Kristie Willett’s Research Interests

Throughout my career I have lead research projects which were designed to fundamentally understand the molecular mechanisms underlying toxicity and/or shed light on the potential adverse outcomes due to relevant anthropogenic contamination. I am particularly dedicated to training and mentoring students and have advised or am currently advising the research of 2 postdoctoral fellows, 9 PhD, 8 MS, and 28 undergraduate students.

The entire list of our publications can be found at: NCBI Bibliography

Five focus areas of research conducted in my laboratory are highlighted below

Mechanisms of PAH/BaP toxicity

While the mutagenic and carcinogenic properties of PAHs have been recognized for decades, my lab has been interested in the developmental and reproductive consequences of PAH exposure. There is a new appreciation that environmental factors that act during key developmental stages can increase the risk of developing adult disease, and that this disease susceptibility can be passed on multi- or transgenerationally. Fish are a well suited, but underutilized, model organism for testing the multigenerational and epigenetic consequences of environmental contaminant exposure. We have used NIEHS R03, R21 and R01 grants to show that benzo[a]pyrene, disrupts aromatase activity, circulating hormone concentrations, and causes developmental defects in both F1 and F2 offspring following an only F0 exposure. Ongoing studies are aimed at discovering the molecular initiating and key events in benzo[a]pyrene’s persistent adverse outcomes following early life exposures.

Quantitation of environmental impacts of regional natural and anthropogenic disasters

As the only environmental toxicology graduate program in Mississippi, we take seriously our role to help provide the best science in the wake of disasters like Hurricane Katrina and the Deep Water Horizon Oil Spill. Accordingly we have routine monitoring locations along the MS-AL coasts wherein we have done chemical and bioassay assessments for PAH, inorganic and endocrine disrupting contaminants. Recently an undergraduate honors student working together with the chemistry department measured and calculated ingestion risks associated with mercury contaminated local fish intake. Now, in collaboration with UM colleagues at the Law School and The Center of Population Studies we are assessing lead in drinking water in Mississippi Delta communities with the help of high school students in the Tri-County Workforce Alliance. This environmental/public health research has been supported by NOAA, USGS/WRRI and the Gulf of Mexico Research Initiative. Former students involved in these projects are now working for example with the Tennessee and Mississippi Departments of Environmental Quality, further shaping our regional environmental policies.

Drug-resistant epilepsy: Efficacy vs toxicity of cannabidiol and Δ9-tetrahydrocannabinol

The goal of this research is to compare the relative morphological, behavioral, reproductive and multigenerational phenotypes that result after developmental exposures to cannabidiol (CBD), cannabidiol oil (CBO) and Δ9-tetrahydrocannabinol (THC). Due to relaxed prohibitions on marijuana use and therapeutic potential of cannabis constituents in the treatment of early-onset pharmaco-resistant epilepsy, exposure of children to these chemicals is increasing. While CBD and CBO show efficacy in reducing seizure frequency, little is known about the potential adverse side-effects of cannabinoids on child physiology, brain development, adult disease, and/or F1 offspring. In this study we are leveraging the advantages of the zebrafish model to comprehensively assess phenotypic alterations caused by developmental exposures and mechanistically link the adverse outcomes with transcriptomic analyses. We plan to differentiate the unique dose-, tissue-, sex- and developmental stage-dependent effects of CBD, CBO and THC. Additionally, there is a critical need for new, non-scheduled drugs for treatment of pediatric epilepsy. We are leveraging our experience with the zebrafish model and extensive natural product and chemical libraries available in our school to develop a high-throughput screen for epilepsy drug discovery. Anti-seizure lead compounds identified in our screens are then further tested for zebrafish developmental toxicity and submitted for additional validation to the in vitro and in vivo cores of our NIH-Center for Biomedical Research Excellence.

Using zebrafish breast cancer xenotransplantation models for natural product drug discovery

There is a need to develop in vivo systems for high throughput screening of anti-cancer compounds because the traditional model (mouse) is slow to develop tumors after xenotransplantation, less amenable for high throughput screening, and expensive to maintain. Zebrafish offer unique advantages as an animal model because they develop rapidly and can be xenotransplanted with human cancer cells and exhibit similar gene expression as humans. Using transparent transgenic zebrafish embryos with fluorescent vasculature, the metastases of the labelled tumor cells can be tracked and the effects of anti-cancer compounds on the tumor cells can be observed. Leads with the highest efficacy and safety are then targeted for additional evaluation of mechanisms of action.

Relative toxicity of nanosilver vs. bulk silver (AgNO3)

As the number of commercial products containing nanosilver explodes because of its antibacterial properties, it is unclear on the regulatory front whether the nanoformulations are uniquely toxic relative to the known aquatic toxicity of bulk silver. With funding from the US Army Corps of Engineers we investigated the potential for differential gill histopathology, mucus production, absorption and gene expression in fathead minnows in order to establish whether different mechanisms of toxicity were at play. Importantly, our mucus measurements established that while mucus secretion was initially protective, with continued exposure the fish lost the ability to secrete mucus, which was consistent with mucus cell degeneration. Also, with collaborators at US Army Engineer Research and Development Center in Vicksburg, MS we used field flow fractionation ICPMS to show, for the first time, silver nanoparticle uptake/persistence in the gastrointestinal tract of the fish. Ultimately, while mechanisms of toxicity may be different at the gene level, regulatory guidelines based on total silver concentrations will be protective against nanosilver toxicity based on our acute exposure results.

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Kristine L. Willett
Department of BioMolecular Sciences
UM School of Pharmacy
The University of Mississippi