Faculty Bibliography

An immunomodulatory role for serotonin (5-HT) has been demonstrated in mammals and evidence for a similar role for 5-HT has recently emerged in fish. However, as limited studies are available, discrepancies often exist regarding the role of 5-HT in the teleost immune response. Therefore, studies were undertaken to help clarify this relationship. Lymphocyte proliferation and extracellular superoxide (O2.-) production were examined in cells from bluegill sunfish injected with either 5-HTP (the immediate precursor to 5-HT) or pCPA (an inhibitor of the rate-limiting enzyme in 5-HT synthesis), or, in vitro following exposure of immune cells to either 5-HT, the 5-HT(1A) receptor agonist, 8-OH-DPAT, or the receptor antagonist, NAN-190. Exposure of fish to 5-HTP increased whole brain 5-HT levels, while pCPA exposure decreased whole brain and splenic 5-HT. In vivo exposure of fish to pCPA depressed T- and B-lymphocyte proliferation; exposure to 5-HTP failed to alter either immune endpoint. In vitro exposure of bluegill splenocytes to 5-HT or 8-OH-DPAT inhibited lymphoproliferation; treatment with NAN-190 had no effect on immune function. Results suggest a link in bluegill between immune function and the serotonergic system. The disparity observed following in vivo- and in vitro-induced serotonergic alterations indicates the complexity of this neuro-immune relationship and emphasizes the need for further studies in this regard

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

The extent of adverse health effects, including induction/exacerbation of infectious lung disease, arising from entrainment of equivalent amounts (or exposure to a fixed increment) of fine particulate matter (PM(2.5)) can vary from region to region or city to city in a region. To begin to explain how differing effects on host resistance might arise after exposure to PM(2.5) from various sites, we hypothesized that select metals (e.g., V, Al, and Mn) in each PM(2.5) caused changes in alveolar macrophage (AM) Fe status that, ultimately, would lead to altered antibacterial function. To test this, iron-response protein (IRP) binding activity in a rat AM cell line was assessed after exposure to Fe alone and in conjunction with V, Mn, and/or Al at ratios of V:Fe, Al:Fe, or Mn:Fe encountered in PM(2.5) samples from New York City, Los Angeles, and Seattle. Results indicated that V and Al each significantly altered IRP activity, though effects were not consistently ratio-(i.e., dose-) dependent; Mn had little impact on activity. We conclude that the reductions in Fe status detected here via the IRP assay arose, in part, from effects on transferrin-mediated Fe(3 +) delivery to the AM. Ongoing studies using this assay are allowing us to better determine: (1) whether mass (and/or molar) relationships between Fe and V, Al, and/or Mn in any PM(2.5) sample consistently govern the extent of change in AM Fe status; (2) how much any specified PM(2.5) constituent (metal or nonmetal) contributes to the overall disruption of Fe status found induced by an intact parent sample; and (3) whether induced changes in binding activity are relatable to other changes expected to occur in the AM, that is, in IRP-dependent mRNA/levels of ferritin/transferrin receptor and Fe-dependent functions. These studies demonstrate that pollutant-induced effects on lung cell Fe status can be assessed in a reproducible manner using an assay that can be readily performed by investigators who might otherwise have no access to other very costly analytical equipment, such as graphite atomic absorption or x-ray fluorescence spectro(photo)meters

