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Neuroinflammatory and Behavioral Outcomes Measured in Adult Offspring of Mice Exposed Prenatally to E-Cigarette Aerosols.

ABSTRACT: BACKGROUND:In an effort to decrease the rates of smoking conventional tobacco cigarettes, electronic cigarettes (e-cigarettes) have been proposed as an effective smoking cessation tool. However, little is known about their toxicological impacts. This is concerning given that e-cigarette use is perceived as less harmful than conventional tobacco cigarettes during pregnancy for both the mother and fetus. OBJECTIVE:The goal of this study was to test the neurodevelopmental consequences of maternal e-cigarette use on adult offspring behavior and neuroimmune outcomes. METHODS:Pregnant female CD-1 mice were randomly assigned to one of three treatment groups (n=8-10?per?group) and exposed daily to either filtered air, propylene glycol and vegetable glycerol (50:50 PG/VG vehicle), or to PG/VG with 16mg/mL nicotine (+Nic). Whole-body exposures were carried out for 3 h/d, 7 d/week, from gestational day (GD)0.5 until GD17.5. Adult male and female offspring (8 weeks old) were assessed across a battery of behavioral assessments followed by region-specific quantification of brain cytokines using multiplex immunoassays. RESULTS:Adult offspring of both sexes exposed to +Nic exhibited elevated locomotor activity in the elevated plus maze and altered stress-coping strategies in the forced swim task. Moreover, male and female offspring exposed to PG/VG with and without nicotine had a 5.2% lower object discrimination score in the novel object recognition task. In addition to differences in offspring behavior, maternal e-cigarette exposure with nicotine led to a reduction in interleukin (IL)-4 and interferon-gamma (IFN?) in the diencephalon, as well as lower levels of hippocampal IFN? (females only). E-cigarette exposure without nicotine resulted in a 2-fold increase of IL-6 in the cerebellum. DISCUSSION:These findings support previous adverse findings of e-cigarette exposure on neurodevelopment in a mouse model and provide substantial evidence of persistent adverse behavioral and neuroimmunological consequences to adult offspring following maternal e-cigarette exposure during pregnancy. https://doi.org/10.1289/EHP6067.

SUBMITTER: Church JS

PROVIDER: S-EPMC7228099 | biostudies-literature | 2020 Apr

REPOSITORIES: biostudies-literature

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Neuroinflammatory and Behavioral Outcomes Measured in Adult Offspring of Mice Exposed Prenatally to E-Cigarette Aerosols.

Church Jamie S JS Chace-Donahue Fiona F Blum Jason L JL Ratner Jill R JR Zelikoff Judith T JT Schwartzer Jared J JJ

Environmental health perspectives 20200415 4

<h4>Background</h4>In an effort to decrease the rates of smoking conventional tobacco cigarettes, electronic cigarettes (e-cigarettes) have been proposed as an effective smoking cessation tool. However, little is known about their toxicological impacts. This is concerning given that e-cigarette use is perceived as less harmful than conventional tobacco cigarettes during pregnancy for both the mother and fetus.<h4>Objective</h4>The goal of this study was to test the neurodevelopmental consequence ...[more]

PMID: 32293200

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Project description:Currently, approximately 8 million adult Americans use electronic cigarettes (e-cigs) daily, including women of childbearing age. It is known that more than 10% of women smoke during their pregnancy, and recent surveys show that rates of maternal vaping are similar to rates of maternal cigarette smoking. However, the effects of inhaling e-cig aerosol on the health of fetuses remain unknown. The objective of the present study was to increase our understanding of the molecular effects caused by in utero exposures to e-cig aerosols on developing mouse lungs and, later in life, on the offspring's susceptibility to developing asthma.MethodsPregnant mice were exposed throughout gestation to either filtered air or vanilla-flavored e-cig aerosols containing 18 mg/mL of nicotine. Male and female exposed mouse offspring were sacrificed at birth, and then the lung transcriptome was evaluated. Additionally, once sub-groups of male offspring mice reached 4 weeks of age, they were challenged with house dust mites (HDMs) for 3 weeks to assess asthmatic responses.ResultsThe lung transcriptomic responses of the mouse offspring at birth showed that in utero vanilla-flavored e-cig aerosol exposure significantly regulated 88 genes in males (62 genes were up-regulated and 26 genes were down-regulated), and 65 genes were significantly regulated in females (17 genes were up-regulated and 48 genes were down-regulated). Gene network analyses revealed that in utero e-cig aerosol exposure affected canonical pathways associated with CD28 signaling in T helper cells, the role of NFAT in the regulation of immune responses, and phospholipase C signaling in males, whereas the dysregulated genes in the female offspring were associated with NRF2-mediated oxidative stress responses. Moreover, we found that in utero exposures to vanilla-flavored e-cig aerosol exacerbated HDM-induced asthma in 7-week-old male mouse offspring compared to respective in utero air + HDM controls.ConclusionsOverall, these data demonstrate that in utero e-cig aerosol exposure alters the developing mouse lung transcriptome at birth in a sex-specific manner and provide evidence that the inhalation of e-cig aerosols is detrimental to the respiratory health of offspring by increasing the offspring' susceptibility to developing lung diseases later in life.

