Faculty Bibliography

One industrially important metal oxide nanoparticle (NP) is cadmium oxide (CdO). A study was performed using timed-pregnant CD-1 mice to determine if Cd associated with inhaled CdO NP could reach the placenta and adversely affect the developing fetus and/or neonate. Pregnant mice were exposed by inhalation either every other day to 100 mug of freshly generated CdO/m(3) (exposure 1) or daily to 230 mug CdO/m(3) (exposure 2). In each exposure, mice were exposed to CdO NP or carrier gas (control) for 2.5 h from 4.5 days post coitus (dpc) through 16.5 dpc. At 17.5 dpc, fetuses and placentas from both exposures 1 and 2 were collected, measured, and weighed. A subgroup from the second exposure was allowed to give birth, and neonates were weighed daily until weaning. Cadmium in the uterus and placenta, as well as in other maternal organs, was elevated in NP-treated mice, but was undetectable in fetuses at 17.5 dpc. Daily inhalation of 230 mug CdO NP/m(3) decreased the incidence of pregnancy (i.e., no evidence of implantation) by 23%, delayed maternal weight gain, altered placental weight, and decreased fetal length, as well as delayed neonatal growth. This study demonstrates that inhalation of CdO NP during pregnancy adversely affects reproductive fecundity and alters fetal and postnatal growth of the developing offspring.

The popularity of smokeless tobacco (ST), or noncombusted tobacco, usually placed within the mouth to be chewed, sucked, or swallowed, is growing rapidly and its prevalence of use is rising globally, due (in part) to greater convenience, as allowable cigarette smoking areas are rapidly decreasing, and increased social acceptability. Though data are limited, ST usage has been directly linked to a number of adverse health outcomes. The potential role that immune dysfunction, including dysregulation of immune cells and their components, may play in the progression of these adverse health outcomes is only just beginning to emerge. Evidence suggesting reproductive outcomes, such as perinatal mortality, preterm birth, and reduced sperm viability, also exists in conjunction with ST use. Cardiovascular health may also be impacted by ST use, resulting in increased blood pressure and endothelial dysfunction, both of which may potentially lead to cardiovascular diseases. This review describes the toxicological implications associated with ST use, with emphasis on immune, reproductive, and cardiovascular outcomes. Epidemiological studies are discussed with respect to experimental studies to help develop the relationship between ST and disease pathology. This review also summarizes the gaps in ST knowledge and potential future directions that are needed to more fully delineate the complex systems driving the adverse health outcomes associated with its use.

Maternal environmental exposures during pregnancy are known to affect disease onset in adult offspring. For example, maternal asthma exacerbations during pregnancy can worsen adult asthma in the offspring. Cigarette smoking during pregnancy is associated with future onset of cardiovascular disease, obesity and diabetes. However, little is known about the effect of maternal environmental exposures on offspring susceptibility to liver disease. This pilot study examined the long-term effect of maternal allergen challenge and/or cigarette smoking during pregnancy on hepatic inflammation and fibrosis in adult mouse offspring. Ovalbumin (OVA) or phosphate-buffered saline (PBS)-sensitized/challenged CD-1 dams were exposed to mainstream cigarette smoke (MCS) or filtered air from gestational day 4 until parturition. Eight weeks postnatally, offspring were sacrificed for comparison of hepatic histology and mRNA expression. Adult male offspring of OVA-sensitized/challenged dams exposed to MCS (OSM) displayed significantly increased liver fibrosis (9.2% collagen content vs. <4% for all other treatment groups). These mice also had 1.8-fold greater collagen 1A1 mRNA levels. From the results here, we concluded that maternal allergen challenge in combination with cigarette smoke exposure during pregnancy may be an important risk factor for liver disease in adult male offspring

