Faculty Bibliography

In situ reactions of metal ions or their compounds are important mechanisms by which particles alter lung immune responses. The authors hypothesized that major determinants of the immunomodulatory effect of any metal include its redox behavior/properties, oxidation state, and/or solubility, and that the toxicities arising from differences in physicochemical parameters are manifest, in part, via differential shifts in lung iron (Fe) homeostasis. To test the hypotheses, immunomodulatory potentials for both pentavalent vanadium (V(V); as soluble metavanadate or insoluble vanadium pentoxide) and hexavalent chromium (Cr(VI); as soluble sodium chromate or insoluble calcium chromate) were quantified in rats after inhalation (5 h/day for 5 days) of each at 100 mug metal/m(3). Differences in effects on local bacterial resistance between the two V(V), and between each Cr(VI), agents suggested that solubility might be a determinant of in situ immunotoxicity. For the soluble forms, V(V) had a greater impact on resistance than Cr(VI), indicating that redox behavior/properties was likely also a determinant. The soluble V(V) agent was the strongest immunomodulant. Regarding Fe homeostasis, both V(V) agents had dramatic effects on airway Fe levels. Both also impacted local immune/airway epithelial cell Fe levels in that there were significant increases in production of select cytokines/chemokines whose genes are subject to regulation by HIF-1 (whose intracellular longevity is related to cell Fe status). Our findings contribute to a better understanding of the role that metal compound properties play in respiratory disease pathogenesis and provide a rationale for differing pulmonary immunotoxicities of commonly encountered ambient metal pollutants

Syngeneic murine tumor models have been widely used by researchers to assess changes in tumor susceptibility associated with exposure to toxicants. Two common tumor models used to define host resistance against transplanted tumors in vivo are EL4 mouse lymphoma cells (established from a lymphoma induced in a C57BL/6 mouse by 9,10-dimethyl-1,2-benzanthracene) and B16F10 mouse melanoma cells (derived through variant selection from a B16 melanoma arising spontaneously in C57BL/6 mice). While C57BL/6 mice are commonly used as the syngeneic host for these tumor models, other mouse strains such as B(6)C(3)F(1) (C57BL/6 x C3H) can also be used. Tumor challenge of the host can be done by subcutaneous (sc) or intravenous (iv) injection, depending upon whether the effects are to be examined on local tumor development or experimental/artificial metastasis. Materials and methodologies for injection of both tumor cell models are described in detail in the subsequent sections

Pyridoxine, a B(6) vitamin, is a co-factor in a variety of enzymatic reactions involved in intermediary metabolism. The effects of pyridoxine deficiency and supplementation on hematological profiles, lymphocyte function, and hepatic CYP1A1 and CYP2E1 were investigated in B(6)C(3)F(1) mice fed a diet containing either 0 (i.e., pyridoxine-deficient diet, [PD]); or 7 mg pyridoxine-HCl/kg (i.e., control diet, [CD]) for 8 or 13 weeks followed by administration of 500 mug pyridoxine-HCl (IP) daily for either 2 (PD-S2 and CD-S2) or 3 (PD-S3 and CD-S3) consecutive days. Results demonstrated that erythrocyte aspartate aminotransferase activity coefficient (EAST-AC) values, which reflect host pyridoxine status, were significantly higher in PD mice than in CD mice, and dropped to control levels after supplementation. PD mice had significantly reduced weight gains, mean corpuscular volume (MCV), hemoglobin (HGB), and hematocrit (HCT) levels compared to CD mice after 8 and 13 weeks on the prescribed diet. In addition, PD mice had significantly lower circulating levels of total white blood cells, but higher red blood cell numbers after 8 weeks (compared to CD mice). Pyridoxine supplementation for 3 days restored HGB levels in PD mice to that of the unsupplemented CD controls; HCT, MCV and MCH levels were also increased in PD-S3 mice compared to their unsupplemented PD counterparts, but failed to reach comparable levels to those seen in mice fed a control diet. The pyridoxine-deficient diet also resulted in decreased mitogen stimulated T-lymphocyte proliferation after a 13-week feeding regimen and increased hepatic CYP1A1 activity that was reversed by pyridoxine supplementation. These studies demonstrate in a murine model that pyridoxine deficiency can cause multiple alterations that, in many cases, can be reversed by supplementation.

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

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

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

Chronic pediatric diseases arising from early-life immune insult and postnatal immune dysfunction are among the most prevalent health challenges for children. Diseases such as childhood asthma and allergies, chronic otitis media, type 1 diabetes, childhood leukemia and pediatric celiac disease all feature dysfunctional immune responses and/ or inappropriately skewed immune capacities. Additionally, these disorders have been increasing in incidence in recent years with previously identified risk factors unable to fully account for the change. Still, some treatment approaches target the initial health complaint and its symptoms without fully addressing either the underlying immune dysfunction of the initial disease or the likelihood for additional associated health risks in later life. Therefore, it is useful to understand both the nature of the immune dysfunction as well as the reported associated health risks. This review characterizes those pediatric immune dysfunctions produced by well-studied immunotoxicants and provides a matrix of those health risks that appear to be linked together via the underlying pediatric immune dysfunction. This information could lead to: 1) improved identification and treatment of underlying immune dysfunction, 2) long-term approaches to health management, and 3) improved prenatal and neonatal prevention strategies to avoid environmentally-induced immune insult and developmental immunotoxicity

Incidence of childhood allergic disease including asthma (AD-A) has risen since the mid-20th century with much of the increase linked to changes in environment affecting the immune system. Childhood allergy is an early life disease where predisposing environmental exposures, sensitization, and onset of symptoms all occur before adulthood. Predisposition toward allergic disease (AD) is among the constellation of adverse outcomes following developmental immunotoxicity (DIT; problematic exposure of the developing immune system to xenobiotics and physical environmental factors). Because novel immune maturation events occur in early life, and the pregnancy state itself imposes certain restrictions on immune functional development, the period from mid-gestation until 2 years after birth is one of particular concern relative to DIT and AD-A. Several prenatal-perinatal risk factors have been identified as contributing to a DIT-mediated immune dysfunction and increased risk of AD. These include maternal smoking, environmental tobacco smoke, diesel exhaust and traffic-related particles, heavy metals, antibiotics, environmental estrogens and other endocrine disruptors, and alcohol. Diet and microbial exposure also significantly influence immune maturation and risk of allergy. This review considers (1) the critical developmental windows of vulnerability for the immune system that appear to be targets for risk of AD, (2) a model in which the immune system of the DIT-affected infant exhibits immune dysfunction skewed toward AD, and (3) the lack of allergy-relevant safety testing of drugs and chemicals that could identify DIT hazards and minimize problematic exposure of pregnant women and children