Project description:ObjectiveTo examine the behavioral functioning of children prenatally exposed to carbamazepine (CBZ), lamotrigine (LTG), levetiracetam (LEV), or valproate (VPA) monotherapy.MethodsIn collaboration with the European Registry of Antiepileptic Drugs and Pregnancy (EURAP), the Dutch EURAP & Development study was designed, a prospective observational study. Between January 2015 and March 2018, the Child Behavior Checklist and the Social Emotional Questionnaire were used to examine the nature and severity of behavioral problems. VPA-exposed children were compared to children exposed to CBZ, LTG, or LEV, taking potential confounders into account. A direct comparison was also made between LTG and LEV, as these are first-choice treatments for many women with epilepsy of childbearing potential.ResultsOf the 405 invited, 181 children were included; 26 were exposed to VPA, 37 to CBZ, 88 to LTG, and 30 to LEV. For most children, both parents completed the behavioral questionnaires. Across all four antiepileptic drug (AED) exposure groups, high percentages of children with clinically relevant behavior problems were found, with behavioral problems occurring in 32% of VPA-exposed children, 14% of CBZ, 16% of LTG, and 14% of LEV. After controlling for potential confounders, VPA-exposed children had significantly more social problems than those exposed to LTG (-2.8, 95% confidence interval [CI] = -5.2 to -0.4; P = 0.022) or LEV (-3.2, CI: -6.1 to -0.3; P = 0.028), and significantly more attention problems than LEV-exposed children (-3.7, CI: -6.7 to -0.8; P = 0.013). LTG-exposed children had significantly more attention deficit (-9.2, CI: -17.3 to 1.1; P = 0.026), but significantly less anxious behavior when compared to LEV-exposed children (9.0, CI: 0.3-17.6; P = 0.042).SignificanceCompared to population norms, a high proportion of children of mothers with epilepsy exposed prenatally to monotherapy with four common AEDs had clinical behavioral problems reported by parents. Different patterns were seen, with some but not all subscales raised for all AED exposure groups. It is important that prenatally AED-exposed children are regularly screened for behavioral problems so that appropriate help can be provided.

Project description:Background: Olanzapine (OLZ) is an antipsychotic with a high risk of metabolic syndrome, and its induced metabolic disturbance may be related to the thermogenic function of brown adipose tissue (BAT). Of note is that schizophrenia itself appears to be associated with a higher incidence of metabolic syndrome. However, whether OLZ affects metabolic disorders by regulating BAT function and its mechanism in animal models of schizophrenia have not been reported. Methods: We induced maternal immune activation (MIA) in pregnant rodents by injection of synthetic double-stranded RNA-poly I:C (a virus-like substance), and rats were injected with poly I:C, 10 mg/kg) or saline on day 13 of gestation. Rat offspring received OLZ (1 mg/kg, tid) or vehicle from adulthood for 28 days, and body weight and food intake were recorded. Morphological alterations of white adipose tissue (WAT) and BAT were analyzed by HE and oil red staining, and expression of BAT-specific marker proteins/genes was detected by western blot and qRT-PCR. In addition, embryonic stem cells C3H10T1/2 were used to direct differentiation into brown-like adipocytes, and C3H10T1/2 cells were treated with OLZ for the differentiation process. The effects of OLZ on brown-like adipocyte differentiation and activity were analyzed using oil red staining, immunofluorescence and flow cytometry. Results: Compared with the Veh (saline) group, the TG, pWAT weight, adipocyte size and liver weight of the Veh (poly I:C) group were significantly increased, suggesting that the offspring of Poly I:C rats had obvious dyslipidemia and lipid accumulation, which were risk factors for metabolic abnormalities such as obesity. In addition, OLZ treatment resulted in altered WAT and BAT morphology in poly I:C or saline exposed offspring, causing lipid accumulation and weight gain and reducing the expression of the BAT-specific marker molecule UCP1 protein/gene. At the same time, OLZ inhibited the directional differentiation and mitochondrial activity of C3H10T1/2 brown-like adipocytes. Conclusion: Poly I:C-elicited MIA and OLZ differentially inhibited BAT activity and mitochondrial biogenesis, leading to weight gain in adult rats, a process involving PPAR-γ/UCP1-related thermogenic proteins.

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Neuroinflammatory and Behavioral Outcomes Measured in Adult Offspring of Mice Exposed Prenatally to E-Cigarette Aerosols.

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Neuroinflammatory and Behavioral Outcomes Measured in Adult Offspring of Mice Exposed Prenatally to E-Cigarette Aerosols.

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