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Placenta and fetal brain share a neurodevelopmental disorder DNA methylation profile in a mouse model of prenatal PCB
Benjamin I Laufer1, Kari Neier2, Anthony E Valenzuela3
1Department of Medical Microbiology and Immunology, School of Medicine, University of California, Davis, Davis, CA 95616, USA; UC Davis Genome Center, University of California, Davis, Davis, CA 95616, USA; MIND Institute, School of Medicine, University of California, Davis, Sacramento, CA 95817, USA.
Insights
Prenatal exposure to polychlorinated biphenyls (PCBs) alters DNA methylation in mouse placenta and fetal brain. These changes are linked to neurodevelopmental disorders (NDDs), suggesting a shared epigenetic mechanism.
Area of Science:
- Environmental Epigenetics
- Developmental Neurotoxicology
- Reproductive Biology
Background:
- Polychlorinated biphenyls (PCBs) are known developmental neurotoxicants.
- PCBs are linked to environmental risk factors for neurodevelopmental disorders (NDDs).
- Epigenetic modifications, such as DNA methylation, are crucial in development and disease.
Purpose of the Study:
- To investigate the impact of prenatal PCB exposure on DNA methylation in mouse placenta and fetal brain.
- To identify shared epigenetic alterations between placenta and brain following PCB exposure.
- To explore the relevance of these alterations to neurodevelopmental disorders.
Main Methods:
- Exposure of pregnant mice to a human-relevant PCB mixture.
- Whole-genome bisulfite sequencing to profile DNA methylation in placenta and fetal brain.
- Bioinformatic analysis to identify differentially methylated regions (DMRs) and associated genes.
Main Results:
- Thousands of DMRs were identified in both placenta and fetal brain of PCB-exposed mice compared to controls.
- PCB-associated DMRs were enriched for neurodevelopmental and cellular signaling pathways, including Wnt and Slit/Robo signaling.
- A significant overlap was observed between placental and brain DMRs, mapping to shared NDD-relevant genes.
Conclusions:
- Prenatal PCB exposure induces distinct DNA methylation changes in both placenta and fetal brain.
- The placenta epigenetically mirrors some of the fetal brain's response to PCBs.
- These shared epigenetic changes in placenta and brain may contribute to PCB-induced neurodevelopmental risks.
Abstract:
Polychlorinated biphenyls (PCBs) are developmental neurotoxicants implicated as environmental risk factors for neurodevelopmental disorders (NDDs). Here, we report the effects of prenatal exposure to a human-relevant mixture of PCBs on the DNA methylation profiles of mouse placenta and fetal brain. Thousands of differentially methylated regions (DMRs) distinguish placenta and fetal brain from PCB-exposed mice from sex-matched vehicle controls. In both placenta and fetal brain, PCB-associated DMRs are enriched for functions related to neurodevelopment and cellular signaling and enriched within regions of bivalent chromatin. The placenta and brain PCB DMRs overlap significantly and map to a shared subset of genes enriched for Wnt signaling, Slit/Robo signaling, and genes differentially expressed in NDD models. The consensus PCB DMRs also significantly overlap with DMRs from human NDD brain and placenta. These results demonstrate that PCB-exposed placenta contains a subset of DMRs that overlap fetal brain DMRs relevant to an NDD.
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