# Investigating the cellular and molecular mechanisms of lower-chlorinated polychlorinated biphenyl developmental neurotoxicity

> **NIH NIH F31** · UNIVERSITY OF CALIFORNIA AT DAVIS · 2023 · $40,288

## Abstract

PROJECT SUMMARY
Polychlorinated biphenyls (PCBs) remain a significant risk to human health, and a primary target of concern is
the developing brain. Epidemiological studies have reported positive associations between developmental
exposures to PCBs and increased risk for neurodevelopmental disorders (NDD); however, experimental studies
designed to assess the strength of these associations and identify biological mechanisms underlying PCB DNT
have focused almost exclusively on the higher chlorinated (HC)-PCBs, the predominant congeners found in the
legacy commercial PCB mixtures. In contrast, data regarding the potential for lower chlorinated (LC)-PCBs to
interfere with neurodevelopment is extremely limited. This is a troubling gap considering recent reports that
environmental levels of LC-PCBs are increasing worldwide and that the LC-PCB congeners 11 and 28 were
found to comprise >70% of PCBs in the serum of pregnant women at increased risk for having a child with an
NDD. We previously reported that PCB 11 and its metabolites formed via cytochrome P450 (CYP)-mediated
oxidation promoted dendritic and axonal growth in vitro, and these effects were observed at concentrations
relevant to the human gestational environment. Interestingly, the potency of the metabolites varied from that of
the parent. Our in vitro studies also suggested that PCB 11 enhanced dendritic growth via activation of CREB-
dependent signaling pathways, but whether the metabolites alter neurodevelopment via the same molecular
mechanism is not known. We also do we know whether (1) other LC-PCBs found in human tissues have DNT
activity; (2) LC-PCBs or their metabolites modulate other neurodevelopmental outcomes known to be regulated
by CREB-dependent signaling, specifically axonal growth and neuronal apoptosis; or (3) the contribution of
cytochrome P450-mediated metabolism to LC-PCB DNT. My central hypothesis is that LC-PCBs and their
metabolites formed via human CYP2A6 and CYP2B6 alter neurodevelopment in primary neurons via
CREB-dependent mechanisms. To test this hypothesis, I will be characterizing the in vitro DNT profile of
human-relevant LC-PCBs and their metabolites, assessing how the metabolism of LC-PCBs by specific human
CYPs influences DNT, and evaluating the role of CREB in LC-PCB DNT. This research will generate data
critically needed to inform risk assessments of the potential for LC-PCBs to exert neurotoxic effects on the
developing brain. Data from these studies will also provide novel mechanistic insights regarding the role of CREB
and CYPS in LC-PCB DNT. Given the association of gain-of-function mutations in CREB with NDDs, and the
well-known functional polymorphisms in human CYPs, data implicating CREB and/or CYP-mediated metabolism
in LC-PCB DNT would suggest testable hypotheses regarding gene-environment interactions that influence NDD
risk and possible dietary and/or pharmacological strategies for reducing LC-PCB DNT in at-risk populations.

## Key facts

- **NIH application ID:** 10678135
- **Project number:** 1F31ES035282-01
- **Recipient organization:** UNIVERSITY OF CALIFORNIA AT DAVIS
- **Principal Investigator:** Jessie Renee Badley
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $40,288
- **Award type:** 1
- **Project period:** 2023-09-30 → 2025-09-29

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10678135

## Citation

> US National Institutes of Health, RePORTER application 10678135, Investigating the cellular and molecular mechanisms of lower-chlorinated polychlorinated biphenyl developmental neurotoxicity (1F31ES035282-01). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10678135. Licensed CC0.

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