Faculty Bibliography

Pyridoxine is a co-factor in many enzymatic reactions and impacts of deficiency have been observed in affected populations. A possible modifying effect of pyridoxine deficiency on benzene toxicity was assessed in male B₆C₃F₁ mice fed either a pyridoxine-deficient diet or a control diet. This treatment was combined with benzene inhalation exposure (100 ppm) or no benzene treatment. Pyridoxine-deficient mice exposed to 100 ppm benzene had significantly lower body, thymus and spleen weights. While total white blood cell counts, percentage of lymphocytes, hematocrit and hemoglobin levels were lower, the percentage of neutrophils was significantly higher in deficient and benzene-exposed mice compared to non-exposed controls. Hepatic CYP2E1 protein expression and activity in the deficient and exposed mice were also significantly higher compared to the non-exposed controls. A significant correlation between CYP2E1 activity and several hematological parameters was observed. These results demonstrated that pyridoxine deficiency significantly impacted benzene-induced hematotoxicity. Moreover, the observed agonistic effect of pyridoxinedeficiency and benzene inhalation exposure on CYP2E1 would seem to indicate an involvement of metabolism, but this needs to be further assessed.

Isoflurane (ISO) is a widely used inhalation anesthetic in experiments with rodents and humans during surgery. Though ISO has not been reported to impart long-lasting side effects, it is unknown if ISO can influence gene regulation in certain tissues, including the heart. Such changes could have important implications for use of this anesthetic in patients susceptible to heart failure/other cardiac abnormalities. To test if ISO could alter gene regulation/expression in heart tissues, and if such changes were reversible, prolonged, or late onset with time, SHR (spontaneously hypertensive) rats were exposed by intratracheal inhalation to a 97.5% air/2.5% ISO mixture on two consecutive days (2 hr/d). Control rats breathed filtered air only. On Days 1, 30, 240, and 360 post-exposure, rat hearts were collected and total RNA was extracted from the left ventricle for global gene expression analysis. The data revealed differentially-expressed genes (DEG) in response to ISO (compared to naïve control) at all post-exposure timepoints. The data showed acute ISO exposures led to DEG associated with wounding, local immune function, inflammation, and circadian rhythm regulation at Days 1 and 30; these effects dissipated by Day 240. There were other significantly-increased DEG induced by ISO at Day 360; these included changes in expression of genes associated with cell signaling, differentiation, and migration, extracellular matrix organization, cell-substrate adhesion, heart development, and blood pressure regulation. Examination of consistent DEG at Days 240 and 360 indicated late onset DEG reflecting potential long-lasting effects from ISO; these included DEG associated with oxidative phosphorylation, ribosome, angiogenesis, mitochondrial translation elongation, and focal adhesion. Together, the data show acute repeated ISO exposures could impart variable effects on gene expression/regulation in the heart. While some alterations self-resolved, others appeared to be long-lasting or late onset. Whether such changes occur in all rat models or in humans remains to be investigated.

Electronic-cigarette (e-cig) vaping is a serious concern, as many pregnant women who vape consider it safe. However, little is known about the harmful effects of prenatal e-cig exposure on adult offspring, especially on extracellular-matrix (ECM) deposition and myogenesis in the lungs of offspring. We evaluated the biochemical and molecular implications of maternal exposure during pregnancy to e-cig aerosols on the adult offspring of both sexes, with a particular focus on pulmonary ECM remodeling and myogenesis. Pregnant CD-1 mice were exposed to e-cig aerosols with or without nicotine, throughout gestation, and lungs were collected from adult male and female offspring. Compared with the air-exposed control group, female mice exposed to e-cig aerosols, with or without nicotine, demonstrated increased lung protein abundance of LEF-1 (lymphoid enhancer-binding factor 1), fibronectin, and E-cadherin, whereas altered E-cadherin and PPARγ (peroxisome proliferator-activated receptor γ) levels were observed only in males exposed to e-cig aerosols with nicotine. Moreover, lipogenic and myogenic mRNAs were dysregulated in adult offspring in a sex-dependent manner. PAI-1 (plasminogen activator inhibitor-1), one of the ECM regulators, was significantly increased in females exposed prenatally to e-cig aerosols with nicotine and in males exposed to e-cig aerosols compared with control animals exposed to air. MMP9 (matrix metalloproteinase 9), a downstream target of PAI-1, was downregulated in both sexes exposed to e-cig aerosols with nicotine. No differences in lung histology were observed among any of the treatment groups. Overall, adult mice exposed prenatally to e-cig aerosols could be predisposed to developing pulmonary disease later in life. Thus, these findings suggest that vaping during pregnancy is unsafe and increases the propensity for later-life interstitial lung diseases.

