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Cigarette smoke exposure has been considered a risk factor for infection with Chlamydia pneumoniae. C. pneumoniae infection is associated with respiratory tract infection and chronic respiratory disease, which is a serious public health concern. To determine whether prior exposure to cigarette smoke worsens C. pneumoniae infection (specifically, increases infectious burden and systemic dissemination) as well as alters cytokine responses in mice, adult female C57BL/6 mice were exposed to either filtered air (FA) or mainstream cigarette smoke (MCS) (15 mg/m(3), total suspended particulates) for 5 days/week for 2 weeks and then infected with C. pneumoniae (10(5) IFU) via intratracheal instillation. Mice were euthanized on Days 7, 14 or 26 post-infection (p.i.). Chlamydial burdens in the lungs and spleen were quantified by quantitative PCR (qPCR) and histologic analyses were performed; cytokine levels (TNFα, IL-4, IFNγ) in bronchoalveolar lavage fluid and serum were assayed by enzyme-linked immunosorbent assay (ELISA). The results indicated that: (1) mice exposed to either FA or MCS had similar chlamydial burdens in the lungs and spleen on Days 14 and 26 p.i.; (2) proximal and distal airway inflammation was observed on Day 14 p.i. in both FA and MCS mice, but persisted in MCS mice until Day 26 p.i.; FA exposed mice demonstrated resolution of distal airway inflammation; and (3) MCS mice displayed higher serum levels of IFNγ and IL-4 on Day 26 p.i. These findings indicate that exposure of mice to MCS (at a concentration equivalent to smoking < 1 pack cigarettes/day) led to greater C. pneumoniae-induced inflammation, as indicated by prolonged inflammatory changes.

Epidemiological studies suggest that maternal smoking increases the incidence in the progeny of certain childhood cancers. Our previous study in mice demonstrated the feasibility of such an association by demonstrating that prenatal exposure to cigarette smoke (CS) elevated the incidence of transplanted tumors and reduced cytotoxic T-lymphocyte (CTL) activity in juvenile male offspring. The current study extends these findings by investigating the relationship between CS-induced CTL suppression and effects on regulators of effector T-cell activity, such as T-regulatory (Treg; CD4+ CD25+ Foxp3+) cells and transforming growth factor (TGF)-β. Results here demonstrate that in utero exposure to CS, at a maternal particle concentration of 15 mg/m3 (4 h/d, 5 d/wk), significantly reduced ex vivo CTL activity of whole splenocytes (and isolated CD8+ cells) against tumor cells both before and after injection of prenatally exposed mice with EL4 lymphoma cells. In contrast, prenatal CS exposure significantly increased levels of thymic Treg cells in a time-dependent manner following tumor cell injection. In vitro production of TGF-β by splenocytes recovered from prenatally exposed, tumor-bearing mice was also altered. Neither prenatal CS exposure nor subsequent administration of EL4 cells exerted any marked effects on lymphoid organ weights, cellularity, or histologic profiles. Given that Treg cells and TGF-β suppress effector T-cell activities, these findings suggest possible immune mechanisms by which early exposure to CS reduces CTL tumoricidal activity during tumor cell development. Data suggest that children of smoking mothers may be less able to mount an appropriate adaptive immune response to tumors, thus increasing their risk for some cancers later in life.

Evidence is rapidly accumulating that links cigarette smoke (CS) exposure in utero with the development of a variety of disease pathologies in the older offspring including, type 2 diabetes, obesity, certain childhood cancers and respiratory disorders. The role that the fetal environment plays in these late-onset outcomes and the underlying cellular/molecular mechanisms by which these CS-induced effects may occur are currently unknown. Although we are becoming more aware of the fact that prenatal insult can underlie childhood/adult diseases, critical knowledge gaps still exist including gene-environment interactions, and how a CS-induced imbalance in immune dynamics (i.e. TH1/TH2) might affect asthma development and/or exacerbation later in life. In this mini-review we introduce the concept of sexual dimorphism in CS-induced late-onset disease outcomes, as well as explore the mechanisms by which CS exposure in utero can lead to cardiovascular, cancer and respiratory abnormalities in the exposed offspring. By addressing such questions using animal models, appropriate intervention strategies can be developed that will help to protect children's health and their long-term quality of life.

