Biology subjects

Pennell, K. D.

Publications and source records attributed to Pennell, K. D..

4 recordsLinked to original sources

bioRxiv2026

Dose-additive and dose-dependent fetal testis toxicity of a nine-phthalate mixture in the rat

Phthalates (ortho-phthalic acid diesters) are used in a variety of manufacturing processes, particularly as non-covalent plasticizers in flexible polyvinyl chloride. Phthalates are male reproductive toxicants that disrupt the development of the fetal testis, resulting in malformed seminiferous cords, multinucleated germ cells (MNGs), and decreased testosterone production. We previously reported that MNGs were a sensitive, dose-dependent marker of dipentyl phthalate (DPEP) germ cell toxicity. To test whether germ cell effects of phthalates are dose-additive, we measured the induction of MNGs by a phthalate mixture. We treated timed pregnant Sprague Dawley rats with an equipotent mixture of nine phthalates, spanning a two-log dose range, from GD 17-21. We found that the phthalate mixture effects on morphogenesis of the testis, assessed through histological analysis of MNGs and seminiferous cord diameter were dose-additive. Consistent with prior results, we also found that the testosterone-reducing effect of the phthalate mixture was dose-additive and dose-dependent. Induction of MNGs had the lowest effective dose of any endpoint that we measured, with a benchmark dose (BMD10) of 9.402 (6.093, 13.13) mg ({sum} all phthalates)/kg/d, which is equivalent to a BMD10 of 3.517 (2.275, 4.919) mg DPEP/kg/d, based on relative potency factors. Quantitative analysis of phthalate metabolites in dam serum showed that the metabolites were present in approximately the same relative concentrations as the parent compounds in the dosing mixture, but with lower levels of monocyclohexyl phthalate and monobenzyl phthalate. Proteomic and spatial transcriptomic analyses showed significant decreases in expression of Leydig cell genes and proteins involved in steroid hormone biosynthesis, as well as enrichment of proteins related to metabolism of lipids and amino acids. Proteomic BMD analysis produced a lowest BMDmedian of 2.156 (0.204, 27.830) mg ({sum} all phthalates)/kg/d, which was within a 4.36-fold margin of the lowest apical endpoint BMD.

pharmacology and toxicology↗

bioRxiv2024

Modulation of blood-tumor barrier transcriptional programs improves intra-tumoral drug delivery and potentiates chemotherapy in GBM

Glioblastoma (GBM) is the most common malignant primary brain tumor. GBM has an extremely poor prognosis and new treatments are badly needed. Efficient drug delivery to GBM is a major obstacle as the blood-brain barrier (BBB) prevents passage of the majority of cancer drugs into the brain. It is also recognized that the blood-brain tumor barrier (BTB) in the growing tumor represents a challenge. The BTB is heterogeneous and poorly characterized, but similar to the BBB it can prevent therapeutics from reaching effective intra-tumoral doses, dramatically hindering their potential. Here, we identified a 12-gene signature associated with the BTB, with functions related to vasculature development, morphogenesis and cell migration. We identified CDH5 as a core molecule in this set and confirmed its over-expression in GBM vasculature using spatial transcriptomics of GBM patient specimens. We found that the indirubin-derivative, 6-bromoindirubin acetoxime (BIA), could downregulate CDH5 and other BTB signature genes, causing endothelial barrier disruption in endothelial monolayers and BBB 3D spheroids in vitro. Treatment of tumor-bearing mice with BIA enabled increased intra-tumoral accumulation of the BBB non-penetrant chemotherapeutic drug cisplatin and potentiated cisplatin-mediated DNA damage by targeting DNA repair pathways. Finally, using an injectable BIA nanoparticle formulation, PPRX-1701, we significantly improved the efficacy of cisplatin in patient-derived GBM xenografts and prolonged their survival. Overall, our work reveals potential targets at the BTB for improved chemotherapy delivery and the bifunctional properties of BIA as a BTB modulator and potentiator of chemotherapy, supporting its further development.

cancer biology↗

bioRxiv2022

High-resolution mass spectrometry reveals environmentally relevant uptake, elimination, and metabolic alterations following early embryonic exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin in zebrafish

