Bisphenol A, an endocrine-disrupting chemical, and brain development

Department of Pathology & Applied Neurobiology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan.
Neuropathology (Impact Factor: 1.65). 01/2012; 32(4):447-57. DOI: 10.1111/j.1440-1789.2011.01287.x
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Bisphenol A (BPA) is an endocrine-disrupting chemical, widely used in various industries and the field of dentistry. The consequent increase in BPA exposure among humans has led us to some concerns regarding the potential deleterious effects on reproduction and brain development. The emphasis of this review is on the effects of prenatal and lactational exposure to low doses of BPA on brain development in mice. We demonstrated that prenatal exposure to BPA affected fetal murine neocortical development by accelerating neuronal differentiation/migration during the early embryonic stage, which was associated with up- and down-regulation of the genes critical for brain development, including the basic helix-loop-helix transcription factors. In the adult mice brains, both abnormal neocortical architecture and abnormal corticothalamic projections persisted in the group exposed to the BPA. Functionally, BPA exposure disturbed murine behavior, accompanied with a disrupted neurotransmitter system, including monoamines, in the postnatal development period and in adult mice. We also demonstrated that epigenetic alterations in promoter-associated CpG islands might underlie some of the effects on brain development after exposure to BPA.

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Available from: Kyoko Itoh, Nov 20, 2014
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    • "). Notably, developmental exposure to low BPA in rats produces an endocrine profile similar to that observed in thyroid resistance syndrome. This syndrome is characterized by the inhibition of TR-mediated negative feedback at the hypothalamus/pituitary level (resulting in the increase of circulating thyroid hormones) and by the increase of thyroid-responsive gene expression in the brain (Itoh et al. 2012; Zoeller et al. 2005). The TR-antagonistic activity of BPA seems to affect also specific developmental events controlled by thyroid hormones such as oligodendrocyte differentiation from precursor cells (Seiwa et al. 2004). "
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    ABSTRACT: Brain development is an organized, but constantly adaptive, process in which genetic and epigenetic signals allow neurons to differentiate, to migrate, and to develop correct connections. Gender specific prenatal sex hormone milieu participates in the dimorphic development of many neuronal networks. Environmental cues may interfere with these developmental programs, producing adverse outcomes. Bisphenol A (BPA), an estrogenic/antiandrogenic endocrine disruptor widely diffused in the environment, produces adverse effects at levels below the acceptable daily intake. This review analyzes the recent literature on the consequences of perinatal exposure to BPA environmental doses on the development of a dimorphic brain. The BPA interference with the development and function of the neuroendocrine hypothalamus and of the nuclei controlling energy balance, and with the hippocampal memory processing is also discussed. The detrimental action of BPA appears complex, involving different hormonal and epigenetic pathways activated, often in a dimorphic way, within clearcut susceptibility windows. To date, discrepancies in experimental approaches and in related outcomes make unfeasible to translate the available information into clear dose–response models for human risk assessment. Evaluation of BPA brain levels in relation to the appearance of adverse effects in future basic studies will certainly give better definition of the warning threshold for human health.
    Dose-Response 06/2015; 13(2). DOI:10.1177/1559325815590394 · 1.22 Impact Factor
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    • "In addition to these " high dose " effects on survival and growth, other studies have shown a variety of effects induced by much lower doses of BPA, i.e. doses below the established NOAEL of 50 ␮g/kg/day, which reproduce better the actual human exposure. The adverse effects induced by a " low dose " of BPA include neuronal and behavioral alterations: documented effects of prenatal exposure to BPA are abnormal development of the neocortex in terms of differentiation and neuronal migration [19] [38], aberrant positions and connections between thalamus and cortex [39], inhibition of the proliferation of neural progenitor cells [21], loss of sexual dimorphism in terms of brain structure and behavior [24], increased anxiety and cognitive deficits [45] [54]. Part of these results are justified by the strong affinity of BPA to the dopamine receptor, the estrogen-like receptor-␤ type [8] and the estrogen-like receptor-␥ type present in hippocampal neurons [51]. "
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    ABSTRACT: Over 50% of the causes of fetal malformations in humans are still unknown. Recent evidence suggests the relationship between environmental exposure to endocrine disruptors and fetal malformations. Our study aims to establish the role of Bisphenol A (BPA), if any, in altering human reproduction. We enrolled 151 pregnant women who were divided into two groups: case group (CS, n=101), women with established diagnosis of developmental defect, and control group (CL, n=50), pregnant women with normally developed fetus. Total, free and conjugated BPA were measured in their blood using GC-MS with isotopic dilution. The results show a correlation between environmental exposure to BPA and the genesis of fetal malformations. Conjugated BPA, which was higher in the CL, casts light on the hypothesis that a reduced ability to metabolize the chemical in the mother can concur to the occurrence of malformation. In a more detailed manner, in case of chromosomal malformations, the average value of free BPA appears to be nearly three times greater than that of the controls. Similarly, in case of central and peripheral nervous system non-chromosomal malformations, the value of free BPA is nearly two times greater than that of the controls. Copyright © 2015 Elsevier B.V. All rights reserved.
    Mutation Research - Fundamental and Molecular Mechanisms of Mutagenesis 03/2015; 774. DOI:10.1016/j.mrfmmm.2015.02.007
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    • "Prenatal BPA exposure impairs murine fetal neocortical development by accelerating neuronal differentiation/migration during the early embryonic stage to affect neuronal plasticity and interferes corticosterone and corticosteroid receptors in the hippocampus [35]–[37]. According to mother report or behavior assessment system for children 2 (BASC-2) and behavior rating inventory of executive function-preschool (BRIEF-P), prenatal BPA exposure is significantly concerned in childhood behavioral problems such as anxiety, depression, inattention and hyperactivity in children less than age 7 [38], [39]. "
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    ABSTRACT: Background Bisphenol A (BPA) is a ubiquitous endocrine disrupting chemical in our daily life, and its health effect in response to prenatal exposure is still controversial. Early-life BPA exposure may impact brain development and contribute to childhood neurological disorders. The aim of the present study was to investigate molecular target genes of neuronal development in trans-placental exposure to BPA. Methodology A meta-analysis of three public microarray datasets was performed to screen for differentially expressed genes (DEGs) in exposure to BPA. The candidate genes of neuronal development were identified from gene ontology analysis in a reconstructed neuronal sub-network, and their gene expressions were determined using real-time PCR in 20 umbilical cord blood samples dichotomized into high and low BPA level groups upon the median 16.8 nM. Principal Findings Among 36 neuronal transcripts sorted from DAVID ontology clusters of 457 DEGs using the analysis of Bioconductor limma package, we found two neuronal genes, sex determining region Y-box 2 (Sox2) and paired box 6 (Pax6), had preferentially down-regulated expression (Bonferroni correction p-value <10−4 and log2-transformed fold change ≤−1.2) in response to BPA exposure. Fetal cord blood samples had the obviously attenuated gene expression of Sox2 and Pax6 in high BPA group referred to low BPA group. Visualized gene network of Cytoscape analysis showed that Sox2 and Pax6 which were contributed to neural precursor cell proliferation and neuronal differentiation might be down-regulated through sonic hedgehog (Shh), vascular endothelial growth factor A (VEGFA) and Notch signaling. Conclusions These results indicated that trans-placental BPA exposure down-regulated gene expression of Sox2 and Pax6 potentially underlying the adverse effect on childhood neuronal development.
    PLoS ONE 07/2014; 9(7):e100576. DOI:10.1371/journal.pone.0100576 · 3.23 Impact Factor
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