Background: Cardiovascular disease (CVD) affects 71 million American adults and remains the leading cause of death in the United States and Europe. Despite studies that suggest that the development of CVD may be linked to intrauterine growth or early events in childhood, little direct experimental evidence supports the notion., Objective: We investigated whether exposure to cigarette smoke in utero alters the risk of developing CVD later in life., Methods: We exposed B(6)C(3)F(1) mice (via whole-body inhalation) to either filtered air or mainstream cigarette smoke (MCS, at a particle concentration of 15 mg/m(3)) from gestational day 4 to parturition. Adult offspring were fed a normal chow diet or switched to a high-fat diet 2 weeks before sacrifice. We measured dam and offspring body weight, plasma lipid parameters, lipoprotein subclass particle numbers and sizes, and total antioxidant capacities., Results: Adult female mice prenatally exposed to MCS demonstrated significantly higher body weight and levels of plasma high-density lipoprotein (HDL) and low-density lipoprotein than did their air-exposed counterparts. When fed a high-fat diet for 2 weeks, males, but not females, exposed prenatally to MCS gained substantially more weight and exhibited dramatic alterations in total cholesterol and HDL levels compared with their air-exposed counterparts., Conclusions: These data provide, for the first time, direct experimental evidence supporting the notion that prenatal exposure to cigarette smoke affects offspring weight gain and induces a lipid profile that could alter the offspring's risk of developing CVD later in life.

Epidemiologic studies indicate that women who smoke cigarettes are more likely to experience adverse reproductive and immunological health effects. Despite these facts, 20-30% of American women still smoke during their reproductive years. As little is known of the relationship between smoking and the immune response during pregnancy, an investigation was conducted using parous and non-parous (virgin) B6C3F1 mice to investigate what role (if any) parity status had on cigarette smoke (CS) induced effects on immune functions important in surveillance against developing tumors. Pregnant mice were exposed to CS for 5 d/wk ( 4 hr/d) from gestational day 4 to parturition; virgin mice were exposed for an equivalent amount of time. Smoke- and parity-associated alterations in pulmonary histology and lung inflammation, along with tumor cell host resistance, and cytotoxic T-lymphocyte (CTL) activity were examined either 24- 48 hr or 5 wk post-exposure/parturition; in the parous mice, gestational parameters were also evaluated. Exposure to CS significantly increased tumor susceptibility in virgin mice first injected with EL4 lymphoma cells at the 5 wk post-exposure timepoint; tumor incidence began to increase in smoke-exposed virgin mice as early as 24- 48 hr post-exposure. Pregnancy itself increased tumor incidence in mice injected with EL4 cells 24- 48 hr after birth, but this effect then dissipated over 5 wk to levels seen in virgin mice. When EL4 injections were first performed at either timepoint in CS-exposed parous mice, the tumor incidence was not significantly different from that in the air-exposed parity-matched controls. CTL activity in CS-exposed parous mice was significantly increased from both nulliparous groups as well as from the parous air control mice examined 5 wk post-exposure. Results suggest that exposure to CS throughout gestation could act in combination with pregnancy-associated changes to up-regulate immune responses, potentially compromising fetal tolerance.

While direct exposure to cigarette smoke (CS) was shown in numerous human and animal studies to impair host immune responses, effects on the offspring following in utero CS exposure are relatively unknown. Thus, a toxicological study was performed that extended our previous investigations examining the effects of relatively low-dose CS exposure on immune tumor surveillance parameters of the prenatally exposed offspring. In the current study, pregnant B6C3F1 mice were exposed by inhalation to mainstream CS (at a concentration equivalent to smoking approximately 1 pack of cigarettes/d) for 5 d/wk, 4 h/d from gestational day 4 to parturition. Smoke-induced effects on a number of immune parameters were examined in 3- (and/or 5-), 10-, and 20-wk-old male and female offspring, including lymphoid organ weight/cellularity; blood and bronchopulmonary lavage cell numbers/profiles; splenic lymphocyte proliferation; mixed lymphocyte reactions; and, host resistance against transplanted melanoma cells. Exposure in utero to CS significantly increased circulating white blood cell and lymphocyte numbers in both sexes for up to 2.5 mo after birth (compared to their age-/sex-matched, air-exposed counterparts). In addition, 3-wk-old male and female offspring from smoke-exposed mothers had decreased mitogen-stimulated T-lymphocyte proliferation, while 5-wk-old male pups had increased mixed lymphocyte response compared to their sex-matched, air-exposed counterparts. Although effects of prenatal smoke exposure on overall offspring immunity were relatively modest, these findings could suggest that early toxic insult by CS may alter subsequent immune homeostasis in the offspring, leading, possibly, to changes in disease vulnerability.

About 1 million babies are born each year after prenatal cigarette smoke (CS) exposure from maternal smoking which does not include involuntary maternal exposure to passive smoke. While past emphasis has been on immediately obvious perinatal consequences (e.g., preterm delivery, and low birthweight), smoking during pregnancy has recently emerged as a possible risk factor for later onset disease outcomes in the prenatally exposed offspring. This review brings together those epidemiologic and toxicologic studies demonstrating a link between prenatal CS exposure and subsequent disease vulnerabilities in the progeny. While disorders such as obesity, and type 2 diabetes are included in this category, this paper focuses on two immunologically-related outcomes, cancer and asthma. The review defines the current state of knowledge in this understudied area of children's health, sheds light on the seriousness of such disease vulnerabilities, and reveals gaps that need to be filled to provide a better understanding of the extent and nature of the problem.