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

The sentiment that woodsmoke, being a natural substance, must be benign to humans is still sometimes heard. It is now well established, however, that wood-burning stoves and fireplaces as well as wildland and agricultural fires emit significant quantities of known health-damaging pollutants, including several carcinogenic compounds. Two of the principal gaseous pollutants in woodsmoke, CO and NOx, add to the atmospheric levels of these regulated gases emitted by other combustion sources. Health impacts of exposures to these gases and some of the other woodsmoke constituents (e.g., benzene) are well characterized in thousands of publications. As these gases are indistinguishable no matter where they come from, there is no urgent need to examine their particular health implications in woodsmoke. With this as the backdrop, this review approaches the issue of why woodsmoke may be a special case requiring separate health evaluation through two questions. The first question we address is whether woodsmoke should be regulated and/or managed separately, even though some of its separate constituents are already regulated in many jurisdictions. The second question we address is whether woodsmoke particles pose different levels of risk than other ambient particles of similar size. To address these two key questions, we examine several topics: the chemical and physical nature of woodsmoke; the exposures and epidemiology of smoke from wildland fires and agricultural burning, and related controlled human laboratory exposures to biomass smoke; the epidemiology of outdoor and indoor woodsmoke exposures from residential woodburning in developed countries; and the toxicology of woodsmoke, based on animal exposures and laboratory tests. In addition, a short summary of the exposures and health effects of biomass smoke in developing countries is provided as an additional line of evidence. In the concluding section, we return to the two key issues above to summarize (1) what is currently known about the health effects of inhaled woodsmoke at exposure levels experienced in developed countries, and (2) whether there exists sufficient reason to believe that woodsmoke particles are sufficiently different to warrant separate treatment from other regulated particles. In addition, we provide recommendations for additional woodsmoke research

The in situ reactions of metal ions/complexes are important in understanding the mechanisms by which environmental and occupational metal particles alter lung immune responses. A better understanding of these reactions in situ will also allow for the improved specificity and controlled toxicity of novel metallocompounds to be used as inhaled diagnostics or therapeutics. Our previous work showed that inhalation of metals (e.g., chromium, vanadium, nickel) caused altered lung immune cell function and host resistance. The data also suggested that the degree of immunomodulation induced depended not only on the amount of metal deposited, but also the compound used. If specificity governs pulmonary immunomodulatory potential, it follows that physicochemical properties inherent to the metal have a role in the elicited effects. We hypothe-size that major determinants of any metal compound's potential are its redox behavior, valency (generally referred to as oxidation state and considered speciation in chemical literature), and/or solubility. In accord with the extensive work carried out with vanadium (chemical symbol V) compounds showing the importance of form used, differences in potential for a range of V agents (pentavalent [V(V)] insoluble vanadium pentoxide and soluble sodium metavanadate, tetravalent [V(IV)] vanadyl dipicolinate, and trivalent [V(III)] bis(dipicolinato)vanadium) were quantified based on induced changes in local bacterial resistance after host inhalation of each agent at 100 mu g V/m(3) (5 hr/d for 5 d). Differences in effect between V(V) forms indicated that solubility was a critical property in in situ pulmonary immunotoxicity. Among the soluble forms, oxidizing vanadate had the greatest impact on resistance; reducing V(III) altered resistance to a lesser extent. Both the V(IV) and insoluble V(V) had no effect. When data was analyzed in the context of pre-infection lung V burdens, soluble V agents with different oxidation states induced varying responses, supporting the hypothesis that differences in immunomodulatory potential might be attributed to redox behavior or valency. Our findings both provide a basis for understanding why some metals could be a greater health risk than others (when encountered in equal amounts) and will assist in the design of inhalable metallopharmaceuticals by allowing researchers to preempt selection of certain metal ions or complexes for use in such products

