2021 Pilot Project Awards
New Direction Pilot Project Award:
Principal Investigator: David Hein, Ph.D.
Collaborator: Raul Salazar-Gonzalez, Ph.D.
Title: "Gene-environmental interactions of novel psychoactive chemicals substituting for illegal drugs of abuse"
Description of Project: New psychoactive substances (NPS) include many different chemicals commonly sold as legal substitutes for classical drugs of abuse. NPS were mostly central stimulants in the phenylethylamine group but more recently the number of NPS is expanding. Public health institutions are closely investigating the epidemiology and toxicovigilance of NPS. The number of NPS has dramatically increased during the last few years. The information about the basic pharmacology of hallucinogenic phenylethylamines from the 2C series is scarce. Published binding studies show an affinity for G-protein–coupled 5-HT and adrenergic receptors, in which the 2C compounds may act either as agonists or antagonists. Toxicological effects including changes in mitochondrial membrane potential, decreased ATP and increased ROS production, increased levels of DNA damage and activation of apoptosis have been reported in preliminary studies.
Arylamine N-acetyltransferase (NATs) are cytosolic enzymes, expressed as the two isoenzymes NAT1 and NAT2. NAT2 is a highly polymorphic gene, depending on the combination of NAT2 alleles, individuals can be categorized into rapid, intermediate or slow acetylators, and this NAT2 phenotype has been shown to have an influence on metabolism, and thus the efficacy and toxicity, of certain drugs. Interestingly, recent reports have demonstrated that NPS compounds, specifically 2C derivatives are N-acetylated by NAT2, but the influence of genetic polymorphism was not considered. In this pilot study we will: 1) evaluate the differences in metabolism of NPS between rapid, intermediate and slow acetylation phenotypes; and 2) investigate the effect of such differences using a comprehensive toxicology evaluation that includes DNA damage markers, apoptosis evaluation, ATP and mitochondrial function as well as oxidative stress markers, in order to assess the toxic effects by the N-acetylation of these compounds in the presence of different NAT2 genotypes. The aims of the pilot proposal are to evaluate 1), Is the N-acetylation of NPS NAT2-genotype-dependent? and 2) Are the toxic effects of the NPS modified by NAT2 genotypes? The evaluation of such gene-environment interaction is of high importance to public health and also have important implications to understand the toxic effects of these drugs of abuse.
New Direction Pilot Project Award:
Principal Investigator: Rachel Neal, Ph.D.
Co-Investigator: Cynthia Corbitt, Ph.D.
Title: "Hepatic metabolic response to the fasting/refeeding transition in offspring exposed in utero to vaping"
Description of Project: This project will examine the impact of maternal vaping on key offspring liver nutrient utilization pathways in conjunction with weight gain, using two murine model systems. Outcomes of this study are critically important and necessary to characterize the potential impacts of maternal vaping on the fetal environment and infant health.
Interdisciplinary Pilot Project Award:
Principal Investigator: Xiao-An Fu, Ph.D.
Co-Investigator: Qunwei Zhang, Ph.D.
Title: "Analysis of harmful compounds in aerosols of electronic cigarettes to evaluate toxicity"
Description of Project: The dramatic increase of toxic chemicals, including formaldehyde, and acetaldehyde in aerosols of the newer generations of electronic cigarettes or e-cigarettes has raised significant public concern over the safety in using e-cigarettes. There were 4.47 million high-school and middle-school students used e-cigarettes in 2020 as reported in the National Youth Tobacco Survey. Currently, the constituents in aerosols of e-cigarettes are not comprehensively measured and the toxic effect of the mixtures of toxicants in aerosols are not well studied. Therefore, there is an urgent need to develop analytic approaches for comprehensive measurements of toxic chemicals in aerosols of e-cigarettes and to evaluate e-cigarette toxicity.
This pilot project will develop a comprehensive approach for measurements of harmful chemicals in flavoring electronic liquids and e-cigarette aerosols and determine exacerbating toxicity of these chemicals through examining human lung cell cytotoxicity. Flavoring chemicals and thermal degradation of these flavoring chemicals and propylene glycol and vegetable glycerol form a mixture of toxicants in aerosols that will exacerbate toxic effect. This project will analyze all harmful organic compounds in aerosols of laboratory formulated e-liquids to understand the sources of toxic compounds. Constituents in five most popular flavoring electronic liquids and e-cigarettes used by teenagers and in aerosols of the e-cigarettes will then be analyzed to identify all toxicants. The toxic effects of e-cigarettes on human lung cells in vitro will be examined. The data obtained from this project will be informed to public by publications and to FDA for regulation of e-cigarettes.
