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Updated: Jun 15, 2025
Long-term Behavioral and Reproductive Consequences of Embryonic Exposure to Low-dose Toxicants
Published on: March 6, 2018
Prenatal low-dose Bisphenol A exposure impacts cortical development via cAMP-PKA-CREB pathway in offspring
Chu Jiang1,2,3, Jun Guan1,2,3, Xiangrong Tang4
1Furong Laboratory, Center for Medical Genetics, School of Life Sciences, Central South University, Changsha, Hunan, China.
Insights
Prenatal exposure to low-dose Bisphenol A (BPA) alters brain development and causes manic-like behaviors in offspring. These effects are linked to overactivation of the cAMP-PKA-CREB pathway, suggesting PKA plays a key role in BPA
Area of Science:
- Neuroscience
- Developmental Biology
- Toxicology
Background:
- Bisphenol A (BPA) is a common plasticizer linked to health disorders.
- Prenatal low-dose BPA exposure, even below safety limits, may cause childhood neurological and behavioral deficits.
- Mechanisms underlying BPA's neurodevelopmental effects are not fully understood.
Purpose of the Study:
- To investigate the impact of prenatal low-dose BPA exposure on cortical neuron development.
- To elucidate the molecular pathways involved in BPA-induced neurodevelopmental and behavioral changes.
- To assess the role of the cAMP-PKA-CREB pathway in mediating these effects.
Main Methods:
- Exposure of pregnant dams to low-dose BPA.
- Analysis of cortical neuron proliferation and migration in offspring.
- Transcriptomic analysis (RNA sequencing) to identify affected pathways.
- Pharmacological inhibition of Protein Kinase A (PKA) using H89.
Main Results:
- Prenatal BPA exposure increased cortical neuron number, proliferation, and reduced migration.
- RNA sequencing revealed aberrant activation of the cAMP-PKA-CREB pathway.
- PKA inhibition (H89) rescued neuronal proliferation and migration deficits.
- BPA-exposed offspring exhibited manic-like behaviors (hyperactivity, antidepressant-like, reduced anxiety); H89 normalized hyperactivity.
Conclusions:
- Overactivation of PKA is a key mediator of BPA-induced alterations in neuronal development.
- Prenatal low-dose BPA exposure causes lasting neurodevelopmental and behavioral changes.
- Manic-like behaviors may result from a combination of altered neuronal development and PKA signaling.
Abstract:
Bisphenol A (BPA) is a widely used plasticizer known to cause various disorders. Despite a global reduction in the use of BPA-containing products, prenatal exposure to low-dose BPA, even those below established safety limits, has been linked to neurological and behavioral deficits in childhood. The precise mechanisms underlying these effects remain unclear. In the present study, we observed a significant increase in the number of cortical neurons in offspring born to dams exposed to low-dose BPA during pregnancy. We also found that this prenatal exposure to low-dose BPA led to increased proliferation but reduced migration of cortical neurons. Transcriptomic analysis via RNA sequencing revealed an aberrant activation of the cAMP-PKA-CREB pathway in offspring exposed to BPA. The use of H89, a selective PKA inhibitor, effectively rescued the deficits in both proliferation and migration of cortical neurons. Furthermore, offspring from dams exposed to low-dose BPA exhibited manic-like behaviors, including hyperactivity, anti-depressant-like responses, and reduced anxiety. While H89 normalized hyperactivity, it didn't affect the other behavioral changes. These results suggest that the overactivation of PKA plays a causative role in BPA-induced changes in neuronal development. Our data also indicate that manic-like behaviors induced by prenatal low-dose BPA exposure may be influenced by both altered neuronal development and abnormal PKA signaling in adulthood.
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