Long-term effects of prenatal arsenic exposure from gestational day 9 to birth on lung, heart, and immune outcomes in the C57BL/6 mouse model.

Prenatal arsenic exposure is a major public health concern, associated with altered birth outcomes and increased respiratory disease risk. However, characterization of the long-term effects of mid-pregnancy (second trimester) arsenic exposure on multiple organ systems is scant. This study aimed to characterize the long-term impact of mid-pregnancy inorganic arsenic exposure on the lung, heart, and immune system, including infectious disease response using the C57BL/6 mouse model. Mice were exposed from gestational day 9 till birth to either 0 or 1000 µg/L sodium (meta)arsenite in drinking water. Male and female offspring assessed at adulthood (10-12 weeks of age) did not show significant effects on recovery outcomes after ischemia reperfusion injury but did exhibit increased airway hyperresponsiveness compared to controls. Flow cytometric analysis revealed significantly greater total numbers of cells in arsenic-exposed lungs, lower MHCII expression in natural killer cells, and increased percentages of dendritic cell populations. Activated interstitial (IMs) and alveolar macrophages (AMs) isolated from arsenic-exposed male mice produced significantly less IFN-γ than controls. Conversely, activated AMs from arsenic-exposed females produced significantly more IFN-γ than controls. Although systemic cytokine levels were higher upon Mycobacterium tuberculosis (Mtb) infection in prenatally arsenic-exposed offspring there was no difference in lung Mtb burden compared to controls. This study highlights significant long-term impacts of prenatal arsenic exposure on lung and immune cell function. These effects may contribute to the elevated risk of respiratory diseases associated with prenatal arsenic exposure in epidemiology studies and point to the need for more research into mechanisms driving these maintained responses.

Immune modulation by chronic exposure to waterpipe smoke and immediate-early gene regulation in murine lungs.

OBJECTIVE: We investigated the effects of chronic waterpipe (WP) smoke on pulmonary function and immune response in a murine model using a research-grade WP and the effects of acute exposure on the regulation of immediate-early genes (IEGs). METHODS: WP smoke was generated using three WP smoke puffing regimens based on the Beirut regimen. WP smoke samples generated under these puffing regimens were quantified for nicotine concentration. Mice were chronically exposed for 6 months followed by assessment of pulmonary function and airway inflammation. Transcriptomic analysis using RNAseq was conducted after acute exposure to characterise the IEG response. These biomarkers were then compared with those generated after exposure to dry smoke (without water added to the WP bowl). RESULTS: We determined that nicotine composition in WP smoke ranged from 0.4 to 2.5 mg per puffing session. The lung immune response was sensitive to the incremental severity of chronic exposure, with modest decreases in airway inflammatory cells and chemokine levels compared with air-exposed controls. Pulmonary function was unmodified by chronic WP exposure. Acute WP exposure was found to activate the immune response and identified known and novel IEG as potential biomarkers of WP exposure. CONCLUSION: Chronic exposure to WP smoke leads to immune suppression without significant changes to pulmonary function. Transcriptomic analysis of the lung after acute exposure to WP smoke showed activation of the immune response and revealed IEGs that are common to WP and dry smoke, as well as pools of IEGs unique to each exposure, identifying potential biomarkers specific to WP exposure.

High fat diet induces airway hyperresponsiveness in mice.

The experiment was conducted to examine the effect of a high fat diet (HFD) on airway hyperresponsiveness (AHR) in mice. Twenty-three adult male C57BL/6 J mice were fed with HFD or regular chow diet for two weeks. The total respiratory resistance was measured by forced oscillation technique at baseline and after methacholine aerosol challenge at 1, 3, 10 and 30 mg/mL. Bronchoalveolar lavage (BAL) was performed. Lipid levels and lipid peroxidation in lung tissue were measured along with gene expression of multiple cytokines. Lungs were digested, and IL-1ß secretion by pulmonary macrophages was determined. HFD feeding resulted in 11% higher body weight compared to chow. HFD did not affect respiratory resistance at baseline, but significantly augmented airway responses to methacholine compared to chow diet (40.5 ± 17.7% increase at 30 mg/ml methacholine, p < 0.05). HFD induced a 3.2 ± 0.6 fold increase in IL-1ß gene expression (p < 0.001) and a 38 fold increase in IL-1ß secretion in the lungs. There was no change in BAL and no change in any other cytokines, lipid levels or lipid peroxidation. Hence, HFD induced AHR in mice prior to the development of significant obesity which was associated with up-regulation of pulmonary IL-1ß.