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Effects of prenatal pesticide exposure on the fetal brain and placenta transcriptomes in a rodent model
Corina Lesseur1, Kirtan Kaur1, Sean D Kelly2
1Department of Environmental Medicine and Public Health, Icahn School of Medicine at Mount Sinai, Box 1057, New York, NY 10029, USA.
Insights
Gestational exposure to organophosphate (chlorpyrifos) and pyrethroid (deltamethrin) pesticides altered gene expression in fetal brain and placenta. Both pesticides impacted pathways related to cell proliferation, with distinct effects on oxidative phosphorylation, ribosome, and signaling pathways.
Area of Science:
- Environmental Toxicology
- Developmental Neuroscience
- Molecular Biology
Background:
- Organophosphate and pyrethroid pesticides are widely used, and prenatal exposure is linked to neurodevelopmental deficits.
- The placenta, a neuroendocrine organ, plays a critical role in fetal development and may mediate toxicant effects.
- Understanding how these pesticides impact placental and fetal brain gene expression is crucial for assessing neurodevelopmental risks.
Purpose of the Study:
- To investigate the effects of prenatal exposure to chlorpyrifos (CPF) and deltamethrin (DM) on the transcriptomes of fetal brain and placenta in mice.
- To identify specific gene expression pathways and networks disrupted by these pesticide exposures.
- To compare the molecular impacts of an organophosphate and a pyrethroid pesticide on developing neuroendocrine and neural tissues.
Main Methods:
- Female mice were exposed to CPF, DM, or vehicle control from before breeding through gestational day 17.
- RNA sequencing was performed on fetal brain and placental tissues.
- Weighted gene co-expression network analysis, differential expression analysis, and pathway analysis were used to evaluate transcriptomic data.
Main Results:
- CPF exposure disrupted ribosome and oxidative phosphorylation pathways in the fetal brain, and endocytosis, Notch, and MAPK signaling in the placenta.
- DM exposure disrupted extracellular matrix and calcium signaling pathways in the brain, and spliceosome, lysosome, and MAPK signaling in the placenta.
- Both CPF and DM led to overexpression of the transcription factor Max, involved in cell proliferation, in both fetal brain and placenta.
Conclusions:
- Gestational exposure to CPF and DM induces distinct yet overlapping pathway-level transcriptome changes in the mouse placenta and fetal brain.
- These molecular alterations, particularly those affecting cell proliferation, may underlie the neurobehavioral deficits observed following pesticide exposure.
- Further research is warranted to elucidate the causal link between these transcriptomic changes and adverse neurodevelopmental outcomes.
Abstract:
Organophosphate and pyrethroid pesticides are among the most extensively used insecticides worldwide. Prenatal exposures to both classes of pesticides have been linked to a wide range of neurobehavioral deficits in the offspring. The placenta is a neuroendocrine organ and the crucial regulator of the intrauterine environment; early-life toxicant exposures could impact neurobehavior by disrupting placental processes. Female C57BL/6 J mice were exposed via oral gavage to an organophosphate, chlorpyrifos (CPF) at 5 mg/kg, a pyrethroid, deltamethrin (DM), at 3 mg/kg, or vehicle only control (CTL). Exposure began two weeks before breeding and continued every three days until euthanasia at gestational day 17. The transcriptomes of fetal brain (CTL n = 18, CPF n = 6, DM n = 8) and placenta (CTL n = 19, CPF n = 16, DM n = 12) were obtained through RNA sequencing, and resulting data was evaluated using weighted gene co-expression networks, differential expression, and pathway analyses. Fourteen brain gene co-expression modules were identified; CPF exposure disrupted the module related to ribosome and oxidative phosphorylation, whereas DM disrupted the modules related to extracellular matrix and calcium signaling. In the placenta, network analyses revealed 12 gene co-expression modules. While CPF exposure disrupted modules related to endocytosis, Notch and Mapk signaling, DM exposure dysregulated modules linked to spliceosome, lysosome and Mapk signaling pathways. Overall, in both tissues, CPF exposure impacted oxidative phosphorylation, while DM was linked to genes involved in spliceosome and cell cycle. The transcription factor Max involved in cell proliferation was overexpressed by both pesticides in both tissues. In summary, gestational exposure to two different classes of pesticide can induce similar pathway-level transcriptome changes in the placenta and the brain; further studies should investigate if these changes are linked to neurobehavioral impairments.
