PCB 37 (3,4, 4’-trichlorobiphenyl) increased apoptosis and modulated neuronal morphogenesis in primary rat cortical neuron-glia cocultures in a concentration-, sex-, age-, and CREB-dependent manner

Jessie R. Badley; Peter M. Andrew; Hans-Joachim Lehmler; Pamela J. Lein

doi:10.1016/j.neuro.2025.08.004

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PCB 37 (3,4, 4’-trichlorobiphenyl) increased apoptosis and modulated neuronal morphogenesis in primary rat cortical neuron-glia cocultures in a concentration-, sex-, age-, and CREB-dependent manner

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PCB 37 (3,4, 4’-trichlorobiphenyl) increased apoptosis and modulated neuronal morphogenesis in primary rat cortical neuron-glia cocultures in a concentration-, sex-, age-, and CREB-dependent manner

Jessie R. Badley, Peter M. Andrew, Hans-Joachim Lehmler and Pamela J. Lein

Neurotoxicology (Park Forest South), Vol.110, pp.168-180

09/2025

DOI: 10.1016/j.neuro.2025.08.004

PMCID: PMC12653993

PMID: 40840865

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Abstract

Higher-chlorinated (HC) polychlorinated biphenyls (PCBs) are known developmental neurotoxicants. In contrast, there are limited data regarding the developmental neurotoxicity of lower-chlorinated (LC) PCBs despite the increasing environmental prevalence and detection of LC-PCBs in contemporary human tissues, including the perinatal brain. This study characterized the neurotoxic effects of the LC-PCB congener PCB 37 in primary male and female rat cortical neuron-glia co-cultures. Cultures were exposed to varying concentrations of PCB 37 for 48 h beginning on day in vitro 0 or 7. Cell viability was assessed by measuring lactate dehydrogenase release into the culture medium and the percentage of live cells identified using Calcein-AM and Hoechst staining. Apoptosis was measured using fluorometric assays of caspase 3/7 activity and Annexin V binding. Axonal and dendritic growth were quantified in neurons immunostained for Tau-1 or transfected with MAP2B-red fluorescent protein, respectively, using automated image analysis protocols. At environmentally relevant concentrations (0.0001, 0.1, and 100 nM) that did not affect cell viability, PCB 37 caused sex-, age-, and concentration-dependent increases in apoptosis, axonal, and dendritic growth. Pretreatment with the CREB inhibitor 666–15 (500 nM) blocked the effects of PCB 37 on apoptosis and dendritic morphology but not axonal growth. These findings suggest that the pro-apoptotic and dendrite-promoting effects of PCB 37 are mediated by CREB signaling, but that CREB-independent mechanisms underlie PCB 37 effects on axonal growth. Overall, these findings identify PCB 37 as a potential developmental neurotoxicant and further support increasing evidence identifying CREB as a convergent mechanism of developmental neurotoxicity. [Display omitted] •Little is known regarding the developmental neurotoxicity of PCB 37.•PCB 37 induces apoptosis in primary rat cortical cultures without cytotoxicity.•PCB 37 alters dendritic and axonal morphology in primary cortical neurons.•The apoptotic and morphology effects of PCB 37 are sex- and age-dependent.•CREB inhibition blocks PCB 37 effects on apoptosis and dendrites, but not axons.

Axonal outgrowth

Dendritic arborization

Developmental neurotoxicity

In vitro model

PCBs

Details

Title: Subtitle: PCB 37 (3,4, 4’-trichlorobiphenyl) increased apoptosis and modulated neuronal morphogenesis in primary rat cortical neuron-glia cocultures in a concentration-, sex-, age-, and CREB-dependent manner
Creators: Jessie R. Badley - University of California, Davis
Peter M. Andrew - University of California, Davis
Hans-Joachim Lehmler - Department of Occupational and Environmental Health, College of Public Health, University of Iowa, 145 N Riverside Drive, Iowa City, IA 52242, United States
Pamela J. Lein - University of California, Davis
Resource Type: Journal article
Publication Details: Neurotoxicology (Park Forest South), Vol.110, pp.168-180
DOI: 10.1016/j.neuro.2025.08.004
PMID: 40840865
PMCID: PMC12653993
NLM abbreviation: Neurotoxicology
ISSN: 0161-813X
eISSN: 1872-9711
Publisher: Elsevier B.V
Number of pages: 13
Grant note: NIH NIEHS: F31 ES035282, T32 ES007059, R01 ES014901 UC Davis MIND Institute Intellectual and Developmental Disabilities Research Center (Eunice Kennedy Shriver National Institute of Child Health and Human Development): P50 HD103526
This work was supported by the NIH NIEHS (F31 ES035282 to JRB; T32 ES007059 predoctoral fellowship to JRB; R01 ES014901 to PJL and HJL) . This project used core facilities supported by the UC Davis MIND Institute Intellectual and Developmental Disabilities Research Center (Eunice Kennedy Shriver National Institute of Child Health and Human Development grant P50 HD103526) . The contents of this manuscript are solely the responsibility of the authors and do not necessarily represent the official views of the NIH.
Language: English
Date published: 09/2025
Academic Unit: Public Health Administration; Occupational and Environmental Health; Iowa Neuroscience Institute; Iowa Superfund Research Program
Record Identifier: 9984949222502771

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