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Search indexed NASA NTRS and DOE OSTI research on propulsion, heat transfer, battery materials and energy systems. Follow report and document links to the original sources.

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At least 289 records · Page 16
All sourcesNASA NTRSDOE OSTI
DOE OSTI2025

Human in vitro metabolism of an environmental mixture of polycyclic aromatic hydrocarbons (PAH) found at the Portland Harbor Superfund Site

Polycyclic aromatic hydrocarbons (PAHs) are widespread environmental contaminants that pose health risks to humans. Toxicity testing approaches of PAHs have evolved from traditional rodent models to New Approach Methodologies (NAMs), such as high-throughput screening in zebrafish, enabling rapid evaluation of chemical hazards. However, translating toxicity findings from laboratory systems to humans remains difficult due to complexity and species-specific differences. Chemical dosimetry modeling offers a quantitative framework to bridge this gap, but its accuracy depends on robust knowledge of PAH metabolism. The objective of this study was to measure human metabolism rates of Supermix-10, the ten most abundant PAHs found at the Portland Harbor Superfund Site, to support development of human pharmacokinetic models. We incubated individual PAHs from Supermix-10 in pooled human liver microsomes and quantified parent PAH disappearance using high-performance liquid chromatography (HPLC) with UV and florescent detection. To assess the potential of mixture interactions, we also measured metabolism of all 10 compounds in an equimolar mixture and compared rates of parent disappearance to those observed for individual PAHs. All Supermix-10 PAHs demonstrated rapid parent compound disappearance in human hepatic microsomes. PAHs grouped into three metabolism patterns: high metabolism rates and capacity (2-methylnaphthalene, acenaphthylene, fluorene, naphthalene), high affinity metabolism that rapidly achieves low-level saturation (benzo[a]anthracene, chrysene), and moderate metabolism rates and capacity (fluoranthene, pyrene, retene, phenanthrene). Smaller PAHs exhibited faster metabolism, and higher metabolism rates correlated inversely with molecular weight. When incubated in an equimolar mixture, Supermix-10 demonstrated significantly slower metabolism (47–89 %) compared to metabolism of individual PAHs at the same concentration. These findings enhance our understanding of PAH metabolism in humans and demonstrate significant mixture interactions under the conditions tested. Furthermore, our findings offer insights into the metabolic behavior of Supermix-10 and provide critical metabolism rate data to support the development of physiological based pharmacokinetic (PBPK) models. Dosimetry models can translate PAH chemical dosimetry from high-throughput testing platforms, like zebrafish and cellular system assays, to human exposures enhancing the accuracy and reliability of PAH risk assessments.

2-methylnaphthalene↗
DOE OSTI2021

Fractalkine enhances endometrial receptivity and activates iron transport towards trophoblast cells in an in vitro co-culture system of HEC-1A and JEG-3 cells

Highlights: • Fractalkine activates SOX-17 and the NRF2-Keap-1 system in HEC-1A endometrium cells. • Fractalkine triggers IL-6 and IL-1β cytokine secretions contributing endometrium receptivity. • Fractalkine regulates iron homeostasis of endometrium. • Fractalkine contributes to the iron availability of the trophoblast cells. Endometrium receptivity and successful implantation require a complex network of regulatory factors whom production is strictly controlled especially at the implantation window. Many regulators like steroid hormones, prostaglandins, cytokines, extracellular matrix proteins and downstream cell signalling pathways are involved in the process of embryo-endometrium interaction. Our work reveals the effect of fractalkine (FKN), a unique chemokine on progesterone receptor, SOX-17 and NRF2 expressions in HEC-1A endometrial cell line. FKN activates fractalkine receptor signalling and the expression of SOX-17 through progesterone receptor in HEC-1A endometrial cells, and as a consequence it increases endometrial receptivity. Fractalkine also activates the NRF2-Keap-1 signal transduction pathway regulating the IL-6 and IL-1β cytokine productions, which increase endometrial receptivity, as well. The NRF2 transcription factor increases the expression of the iron exporter ferroportin in HEC-1A cells activating iron release towards JEG-3 trophoblast cells. The iron measurements show that iron content of endometrial cells decreases while heme concentration increases at FKN treatment. At the same time, the trophoblast cells show increased iron uptake and total iron content. Based on our results it seems that FKN enhances the establishment of endometrial receptivity and meanwhile it regulates the iron homeostasis of endometrium contributing to the iron availability of the trophoblast cells and the embryo.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2022

In Vitro and In Vivo Inhibition of the Mycobacterium tuberculosis Phosphopantetheinyl Transferase PptT by Amidinoureas

A newly validated target for tuberculosis treatment is phosphopantetheinyl transferase, an essential enzyme that plays a critical role in the biosynthesis of cellular lipids and virulence factors in Mycobacterium tuberculosis. The structure–activity relationships of a recently disclosed inhibitor, amidinourea (AU) 8918 (1), were explored, focusing on the biochemical potency, determination of whole-cell on-target activity for active compounds, and profiling of selective active congeners. These studies show that the AU moiety in AU 8918 is largely optimized and that potency enhancements are obtained in analogues containing a para-substituted aromatic ring. Preliminary data reveal that while some analogues, including 1, have demonstrated cardiotoxicity (e.g., changes in cardiomyocyte beat rate, amplitude, and peak width) and inhibit Ca v 1.2 and Na v 1.5 ion channels (although not hERG channels), inhibition of the ion channels is largely diminished for some of the para-substituted analogues, such as 5k (p-benzamide) and 5n (p-phenylsulfonamide).

60 APPLIED LIFE SCIENCES↗