R density within the NAc in adult male, but not female, offspring. Finally, we show prenatal and adult behavioral deficits in opioid-exposed offspring, including impaired extinction of oxycodone-conditioned place preference in males. This work demonstrates for the first time that microglia play a key role in translating prenatal opioid exposure to changes in neural systems and behavior.
| S-EPMC9372181 | biostudies-literature
Project description:Although prenatal tobacco exposure (PTE) is associated with several adverse offspring mental health outcomes, mechanisms remain unclear. We test whether associations between PTE and offspring psychopathology are explained by birthweight, one of the earliest-occurring outcomes of PTE. The analysis focuses on 238 offspring from a family study of depression with (1) collected prenatal histories and (2) at least one clinical interview in adulthood to assess psychiatric problems. Exposure was categorized by maternal smoking of ≥10 cigarettes daily/nearly daily; diagnostic outcomes were confirmed by clinicians using the best-estimate procedure, blind to exposure. After adjusting for potential confounders, PTE was associated with 0.7lb(9%) lower birthweight (p=0.0002), increased rates of disruptive behavior disorders [males: OR=2.66(1.15,6.16), and (trend) substance use disorders [females: OR=2.23(0.98,5.09)], and decreased rates of mood disorders (males: OR=0.42(0.17,0.98)]. Birthweight was not independently associated with diagnoses and did not mediate the association between exposure and psychopathology. Maternal smoking has long-term adverse consequences for offspring. Although birthweight cannot be manipulated, smoking is a modifiable risk factor. Thus, cessation efforts focused on pregnant women may not only improve maternal wellbeing, but also mitigate adverse proximal (e.g., birthweight) and long-term (psychopathology) outcomes in offspring.
| S-EPMC5438886 | biostudies-literature
Project description:Nicotine, a definite risk factor during pregnancy, is an immunomodulator. This study was designed to investigate the effects of prenatal nicotine exposure (PNE) on the balance of Th1/Th2 in offspring, and further explore the developmental origin mechanisms from the perspective of fetal thymocytes apoptosis. Pregnant Balb/c mice were administered 1.5 mg/kg nicotine subcutaneously twice per day from gestational day (GD) 9 to GD18. Results showed that PNE could cause a Th2 shift in male offspring, manifested as increased ratio of IgG1/IgG2a, IL-4 production in serum, and IL-4/IFN-γ expression ratio in spleen. Increased apoptosis of total thymocytes and CD4SP and reduced cell proportion of CD4SP were found in PNE male offspring on postnatal day (PND) 14 and PND 49. In the fetuses, decreased body weight and organ index of fetal thymus, histological changes in fetal thymus, reduced CD4SP proportion and increased fetal thymocyte apoptosis were observed in nicotine group. The increased mRNA expression of genes involved in Fas-mediated apoptotic pathway and protein expression of Fas were also detected. In conclusion, PNE could cause a Th2 shift in male offspring mediated by reduced CD4+ T cells output, which may result from the increasing apoptosis of total thymocytes and CD4SP.
| S-EPMC5157046 | biostudies-literature
Project description:Introduction: Cigarette smoke (CS) exacerbates the severity of diseases not only in lungs, but also in systemic organs having no direct contact with smoke. In addition, smoking during pregnancy can have severe health consequences for both the mother and the fetus. Therefore, our aim was to evaluate effects of prenatal exposure to CS on acetaminophen (APAP)-induced acute liver injury (ALI) in offspring. Methods: Female C57BL/6 mice on day 6 of gestation were exposed to mainstream CS (MSCS) at 0, 150, 300, or 600 μg/L for 2 h a day, 5 days a week for 2 weeks using a nose-only exposure system. At four weeks old, male offspring mice were injected intraperitoneally with a single dose of APAP at 300 mg/kg body weight to induce ALI. Results: Maternal MSCS exposure significantly amplified pathological effects associated with ALI as evidenced by elevated serum alanine aminotransferase levels, increased hepatocellular apoptosis, higher oxidative stress, and increased inflammation. Interestingly, maternal MSCS exposure reduced microRNA (miR)-34a-5p expression in livers of offspring. Moreover, treatment with a miR-34a-5p mimic significantly mitigated the severity of APAP-induced hepatotoxicity. Overexpression of miR-34a-5p completely abrogated adverse effects of maternal MSCS exposure in offspring with ALI. Mechanistically, miR-34a-5p significantly decreased expression levels of hepatocyte nuclear factor 4 alpha, leading to down-regulated expression of cytochrome P450 (CYP)1A2 and CYP3A11. Discussion: Prenatal exposure to MSCS can alter the expression of miRNAs, even in the absence of additional MSCS exposure, potentially increasing susceptibility to APAP exposure in male offspring mice.
