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Published on: April 27, 2019
Benzo[a]pyrene impairs neurodifferentiation in PC12 cells
Theodore A Slotkin1, Frederic J Seidler
1Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, NC 27710, USA. t.slotkin@duke.edu
Insights
Prenatal exposure to benzo[a]pyrene (BaP) directly impairs neurodevelopment in neuronal cells. This toxicant disrupts neurotransmitter development, potentially explaining adverse neurobehavioral effects observed in animal studies.
Area of Science:
- Neuroscience
- Toxicology
- Developmental Biology
Background:
- Prenatal exposure to environmental toxicants like benzo[a]pyrene (BaP) is linked to neurobehavioral anomalies in animal models.
- The direct impact of BaP on neuronal development requires further investigation.
Purpose of the Study:
- To investigate the direct effects of benzo[a]pyrene (BaP) on neurodevelopment.
- To compare BaP's effects with chlorpyrifos (CPF), an organophosphate insecticide, using neuronotypic PC12 cells.
Main Methods:
- Assessed cell replication, cell number, neurite outgrowth, and phenotypic differentiation in PC12 cells exposed to BaP and CPF.
- Measured neurotransmitter markers (tyrosine hydroxylase and choline acetyltransferase) to evaluate neurodifferentiation.
- Utilized undifferentiated and nerve growth factor-induced differentiating PC12 cell models.
Main Results:
- Unlike CPF, BaP did not inhibit DNA synthesis in undifferentiated cells.
- BaP increased cell numbers during differentiation, suggesting a delay in cell cycle exit, while CPF decreased them.
- BaP decreased cell enlargement and neurite outgrowth indices, contrasting with CPF's effects.
- BaP significantly reduced both dopamine and acetylcholine phenotype markers, with a greater impact on the acetylcholine phenotype.
Conclusions:
- Low, non-toxic levels of BaP directly impair neurodifferentiation in developing neuronal cells.
- BaP's disruption of neurotransmitter phenotype emergence and promotion of excess cell numbers contribute to adverse neurodevelopmental outcomes.
- These findings highlight BaP's direct neurotoxic potential during critical developmental windows.
Abstract:
Animal studies indicate neurobehavioral anomalies after prenatal exposure to benzo[a]pyrene (BaP). In order to determine if BaP directly affects neurodevelopment, we compared its effects to those of the organophosphate insecticide, chlorpyrifos (CPF), in undifferentiated and differentiating neuronotypic PC12 cells, evaluating indices of cell replication, cell number, neurite outgrowth and phenotypic differentiation. Unlike CPF, BaP did not inhibit DNA synthesis in undifferentiated cells. In cells undergoing nerve growth factor-induced differentiation, CPF reduced cell numbers (assessed by DNA content) whereas BaP increased them, suggesting a delay in the transition between cell replication and differentiation. Indices of cell enlargement (total protein/DNA) and neurite outgrowth (membrane protein/DNA) also showed opposite effects of CPF (increases) and BaP (decreases). We directly confirmed BaP impairment of neurodifferentiation by measuring markers for the two neurotransmitter phenotypes expressed by PC12 cells: tyrosine hydroxylase (dopamine phenotype) and choline acetyltransferase (acetylcholine phenotype). BaP significantly reduced both markers in differentiating cells, with a preferentially greater effect on the acetylcholine phenotype. Our results indicate that low, non-toxic levels of BaP can impair neurodifferentiation, resulting in excess cell numbers at the expense of the emergence of neurotransmitter phenotypes. BaP thus has direct actions on developing neuronal cells that could contribute to the adverse neurodevelopmental effects seen with in vivo exposures.
