# Airborne PCBs: Sources, Exposures, Toxicities, Remediation: K.C. Donnelly Externship - Promotion of Translational/Transdisciplinary Efforts in Graduate and Post-Doctoral Research

> **NIH NIH P42** · UNIVERSITY OF IOWA · 2022 · $15,450

## Abstract

PROJECT DESCRIPTION
Due to inadvertent production and exposure to polychlorinated biphenyls (PCBs) from environmental sources,
adverse health effects remain a critical public health issue long after the ban of commercial production.
Through the proposed research, our goal is to gain knowledge related to P450-mediated metabolism through
the KC Donnelly externship in partnership with the National Center for Toxicology Research (NCTR).
Xenobiotic processing genes (XPGs), such as cytochrome P450s, are known to be expressed and active in the
brain [1-8]. This can then lead to the metabolism of central nervous system (CNS)-active chemicals, leading to
alterations in toxicokinetics and toxicodynamics of target cells through systemic circulation [9, 10]. Currently, I
am working on examining metabolism of PCBs in rat primary astrocytes. However, it is still uncertain where
metabolism of PCBs begins. Specifically, following ISRP Project 1, Aim 2, I will be examining region-specific
biotransformation of PCBs and PCB metabolites in the adolescent rat brain in vitro (primary cells in culture) to
characterize the following local metabolic conversions: oxidation of parent PCBs to OH-PCBs; conjugation of
OH- and diOH-PCBs; deconjugation of OH-PCB sulfates (and glucuronides); and oxidation of diOH-PCBs to
reactive quinones and subsequently, glutathione adducts (reviewed in [11-13]). To expand upon this work, the
precise human metabolism of lower chlorinated PCBs is still uncertain and needs to be explored.Therefore, my
overall objective is to examine the P450 isoform-specific metabolism of lower-chlorinated PCBs in state-of-the-
art P450-overexpressing human hepatocytes developed by Dr. Lei Guo's laboratory at the National Center for
Toxicology Research (NCTR) [14]. This model will be used to test the hypothesis that lower-chlorinated PCBs
discovered by the ISRP in indoor and outdoor air, such as 2,2'5,5'-tetrachlorobiphenyl (PCB52) and 3,3’-
dichlorobiphenyl (PCB11), are oxidized with different stereoselectivity by several human P450 isoforms, such
as CYP2A6, CYP2B6, and CYP3A4 I will test this hypothesis by (1) determining which human P450 isoform is
involved in the metabolism of PCB11 and PCB52 and (2) characterizing the PCB metabolites formed by
different P450 isoforms using nontarget-high resolution mass spectrometry (Nt-HRMS). These results will
inform future translational studies that assess the role of these P450 isoforms in the brain specific metabolism
in human-relevant cell culture models. After treating the P450-overexpressing hepatocytes, both cell pellets
and supernatant fractions will be collected to assess levels of metabolites present. Supernatant and cells will
be flash frozen. These samples would then be transported back to the University of Iowa, where subsequent
quantification of key metabolites would be accomplished with standards provided by the ISRP Synthesis Core
[15-19]. The proposed studies will investigate the P450 specific metabolism ...

## Key facts

- **NIH application ID:** 10579012
- **Project number:** 3P42ES013661-17S1
- **Recipient organization:** UNIVERSITY OF IOWA
- **Principal Investigator:** Keri C Hornbuckle
- **Activity code:** P42 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $15,450
- **Award type:** 3
- **Project period:** 2022-08-15 → 2025-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10579012

## Citation

> US National Institutes of Health, RePORTER application 10579012, Airborne PCBs: Sources, Exposures, Toxicities, Remediation: K.C. Donnelly Externship - Promotion of Translational/Transdisciplinary Efforts in Graduate and Post-Doctoral Research (3P42ES013661-17S1). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10579012. Licensed CC0.

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