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Impact of gestational nicotine exposure on intrauterine and fetal infection in a rodent model.

ABSTRACT: We investigated the interaction between prenatal nicotine exposure and intrauterine infection using established rat models. Beginning at gestation day (GD) 6, dams were continuously infused with either saline or 6 mg/kg/day nicotine (Nic). At GD 14, dams received either sterile broth or 105 colony-forming units Mycoplasma pulmonis (MP), resulting in four treatment groups: control (4 dams, 33 fetal units); MP only (5 dams, 55 fetal units); Nic only (5 dams, 61 fetal units), and Nic + MP (7 dams, 82 fetal units). At GD 18, nicotine exposure significantly increased (P ? 0.02) the percentage of amniotic fluids and fetuses infected by MP but did not impact colonization rates of maternal sites. Nicotine exposure significantly reduced the numbers of MP in the placenta required for high microbial loads (?104 color-changing units) in the amniotic fluid (P < 0.01). Fetal inflammatory response lesions were most extensive in the Nic only and Nic + MP groups (P < 0.0001). Control and MP only placentas were interleukin (IL)10-dominant, consistent with an M2/Th2 environment. Placentas exposed to nicotine shifted to a neutral environment, with equivalent levels of interferon gamma (IFNG) and IL10. Both IL6 and tumor necrosis factor (TNF) levels in amniotic fluid were highly elevated when both nicotine and infection were present. Our study suggests that prenatal exposure to nicotine increases the risk for intrauterine infection, lowers the infectious dose required to breach the placental barrier and infect the amniotic fluid and fetus, and alters the pathology and inflammatory profile associated with maternal and fetal sites.

SUBMITTER: von Chamier M

PROVIDER: S-EPMC5803783 | biostudies-literature | 2017 May

REPOSITORIES: biostudies-literature

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Impact of gestational nicotine exposure on intrauterine and fetal infection in a rodent model.

von Chamier Maria M Reyes Leticia L Hayward Linda F LF Brown Mary B MB

Biology of reproduction 20170501 5

We investigated the interaction between prenatal nicotine exposure and intrauterine infection using established rat models. Beginning at gestation day (GD) 6, dams were continuously infused with either saline or 6 mg/kg/day nicotine (Nic). At GD 14, dams received either sterile broth or 105 colony-forming units Mycoplasma pulmonis (MP), resulting in four treatment groups: control (4 dams, 33 fetal units); MP only (5 dams, 55 fetal units); Nic only (5 dams, 61 fetal units), and Nic + MP (7 dams, ...[more]

PMID: 28419180

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Project description:IntroductionBoth smoking and infection adversely impact pregnancy. Previously, our group identified in a rodent model that 6 mg/kg/d nicotine increased the risk of fetal infection at gestation day (GD) 18. Here, we investigate lower nicotine doses.MethodsPregnant Sprague-Dawley rats received nicotine infusion at 0, 1, or 3 mg/kg/d (no, low-, and mid-dose nicotine, respectively) from GD 6, with intravenous inoculation with Mycoplasma pulmonis (MP) at 107 CFU (N = 20) or sterile broth (sham) (N = 11) on GD 14. Uterus and fetuses were retrieved on GD 18 for MP culture and histopathologic evaluation of maternal and fetal inflammatory responses (MIR and FIR).ResultsAt 1 mg/kg/d nicotine, MP colonization rates were decreased, from 100% (9 of 9) to 40% (2 of 5) of MP-inoculated dams (p = .03), and 59% (66 of 111) to 39% (24 of 62) of fetuses (p = .01), versus no nicotine. Low-dose nicotine resulted in increased MIR and FIR in the sham-inoculated group; in the MP-inoculated group, this resulted in reduced relative risk (RR) for placental colonization (RR, 95% CI with high MIR = 0.14, 0.02 to 0.65; FIR = 0.38, 0.12 to 0.93). In contrast, 3 mg/kg/d nicotine treatment did not alter colonization rates; furthermore, FIR was completely suppressed, even in the face of placental or amniotic fluid colonization.ConclusionThe 1 mg/kg/d nicotine dose decreased risk of intrauterine infection, with increased MIR and FIR. The 3 mg/kg/d nicotine dose inhibited FIR, and increased risk for intrauterine infection. Nicotine alterations of the intrauterine environment were markedly dose-dependent.ImplicationsNicotine exposure alters intrauterine infection and inflammation in a dose-dependent manner, potentially impacting fetal development and programming. Previous work in a rodent model showed that high-dose nicotine (6 mg/kg/d) exposure exacerbated intrauterine infection during pregnancy. The current study found that low-dose nicotine (1 mg/kg/d) exposure reduced colonization of placenta and amniotic fluid; this decrease was associated with increased intrauterine inflammation. Exposure to mid-dose nicotine (3 mg/kg/d) suppressed fetal inflammation. Elucidation of underlying mechanisms of these phenomena will inform public health and clinical care decisions, particularly in the context of risk assessment of nicotine replacement therapy during pregnancy for smoking cessation.