| S-EPMC11319911 | biostudies-literature
Project description:Toll-like receptor 2 (TLR2), which recognizes several lipopeptides and transduces inflammatory signaling, promotes the pathogenesis of diet-induced dyslipidemia and obesity. TLR2-deficient mice were shown to have improved insulin sensitivity and reduced diet-induced metabolic syndrome. Previous studies demonstrated that prenatal lipopolysaccharide (LPS) exposure causes dyslipidemia accompanied by increased body weight and insulin resistance in offspring. To determine whether TLRs are involved in this complex abnormal phenotype, we analyzed TLR2 and TLR4 expression levels in adipose tissues from offspring with prenatal LPS-exposure (offspring-pLPS) and compared these levels to those of control offspring with prenatal saline-exposure (offspring-pSaline). TLR2 expression was specifically upregulated in the adipose tissue of offspring-pLPS mice. However, unexpectedly, TLR2-deficient offspring-pLPS mice not only presented with an abnormal phenotype comparable to that of wild-type offspring-pLPS mice but also exhibited significantly more severe hyperlipidemia. Our further analyses revealed a dramatic upregulation of TLR4 expression and overactivation of the TLR4/Myd88 signaling pathway in TLR2-deficient offspring-pLPS adipose tissue. Our finding suggests a compensatory genetic interaction between TLR2 and TLR4 in the context of prenatal inflammatory stimulation, and this interaction likely contributes to the prenatal inflammation-induced hyperlipidemia and lipid overload-induced obesity, thus providing a potential mechanism for the fetal origin of adult metabolic diseases.
| S-EPMC6713936 | biostudies-literature
Project description:ObjectiveTo study the association between nicotine or cannabis metabolite presence in maternal urine and child neurodevelopmental outcomes.MethodsWe conducted a secondary analysis of two parallel multicenter randomized controlled trials of treatment for hypothyroxinemia or subclinical hypothyroidism among pregnant individuals enrolled at 8-20 weeks of gestation. All maternal-child dyads with a maternal urine sample at enrollment and child neurodevelopmental testing were included (N=1,197). Exposure was urine samples positive for nicotine (cotinine) or cannabis 11-nor-9-carboxy-delta-9-tetrahydrocannabinol [THC-COOH]) or both metabolites. Primary outcome was child IQ at 60 months. Secondary outcomes included cognitive, motor and language, attention, behavioral and social competency, and differential skills assessments at 12, 24, 36, and 48 months. Quantile regression analysis was performed with confounder adjustment.ResultsOf 1,197 pregnant individuals, 99 (8.3%) had positive cotinine samples and 47 (3.9%) had positive THC-COOH samples; 33 (2.8%) were positive for both. Groups differed in self-reported race and ethnicity, education, marital status, insurance, and thyroid status. Median IQ was similar between cotinine-exposed and -unexposed children (90 vs 95, adjusted difference in medians -2.47, 95% CI -6.22 to 1.29) and THC-COOH-exposed and -unexposed children (89 vs 95, adjusted difference in medians -1.35, 95% CI -7.76 to 5.05). In secondary outcome analysis, children with THC-COOH exposure compared with those unexposed had higher attention scores at 48 months of age (57 vs 49, adjusted difference in medians 6.0, 95% CI 1.11-10.89).ConclusionsNeither prenatal nicotine nor cannabis exposure was associated with a difference in IQ. Cannabis exposure was associated with worse attention scores in early childhood. Longitudinal studies assessing associations between child neurodevelopmental outcomes and prenatal nicotine and cannabis exposure with a focus on timing and quantity of exposure are needed.Clinical trial registrationClinicalTrials.gov, NCT00388297.
| S-EPMC8715943 | biostudies-literature