In Utero Exposure to Second-Hand Smoke Aggravates Adult Responses to Irritants

Abstract

In utero exposure to second-hand smoke (SHS) is associated with exacerbated asthmatic responses in children. We tested the hypothesis that in utero SHS will aggravate the lung responses of young adult mice re-exposed to SHS. We exposed Balb/c mice in utero to SHS (S) or filtered air (AIR; A), and re-exposed the male offspring daily from 11-15 weeks of age to either SHS (AS and SS) or AIR (AA and SA). After the adult exposures, we analyzed samples of bronchoalveolar lavage fluid (BALF), examined the results of histopathology, and assessed pulmonary function and gene expression changes in lung samples. In SS mice, compared with the other three groups (AA, AS, and SA), we found decreases in breathing frequency and increases in airway hyperresponsiveness (AHR), as well as low but significantly elevated concentrations of BALF proinflammatory cytokines (IL-1b, IL-6, and keratinocytederived chemokine). Lung morphometric analyses revealed enlarged airspaces and arteries in SA and SS mice compared with their in utero AIR counterparts, as well as increased collagen deposition in AS and SS mice. Unique gene expression profiles were found for in utero, adult, and combined exposures, as well as for mice with elevated AHR responses. The profibrotic metalloprotease genes, Adamts9 and Mmp3, were up-regulated in the SS and AHR groups, suggesting a role for in utero SHS exposure on the adult development of chronic obstructive pulmonary disease. Our results indicate that in utero exposures to environmentally relevant concentrations of SHS alter lung structure more severely than do adult SHS exposures of longer duration. These in utero exposures also aggravate AHR and promote a profibrotic milieu in adult lungs.Keywords: second-hand smoke; in utero exposure; airway hyperresponsiveness; lung structure changes; gene expressionIn utero exposure to second-hand smoke (SHS), which exerts striking effects on lung function (1), has been associated with exacerbated asthmatic responses in children (1, 2). Altered lung function, an increased risk of asthma, and persistent lung function deficits in children have been linked with in utero and postnatal exposures to SHS (3-7). The synergistic effects of in utero smoke exposure with various nontobacco allergens have also been reported. Mild in utero SHS exposure exacerbates responses of BALB/c mice exposed to ovalbumin (OVA) from 11-15 weeks of age (8). These functional, histological, and inflammatory responses are accompanied by distinct changes in lung gene expression (9). Children exposed in utero to maternal smoking manifest a higher risk of sensitization to house dust mites (10). A recent study of mice found that in utero smoke exposure promotes Th2 polarization and induces allergic asthma in response to Aspergillus fumigatus sensitization (11). Whether and how in utero SHS exposures potentiate subsequent adult physiological and transcriptome responses to SHS exposure, without any other irritant challenges, are not fully understood.Evidence also indicates that exposure to environmental pollu...

In utero exposure to second‐hand smoke activates pro‐asthmatic and oncogenic miRNAs in adult asthmatic mice

“…The low correlation (Pearson's r 5 0.1, between RNA-seq and microarray) and more blue dots scattered near the vertical line (x 5 0) in panel B&C, indicated that the RNA-seq had better sensitivity, particularly among low abundance genes (lowest 25%, in blue dots). our lab Rouse et al, 2007;Xiao et al, 2012], the effects of in utero SHS followed by no subsequent adult exposure to any environmental agent produces very few differences (notably in BALF cytology) between the in utero SHS-exposed mice compared to air controls. Mice exposed in utero to air or SHS exhibit similar responses at 15 and 23 weeks of age.…”

“…Previously, we reported that in utero second-hand smoke (SHS) exposure aggravates adult responses to subsequent post-natal exposures to environmental irritants, including ovalbumin (OVA) Xiao et al, 2013] and SHS [Xiao et al, 2012]. In the most recent studies [Xiao et al, 2013], where we challenged all adult mice with OVA to induce allergic asthma, we found that the effects of in utero SHS exposure persisted into adulthood, further aggravated lung inflammation, elevated Th2 cytokine levels in bronchoalveolar lavage fluid (BALF), increased airway hyperresponsiveness (AHR), and altered gene expression profiles (microarray-based).…”

In UteroExposure to Second-Hand Smoke Aggravates the Response to Ovalbumin in Adult Mice

“…We conducted SHS exposures on BALB/c mice (Harlan, Indianapolis, IN), as described previously (3,11). Briefly, half of the mated females, randomly selected, were exposed to SHS generated from 3R4F filtered research cigarettes (10 mg/m 3 ; University of Kentucky, Lexington, KY) mixed with AIR daily, from Days 6 to 19 of gestation.…”

“…This was performed as described previously (3,11). For each mouse at each methacholine dose level (3-50 mg/ml), readings over 5 minutes were averaged for Penh and f. Penh values represent the degree of AHR in each animal.…”

“…Second-hand smoke (SHS) exposure in utero aggravates responses to subsequent post-natal exposures to environmental irritants, including house dust mites (1), Aspergillus fumigatus (2) and SHS (3). The most common observation among these studies is increased airway hyperresponsiveness (AHR), a hallmark of allergic asthma.…”