Project description:BackgroundIn utero exposure to diabetes has been shown to contribute to preterm birth, though the underlying biological mechanisms are yet to be fully elucidated. Fetal epigenetic variations established in utero may be a possible pathway. This study aimed to investigate whether in utero exposure to diabetes was associated with a change in newborn DNA methylation, and whether the identified CpG sites mediate the association between diabetes and preterm birth in a racially diverse birth cohort population.MethodsThis study included 954 mother-newborn pairs. Methylation levels in the cord blood were determined using the Illumina Infinium MethylationEPIC BeadChip 850 K array platform. In utero exposure to diabetes was defined by the presence of maternal pregestational or gestational diabetes. Preterm birth was defined as gestational age at birth less than 37 weeks. Linear regression analysis was employed to identify differentially methylated CpG sites. Differentially methylated regions were identified using the DMRcate Package.Results126 (13%) newborns were born to mothers with diabetes in pregnancy and 173 (18%) newborns were born preterm, while 41 newborns were born both preterm and to mothers with diabetes in pregnancy. Genomic-wide CpG analysis found that eighteen CpG sites in cord blood were differentially methylated by maternal diabetes status at an FDR threshold of 5%. These significant CpG sites were mapped to 12 known genes, one of which was annotated to gene Major Histocompatibility Complex, Class II, DM Beta (HLA-DMB). Consistently, one of the two identified significant methylated regions overlapped with HLA-DMB. The identified differentially methylated CpG sites mediated the association between diabetes in pregnancy and preterm birth by 61%.ConclusionsIn this US birth cohort, we found that maternal diabetes was associated with altered fetal DNA methylation patterns, which substantially explained the link between diabetes and preterm birth.

Project description:BackgroundIndividuals exposed to gestational stressors such as alcohol exhibit a spectrum of growth patterns, suggesting individualized responses to the stressors. We hypothesized that intrauterine growth responses to gestational alcohol are modified not only by the stressor's severity but by fetal sex and the placenta's adaptive capacity.MethodsPregnant C57BL/6J mice were assigned to one of three groups. Group 1 consumed a normal protein diet (18% protein by weight) and received 4.5 g alcohol/kg body weight (NP-Alc-8) or isocaloric maltodextrin (NP-MD-8) daily from embryonic day (E) 8.5-E17.5. Group 2 consumed the same diet but received alcohol (NP-Alc-13) or maltodextrin (NP-MD-13) daily from E13.5-E17.5. Group 3 consumed the same diet but containing a lower protein content (12% protein by weight) from E0.5 and also received alcohol (LP-Alc-8) or maltodextrin (LP-MD-8) daily from E8.5-E17.5. Maternal, placental, and fetal outcomes were assessed on E17.5 using 2-way ANOVA or mixed linear model.ResultsWe found that intrauterine growth differed in the alcohol-exposed fetuses depending on sex and insult severity. Both NP-Alc-8 (vs. NP-MD-8) males and females had lower body weight and asymmetrical growth, but only NP-Alc-8 females had lower placental weight (P < 0.05). NP-Alc-13 (vs. NP-MD-13) females, but not their male littermates, had lower body weight (P = 0.019). Alcohol exposure beginning from E8.5 (vs. E13.5) decreased the ratio of fetal liver-to-body weight and increased the ratio of fetal brain-to-liver weight in both sexes (P < 0.05). LP-Alc-8 (vs. NP-MD-8) group had smaller litter size (P = 0.048), but the survivors had normal placental and body weight at E17.5. Nevertheless, LP-Alc-8 fetuses still showed asymmetrical growth. Correlation analyses reveal a relationship between litter size and placental outcomes, which were related to fetal outcomes in a sex-dependent manner, suggesting that the placenta may mediate the consequence of LP-Alc-altered litter size on fetal development.ConclusionsOur data indicate that the placenta is strongly involved in the fetal stress response and adapts in a sex-dependent fashion to support fetal development under the alcohol stressor. These variables may further influence the spectrum of intrauterine growth outcomes observed in those diagnosed with fetal alcohol spectrum disorder.

Project description:BackgroundImpaired in utero fetal growth trajectory may have long term health consequences of the newborns and increase risk of adulthood metabolic diseases. Prenatal exposure to air pollution has been linked to fetal development restriction; however, the impact of exposure to ambient air pollutants on the entire course of intrauterine fetal development has not been comprehensively investigated.MethodsDuring 2015-2018, two cohorts of mother-infant dyads (N = 678 and 227) were recruited in Shanghai China, from which three categories of data were systematically collected: (1) daily exposure to six air pollutants during pregnancy, (2) fetal biometry in the 2nd (gestational week 24, [GW24]) and 3rd trimester (GW36), and (3) neonatal outcomes at birth. We investigated the impact of prenatal exposure to air pollutant mixture on the trajectory of fetal development during the course of gestation, adjusting for a broad set of potential confounds.ResultsPrenatal exposure to PM2.5, PM10, SO2 and O3 significantly reduced fetal biometry at GW24, where SO2 had the most potent effect. For every 10 μg/m3 increment increase of daily SO2 exposure during the 1st trimester shortened femur length by 2.20 mm (p = 6.7E-21) translating to 5.3% reduction from the average of the study cohort. Prenatal air pollution exposure also decreased fetal biometry at GW36 with attenuated effect size. Comparing to the lowest exposed quartile, fetus in the highest exposed quartile had 6.3% (p = 3.5E-5) and 2.1% (p = 2.4E-3) lower estimated intrauterine weight in GW24 and GW36, respectively; however, no difference in birth weight was observed, indicating a rapid catch-up growth in the 3rd trimester.ConclusionsTo our knowledge, for the first time, we demonstrated the impact of prenatal exposure to ambient air pollutants on the course of intrauterine fetal development. The altered growth trajectory and rapid catch-up growth in associated with high prenatal exposure may lead to long-term predisposition for adulthood metabolic disorders.

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Impact of gestational nicotine exposure on intrauterine and fetal infection in a rodent model.

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Impact of gestational nicotine exposure on intrauterine and fetal infection in a rodent model.

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