Kazuya Miyagawa

Memory impairment associated with a dysfunction of the hippocampal cholinergic system induced by prenatal and neonatal exposures to bisphenol-A

One of the most common chemicals that behaves as an endocrine disruptor is the compound 4,4-isopronylidenediphenol, called bisphenol-A. In the previous study, we reported that exposure to bisphenol-A induced the abnormality of dopamine receptor functions in the mouse limbic area, resulting in a supersensitivity of drugs of abuse-induced pharmacological actions. The present study was undertaken to investigate whether prenatal and neonatal exposures to bisphenol-A could alter other behavioral abnormalities such as anxiogenic behavior, motor learning behavior, or memory. In the present study, adult female mice were chronically treated with bisphenol-A-admixed powder food from mating to weaning. All experiments were performed using male pups. Here we found that prenatal and neonatal exposures to bisphenol-A failed to induce anxiogenic effects and motor-learning impairment using the light-dark test, elevated plus maze test, and rota-rod test. On the other hand, we found that prenatal and neonatal exposures to bisphenol-A induced the memory impairment using the step-through passive avoidance test. Immunohistochemical study showed the dramatic reduction in choline acetyltransferase-like immunoreactivity, which is a marker of acetylcholine (ACh) production, in the hippocampus of mice prenatally and neonatally exposed to bisphenol-A. These results suggest that chronic exposures to bisphenol-A could induce the memory impairment associated with the reduction in ACh production in the hippocampus.

Dynamic Changes in Dopaminergic Neurotransmission Induced by a Low Concentration of Bisphenol-A in Neurones and Astrocytes

One of the most common chemicals that behaves as an endocrine disruptor is the compound 4,4′‐isopronylidenediphenol, called bisphenol‐A (BPA). We previously reported that prenatal and postnatal exposure to BPA potentiated central dopaminergic neurotransmission, resulting in supersensitivity to psychostimulant‐induced pharmacological actions. Many recent findings have supported the idea that astrocytes, which are a subpopulation of glial cells, play a critical role in neuronal transmission in the central nervous system. The present study aimed to investigate the role of neurone–astrocyte communication in the enhancement of dopaminergic neurotransmission induced by BPA. We found that treatment of mouse purified astrocytes and neurone/glia cocultures with BPA in vitro caused the activation of astrocytes, as detected by a stellate morphology and an increase in levels of glial fibrillary acidic protein. A low concentration of BPA significantly enhanced the Ca2+ responses to dopamine in both neurones and astrocytes. Furthermore, a high concentration of BPA markedly induced the activation of caspase‐3, which is a marker of neuronal apoptotic cell death in mouse midbrain neurone/glia cocultures. By contrast, treatment with 17β‐oestradiol (E2) had no such effects. Prenatal and neonatal exposure to BPA led to an enhancement of the dopamine‐dependent rewarding effect induced by morphine. These findings provide evidence that BPA alters dopamine responsiveness in neurones and astrocytes and that, at least in part, it may contribute to potentiate the development of psychological dependence on drugs of abuse.

Prenatal and neonatal exposure to low-dose of bisphenol-A enhance the morphine-induced hyperlocomotion and rewarding effect

Bisphenol-A has been extensively evaluated for toxicity in a variety of tests as the most common environmental endocrine disruptors. In the previous study, we reported that prenatal and neonatal exposure to high-dose of bisphenol-A affects the development of central dopaminergic system in the mouse limbic area. The present study was then undertaken to investigate whether prenatal and neonatal exposure to lower dose of bisphenol-A could change the morphine-induced several pharmacological actions such as rewarding effect and hyperlocomotion in mice. Prenatal and neonatal exposure to low-dose of bisphenol-A enhanced the morphine-induced hyperlocomotion and rewarding effect. Additionally, the treatment with bisphenol-A produced an up-regulation of dopamine receptor function to activate G-protein in the mouse limbic forebrain, which is thought to play a critical role for hyperlocomotion and rewarding effects by drugs of abuse. These findings suggest that prenatal and neonatal exposure to low-dose of bisphenol-A can potentiate the central dopamine receptor-dependent neurotransmission, resulting in the supersensitivity of the morphine-induced hyperlocomotion and rewarding effects in the mouse.

Prenatal and neonatal exposure to bisphenol-A affects the morphine-induced rewarding effect and hyperlocomotion in mice.

Bisphenol-A (BPA), one of the most common environmental endocrine disrupters, has been extensively evaluated for toxicity and carcinogenicity. However, little is still known about its action on the CNS. Here we found that prenatal and neonatal exposure to BPA resulted in the enhancement of the rewarding effect and hyperlocomotion induced by morphine in mice. Under these conditions, no change in the G-protein activation by morphine and mu-opioid receptor expression in the lower midbrain was observed by prenatal and neonatal exposure to BPA. These results suggest that chronic exposure to BPA produces the supersensitivity of the morphine-induced rewarding effect and hyperlocomotion without direct changes in mu-opioid receptor function in the lower midbrain. The present data provide further evidence that prenatal and neonatal exposure to BPA can directly influence the development of the central dopaminergic system.

Changes in central dopaminergic systems and morphine reward by prenatal and neonatal exposure to bisphenol-A in mice: evidence for the importance of exposure period.

Bisphenol‐A has been extensively evaluated for toxicity in a variety of tests as the most common environmental endocrine disruptors. In a previous study, we reported that exposure to bisphenol‐A affects the development of the central dopaminergic system in the mouse limbic area. The present study was undertaken to investigate the relationship between the developmental toxicity of bisphenol‐A and its exposure period. The exposure to bisphenol‐A during either organogenesis or lactation, but not implantation and parturition, significantly enhanced the morphine‐induced hyperlocomotion and rewarding effects. Furthermore, exposure to bisphenol‐A during either organogenesis or lactation also produced an up‐regulation of dopamine receptor function to activate G‐protein in the mouse limbic forebrain. These results indicate that both organogenesis and lactation are more sensitive to the bisphenol‐A‐induced developmental neuronal toxicology than any other periods. In conclusion, the present data suggest that the organogenesis and lactation are the most important period to cause the alternation of dopaminergic system by bisphenol‐A exposure in the mouse.