Changes in a host's environment (i.e. physical or chemical) can alter normal immune function. In aquatic organisms, exposure to stress can result in significant changes in innate immunity. In the natural environment, fish are exposed to multiple stressors simultaneously. Temperature change and/or chemical exposure as individual environmental stressors have been shown in various fish species to alter all aspects of the immune response. These same stressors have also been shown to alter plasma steroid levels in exposed fish. For this study, the effects of elevated temperature and nickel pollution on specific immune parameters of Japanese medaka (Oryzias latipes) were determined. Fish were exposed for 1, 7 or 14d to either: waterborne nickel (Ni) at the nominal concentration of 125ppb; a 5 degrees C (+/-0.5 degrees C) rapid increase in water temperature; or, both potential stressors in combination. Medaka maintained at room temperature (25 degrees C+/-1 degrees C) served as the controls. Altered function of the innate and adaptive arms of the immune response was evaluated by assessing kidney macrophage-mediated superoxide (O(2)(-)) production and splenic T-cell proliferation, respectively. Plasma cortisol levels were analysed in the same fish as a marker of the physiological stress response. While kidney cell number was unaffected by exposure of fish to either stressor alone or both factors in combination, spleen cellularity was decreased (compared to control fish) in medaka exposed for 1d to thermal stress in combination with Ni, and to a lesser extent to thermal stress alone. T-lymphocyte proliferation by medaka splenocytes was not affected by any exposure paradigm. Unstimulated intracellular O(2)(-) production by kidney phagocytes was significantly elevated (compared to control) in medaka exposed for 1d to either thermal stress alone or temperature change in combination with Ni; by 7d, only the stressor combination significantly increased baseline O(2)(-) production. Resting levels of extracellular O(2)(-) production was significantly reduced in fish maintained for 1d at the elevated temperature. Effects on phorbol 12-myristate 13 acetate (PMA)-stimulated intracellular and extracellular O(2)(-) production were less dramatic than those observed for resting phagocytes. Exposure of medaka to elevated temperature for 14d tended (p<0.06) to reduce PMA-stimulated intracellular O(2)(-) production (compared to the time-matched control). Although exposure of fish for 14d to elevated temperature only slightly reduced stimulated extracellular O(2)(-) production, exposure for the same duration to Ni alone significantly depressed oxyradical production by kidney phagocytes (compared to the time-matched controls). Decreased plasma cortisol levels were observed in fish exposed for 7d to either an elevated water temperature or Ni (compared to the time-matched control); by 14d of exposure, no significant treatment-induced effects on cortisol levels were observed. These findings add to the growing body of literature seeking to determine what effects, if any, exposure to multiple aquatic pollution-induced effects have upon fish health and the health of impacted ecosystems

Epidemiologic evidence indicates that maternal smoking increases the risk of preterm birth. While a number of plausible mechanisms for early delivery have been offered, the role of gestational hormones in this smoke-induced outcome is uncertain. Thus, a toxicologic study was performed to examine the effects and underlying hormonal mechanisms of mainstream cigarette smoke (MCS) exposure on gestational duration. Pregnant B6C3F1 mice were exposed by inhalation to MCS for 5 days/week (4 hrs/day) from Gestational Day (GD) 4 to parturition. Smoke-induced effects on gestational length, interpubic ligament length, maternal hormone secretion patterns (estradiol-17beta, progesterone, prolactin, and relaxin), body weight gain, postimplantation loss, litter size, and offspring sex ratio were examined. Dams exposed to MCS at a concentration equivalent to smoking less than one pack of cigarettes/day (carbon monoxide = 25 parts per million, total suspended particulates = 16 mg/m3) demonstrated a significant (P < 0.05) shortening of gestational duration (compared with pregnant, air-exposed mice). In addition, MCS-exposed mice sacrificed on GD 18 had significantly (P < 0.05) increased interpubic ligament length, elevated serum estrogen levels, and a reduced progesterone to estradiol-17beta ratio (compared with air-exposed controls); levels of progesterone and prolactin were only modestly decreased and increased, respectively, in the MCS-exposed mice. Smoke exposure had no significant effects on maternal relaxin levels, body weight gain, postimplantation loss, litter size, or sex ratio. Results of this study demonstrate that inhalation exposure of pregnant mice to a low dose of MCS shortens gestation and alters hormone secretory patterns, which are important for maintaining pregnancy and inducing parturition. These findings support the view that pregnant women who smoke (even modestly) may be at increased risk for preterm birth, and that early delivery may be related (at least partly) to MCS-induced