This study aimed to evaluate self-reported exposure to the Ringwood Mines/Landfill Superfund Site in relation to chronic health outcomes among members of the Ramapough Lunaape Turtle Clan nation and other local residents of Ringwood, New Jersey. Community surveys on personal exposure to the nearby Superfund site, self-reported health conditions, and demographics were conducted with 187 members of the Ramapough Lunaape Turtle Clan Nation and non-Native Americans residing in Ringwood, New Jersey from December 2015 to October 2016. Multiple logistic regression was performed to assess the association between ethnicity and a Superfund site exposure score developed for this study, as well as between exposure score and several chronic health conditions. Native Americans were 13.84 times (OR 13.84; 95% CI 4.32, 44.37) more likely to face exposure opportunities to Superfund sites as compared to non-Native Americans in the same New Jersey borough. For the entire surveyed cohort, increased Superfund site exposure routes was significantly associated with bronchitis (OR 4.10; 95% CI 1.18, 14.23). When the analyses were restricted to Native Americans, the association between self-reported Superfund site exposure and bronchitis remained significant (OR 17.42; 95% CI 1.99, 152.45). Moreover, the association between greater exposure score and asthma in this same population also reached statistical significance (OR 6.16; 95% CI 1.38, 27.49). This pilot study demonstrated a significant association between being a Ringwood resident of Native American ethnicity and self-declared opportunities for Superfund site exposure. It also showed a strong association between self-reported Superfund site exposure and the prevalence of bronchitis and asthma.

Maternal exposures during pregnancy affect the onset and progression of adult diseases in the offspring. A prior mouse study indicated that maternal tobacco smoke exposure affects hepatic fibrosis in adult offspring. Gutkha, a broadly used smokeless tobacco (ST) product, is widely used by pregnant woman in many countries. The objective of this murine study was to evaluate whether oral maternal exposure to gutkha during pregnancy alters non-alcoholic fatty liver disease (NAFLD) in adult offspring: risk factors for the progression of NAFLD to cirrhosis in adults remain elusive. Buccal cavity 'painting' of pregnant mice with gutkha began on gestational days (GD) 2-4 and continued until parturition. Beginning at 12 weeks of age, a subset of offspring were transitioned to a high-fat diet (HFD). Results demonstrated that prenatal exposure to gutkha followed by an HFD in adulthood significantly increased the histologic evidence of fatty liver disease only in adult male offspring. Changes in hepatic fibrosis-related cytokines (interleukin (IL)-1b and IL-6) and in hepatic collagen mRNA expression were observed when comparing adult male offspring exposed to gutkha in utero to those not exposed. These findings indicate that maternal use of gutkha during pregnancy affects NAFLD in adult offspring in a sex-dependent manner.

Wood is a type of biomass commonly burnt as a means of energy. When burnt, it releases harmful components linked to adverse health outcomes. In the scientific community toxicologists and epidemiologists continue to consider the individual components of woodsmoke "” such as particulate matter and polycyclic aromatic hydrocarbons "” as a way to better understand the relationship between inhaled woodsmoke and acute and chronic disease. In recent years, research focus has shifted toward the underlying mechanisms that could be associated with long-term health consequences. Alongside this research, novel studies in molecular toxicology that examine the impacts of woodsmoke could provide a link between woodsmoke and telomere length. Such studies could provide scientists with a better understanding on how woodsmoke leads to chronic diseases. As researchers from various disciplines come together to work on this complex and widespread issue, hope emerges to reduce the morbidity and mortality associated with this global air pollutant.

BACKGROUND:Economic and social marginalization among American Indians and Alaska Natives (AI/ANs) results in higher chronic disease prevalence. Potential causal associations between toxic environmental exposures and adverse health outcomes within AI/AN communities are not well understood. OBJECTIVES/OBJECTIVE:This review examines epidemiological literature on exposure to toxicants and associated adverse health outcomes among AI/AN populations. METHODS:PubMed, Embase, Cochrane, Environment Complete, Web of Science Plus, DART, and ToxLine were searched for English-language articles. The following data were extracted: lead author's last name, publication year, cohort name, study location, AI/AN tribe, study initiation and conclusion, sample size, primary characteristic, environmental exposure, health outcomes, risk estimates, and covariates. RESULTS:About 31 articles on three types of environmental exposures met inclusion criteria: persistent organic pollutants (POPs), heavy metals, and open dumpsites. Of these, 17 addressed exposure to POPs, 10 heavy metal exposure, 2 exposure to both POPs and heavy metals, and 2 exposure to open dumpsites. Studies on the Mohawk Nation at Akwesasne; Yupik on St. Lawrence Island, Alaska; Navajo Nation; Gila River Indian Community; Cheyenne River Sioux; 197 Alaska Native villages; and 13 tribes in Arizona, Oklahoma, North Dakota, and South Dakota that participated in the Strong Heart Study support associations between toxicant exposure and various chronic conditions including cardiovascular conditions, reproductive abnormalities, cancer, autoimmune disorders, neurological deficits, and diabetes. DISCUSSION/CONCLUSIONS:The complex interplay of environmental and social factors in disease etiology among AI/ANs is a product of externally imposed environmental exposures, systemic discrimination, and modifiable risk behaviors. The connection between environmental health disparities and adverse health outcomes indicates a need for further study.

BACKGROUND:In an effort to decrease the rates of smoking conventional tobacco cigarettes, electronic cigarettes (e-cigarettes) have been proposed as an effective smoking cessation tool. However, little is known about their toxicological impacts. This is concerning given that e-cigarette use is perceived as less harmful than conventional tobacco cigarettes during pregnancy for both the mother and fetus. OBJECTIVE:The goal of this study was to test the neurodevelopmental consequences of maternal e-cigarette use on adult offspring behavior and neuroimmune outcomes. METHODS: RESULTS: DISCUSSION/CONCLUSIONS:These findings support previous adverse findings of e-cigarette exposure on neurodevelopment in a mouse model and provide substantial evidence of persistent adverse behavioral and neuroimmunological consequences to adult offspring following maternal e-cigarette exposure during pregnancy. https://doi.org/10.1289/EHP6067.