Dioxin and dioxin-like compounds are ubiquitous environmental contaminants that induce toxicity by binding to the aryl hydrocarbon receptor (AHR), a ligand activated transcription factor. The zebrafish model has been used to define the developmental toxicity observed following exposure to exogenous AHR ligands such as the potent agonist 2,3,7,8-tetrachlorodibenzo-p-dioxin (dioxin, TCDD). While the model has successfully identified cellular targets of TCDD and molecular mechanisms mediating TCDD-induced phenotypes, fundamental information such as the body burden produced by standard exposure paradigms is still unknown. We performed targeted gas chromatography (GC) high-resolution mass spectrometry (HRMS) in tandem with non-targeted liquid chromatography (LC) HRMS to quantify TCDD uptake, model the elimination dynamics of TCDD, and determine how TCDD exposure affects the zebrafish metabolome. We found that 10 ppb, 1 ppb, and 50 ppt waterborne exposures during early embryogenesis produced environmentally relevant body burden of TCDD: 38 {+/-} 4.34, 26.6 {+/-} 1.2, and 8.53 {+/-} 0.341 pg/embryo, respectively, at 24 hours post fertilization. In addition, we discovered that TCDD exposure was associated with the dysregulation of several metabolic pathways that are critical for brain development and function including glutamate metabolism, chondroitin sulfate biosynthesis, and tyrosine metabolism pathways. Together, these data demonstrate that existing exposure paradigms produce environmentally relevant body burdens of TCDD in zebrafish and provide insight into the biochemical pathways impacted by toxicant-induced AHR activation. HIGHLIGHTSO_LIHistorical TCDD exposure paradigms produce environmentally relevant body burdens in zebrafish embryos. C_LIO_LITCDD elimination for high doses can be modeled using an exponential regression. C_LIO_LIExposure to TCDD alters metabolic pathways that are essential for brain development and function. C_LI GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=81 SRC="FIGDIR/small/490602v2_ufig1.gif" ALT="Figure 1"> View larger version (31K): org.highwire.dtl.DTLVardef@17ba806org.highwire.dtl.DTLVardef@1543d58org.highwire.dtl.DTLVardef@1878204org.highwire.dtl.DTLVardef@168f21d_HPS_FORMAT_FIGEXP M_FIG C_FIG

pharmacology and toxicology↗

bioRxiv2021

Cross-species metabolomic analysis of DDT and Alzheimer's disease-associated tau toxicity

BackgroundThe formation of hyperphosphorylated tau (p-tau) protein tangles in neurons is a pathological marker of Alzheimers disease (AD). Exposure to the pesticide dichlorodiphenyltrichloroethane (DDT) has been associated with increased risk of AD. ObjectivesTo determine if there was a connection between DDT exposure and tau toxicity we investigated whether exposure to DDT can exacerbate tau protein toxicity in C. elegans. In addition, we examined the association between p-tau protein and metabolism in a human population study and in a transgenic C. elegans strain neuronally expressing a mutant tau protein fragment that is prone to aggregation. MethodsIn the human population study, we used a metabolome-wide association framework to determine the association between p-tau measured in the cerebrospinal fluid (CSF) and metabolomic features measured in both plasma (n = 142) and CSF (n = 78) using high-resolution metabolomics (HRM). Using the same HRM method, we determined changes in metabolomic features in the transgenic C. elegans strain compared to its control strain. Metabolites associated with p-tau in both species were analyzed for overlap. We also examined the effect of DDT and aggregating tau protein on growth, swim behavior, mitochondrial function, metabolism, learning, and lifespan in C. elegans. ResultsPlasma and CSF-derived features associated with p-tau level were related to drug, amino acid, fatty acid and mitochondrial metabolism pathways. Five metabolites overlapped between plasma and C. elegans, and 4 between CSF and C. elegans. DDT exacerbated the inhibitory effect of aggregating tau protein on growth and basal respiration. In the presence of aggregating tau protein, DDT induced more curling and was associated with reduced levels of amino acids but increased levels of uric acid and adenosylselenohomocysteine. Developmental exposure to DDT blunted the lifespan reduction caused by aggregating tau protein. ConclusionThe model organism C. elegans can complement human studies by providing a means to study mechanisms of environmental toxicants. Specifically, our C. elegans data show that DDT exposure and tau protein aggregation both inhibit mitochondrial function and DDT exposure can exacerbate the mitochondrial inhibitory effects of tau protein aggregation providing a plausible explanation for the observed human associations.

pharmacology and toxicology↗