Attention to non-coplanar polychlorinated biphenyl (PCB) congeners in immunotoxicological research is increasing. However, the exact mechanism by which these congeners may induce immune dysfunction is still undefined. Because the serotonergic nervous system has been shown to be involved in the regulation of some immune responses, and also serves as a sensitive target for PCBs, the relationship (if any) between non-coplanar PCB exposure, immune responsiveness and the neurotransmitter serotonin (5-HT) was examined. Using bluegill sunfish (Lepomis macrochirus) as a model, changes in brain 5-HT levels, 5-HT synthesis and metabolism, and innate and cell-mediated immune parameters were evaluated following a single intraperitoneal injection of PCB 153 (5.0 or 50 mug/g body weight). Results revealed that 3 d following administration, PCB exposure decreased brain 5-HT levels (in the absence of effects on some enzymes involved in 5-HT synthesis and metabolism), increased oxyradical production by kidney phagocytes, and reduced splenic T- and B-lymphocyte proliferation. In vivo treatment of PCB-exposed fish with 5-hydroxy-L-tryptophan (the immediate precursor to 5-HT) ameliorated the observed PCB-induced immunotoxicity; in vitro treatment of immune cells from PCB-exposed fish with 5-HT failed to reverse the effects. Taken together, results from this study could suggest a link between PCB-induced alterations of brain 5-HT levels and subsequent immune dysfunction. These studies highlight the importance of indirect mechanisms of immunotoxicity, and, specifically, suggest a role for the neuroimmune axis in non-coplanar PCB-induced immune alterations

BACKGROUND: Diseases rarely, if ever, occur in isolation. Instead, most represent part of a more complex web or 'pattern' of conditions that are connected via underlying biological mechanisms and processes, emerge across a lifetime, and have been identified with the aid of large medical databases. OBJECTIVE: We have described how an understanding of patterns of disease may be used to develop new strategies for reducing the prevalence and risk of major immune-based illnesses and diseases influenced by environmental stimuli. FINDINGS: Examples of recently defined patterns of diseases that begin in childhood include not only metabolic syndrome, with its characteristics of inflammatory dysregulation, but also allergic, autoimmune, recurrent infection, and other inflammatory patterns of disease. The recent identification of major immune-based disease patterns beginning in childhood suggests that the immune system may play an even more important role in determining health status and health care needs across a lifetime than was previously understood. CONCLUSIONS: Focusing on patterns of disease, as opposed to individual conditions, offers two important venues for environmental health risk reduction. First, prevention of developmental immunotoxicity and pediatric immune dysfunction can be used to act against multiple diseases. Second, pattern-based treatment of entryway diseases can be tailored with the aim of disrupting the entire disease pattern and reducing the risk of later-life illnesses connected to underlying immune dysfunction. Disease-pattern-based evaluation, prevention, and treatment will require a change from the current approach for both immune safety testing and pediatric disease management

BACKGROUND: Childhood susceptibility to diseases linked with immune dysfunction affects over a quarter of the pediatric population in some countries. While this alone is a significant health issue, the actual impact of immune-related diseases extends over a lifetime and involves additional secondary conditions. Some comorbidities are well known (e.g., allergic rhinitis and asthma). However, no systematic approach has been used to identify life-long patterns of immune-based disease where the primary condition arises in childhood. Such information is useful for both disease prevention and treatment approaches. DATA SOURCES: Recent primary research papers as well as review articles were obtained from PubMed, Chem Abstracts, Biosis and from the personal files of the authors. Search words used were: the diseases and conditions shown Figs. 1 and 2 in conjunction with comorbid, comorbidities, pediatric, childhood, adult, immune, immune dysfunction, allergy, autoimmune, inflammatory, infectious, health risks, environment, risk factors. RESULTS: Childhood diseases such as asthma, type-1 diabetes, inflammatory bowel disease, respiratory infections /rhinitis, recurrent otitis media, pediatric celiac, juvenile arthritis and Kawasaki disease are examples of significant childhood health problems where immune dysfunction plays a significant role. Each of these pediatric diseases is associated with increased risk of several secondary conditions, many of which appear only later in life. To illustrate, four prototypes of immune-related disease patterns (i.e., allergy, autoimmunity, inflammation and infectious disease) are shown as tools for: 1) enhanced disease prevention; 2) improved management of immune-based pediatric diseases; and 3) better recognition of underlying pediatric immune dysfunction. CONCLUSIONS: Identification of immune-related disease patterns beginning in childhood provides the framework for examining the underlying immune dysfunctions that can contribute to additional diseases in later life. Many pediatric diseases associated with dysfunctional immune responses have been linked with an elevated risk of other diseases or conditions as the child ages. Diseases within a pattern may be interlinked based on underlying immune dysfunctions and/or current therapeutic approaches for managing the entryway diseases. It may be beneficial to consider treatment options for the earliest presenting diseases that will concomitantly reduce the risk of immune-linked secondary conditions. Additionally, improved disease prevention is possible with more relevant and age-specific immune safety testing

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