Interdisciplinary Pilot Project Award:
Principal Investigator: Jun Cai, M.D., Ph.D.
Co-Investigator: Lu Cai, M.D., Ph.D., Gregory Barnes, M.D., Ph.D.
Title: "Disruption of β-catenin destruction complex and ASD-like behaviors in whole-life cadmium exposure and postnatal obesity"
Description of Project: Autism spectrum disorder (ASD) is a neurodevelopmental disease affecting young children and adults, which is characterized by communication, sensory and social deficits as well as repetitive behaviors. Both genetic vulnerability and environmental factors contribute to the etiology of ASD. However, it is rarely known how environmental factors trigger gene modifications for the development of ASD. The accumulating evidence indicates an association of either exposure to toxic metals including cadmium (Cd) or obesity with ASD or other neurodevelopmental disorders (NDD) in humans. Our preliminary study showed that high-fat diet (HFD) significantly increases the Cd accumulation in kidney, liver, heart and brain of the mice with a 24-week postweaning HFD feeding and whole-life exposure to low-dose Cd compared to those with Cd exposure only. The Wnt/β-catenin/GSK3β pathway, the vital hub in the onset/development of ASD/NDD, is disrupt in the cortexes of those offspring mouse brains. Cd exposure enhances the phosphorylation of serine 9 in GSK3β and HFD promotes transcriptional expression of GSK3β, probably altering the cellular accumulation of β-catenin. In this pilot project, we will test the hypothesis that whole-life low-dose Cd exposure disrupts the β-catenin destruction complex and develops the ASD-like behaviors in mice, which would be exacerbated by postweaning HFD. To test this hypothesis, we will collaborate with Drs. Lu Cai and Gregory N. Barnes (members of the CIEHS), who have an extensive expertise in the fields of cadmium toxicity, obesity, genetics, and autism. We propose 1) to examine the levels of Cd and essential metals (zinc, iron, copper, etc.) as well as neuropathological changes in different brain regions (cortex, hippocampus, and cerebellum) that are involved in ASD; 2) to identify the key factors involving in disrupting the β-catenin destruction complex and their cellular colocalization; 3) to assess the ASD-like behaviors in the offspring. We collaborated with Dr. Lu Cai and collected the offspring brain tissues at 10 and 24 weeks post-weaning for Aim 1 and Aim 2. A new batch of mice will be set up to test their ASD-like behaviors at 10 weeks post-weaning for Aim 3. Upon successful completion of these pilot studies, we will define the gene-environment interactions among cadmium toxicity, diet and ASD/NDD pathogenesis. These results will identify putative molecular target(s) for developing new interventions to treat ASD/NDD. The data achieved from this pilot project will provide strong supporting evidence for our hypothesis to apply for extramural funding.
Community-Engaged Pilot Project Award:
Principal Investigators: Rachel Neal, Ph.D. and Luz Huntington Moskos, Ph.D., R.N, C.P.N.
Title: "Citizen Science Approach to Studying the Community Impact of Hemp Processing Facilities in Cadiz KY"
Description of Project: The CIEHS community-engaged pilot project titled, “Citizen Science Approach to Studying the Community Impact of Hemp Processing Facilities in Cadiz KY” will involve a citizen scientist model of environmental monitoring. The aims of this work are to support community odor reporting, to disseminate information on the health impacts of PM 2.5 and PM 10, VOCs and, finally, to train community members in environmental sampling. The study of the environmental impact of hemp cultivation and processing is in its infancy. Nationwide, hemp processing plants represent a significant community environmental challenge due to the overwhelming odor profile that has led to citizen complaints to local and regional air quality boards. In Kentucky, there are multiple drying and cannabinoid extraction plants using a variety of industrial processes resulting in odors, reduced adjacent highway visibility, and lack of air pollution release permitting prior to operation. This community-engaged work will provide community members with their own data and strive to increase their environmental health literacy related to outdoor air quality.