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Low-dose exposure to bisphenol A and replacement bisphenol S induces precocious hypothalamic neurogenesis in embryonic zebrafish.

ABSTRACT: Bisphenol A (BPA), a ubiquitous endocrine disruptor that is present in many household products, has been linked to obesity, cancer, and, most relevant here, childhood neurological disorders such as anxiety and hyperactivity. However, how BPA exposure translates into these neurodevelopmental disorders remains poorly understood. Here, we used zebrafish to link BPA mechanistically to disease etiology. Strikingly, treatment of embryonic zebrafish with very low-dose BPA (0.0068 ?M, 1,000-fold lower than the accepted human daily exposure) and bisphenol S (BPS), a common analog used in BPA-free products, resulted in 180% and 240% increases, respectively, in neuronal birth (neurogenesis) within the hypothalamus, a highly conserved brain region involved in hyperactivity. Furthermore, restricted BPA/BPS exposure specifically during the neurogenic window caused later hyperactive behaviors in zebrafish larvae. Unexpectedly, we show that BPA-mediated precocious neurogenesis and the concomitant behavioral phenotype were not dependent on predicted estrogen receptors but relied on androgen receptor-mediated up-regulation of aromatase. Although human epidemiological results are still emerging, an association between high maternal urinary BPA during gestation and hyperactivity and other behavioral disturbances in the child has been suggested. Our studies here provide mechanistic support that the neurogenic period indeed may be a window of vulnerability and uncovers previously unexplored avenues of research into how endocrine disruptors might perturb early brain development. Furthermore, our results show that BPA-free products are not necessarily safer and support the removal of all bisphenols from consumer merchandise.

SUBMITTER: Kinch CD

PROVIDER: S-EPMC4321238 | biostudies-literature | 2015 Feb

REPOSITORIES: biostudies-literature

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Low-dose exposure to bisphenol A and replacement bisphenol S induces precocious hypothalamic neurogenesis in embryonic zebrafish.

Kinch Cassandra D CD Ibhazehiebo Kingsley K Jeong Joo-Hyun JH Habibi Hamid R HR Kurrasch Deborah M DM

Proceedings of the National Academy of Sciences of the United States of America 20150112 5

Bisphenol A (BPA), a ubiquitous endocrine disruptor that is present in many household products, has been linked to obesity, cancer, and, most relevant here, childhood neurological disorders such as anxiety and hyperactivity. However, how BPA exposure translates into these neurodevelopmental disorders remains poorly understood. Here, we used zebrafish to link BPA mechanistically to disease etiology. Strikingly, treatment of embryonic zebrafish with very low-dose BPA (0.0068 μM, 1,000-fold lower t ...[more]

PMID: 25583509

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Project description:Purpose: the goal of this project is to study the effects of the bisphenol A (BPA) in the transcriptome profiling (RNA-seq) of exposed zebrafish larvae. Methods: Total RNA was isolated from the samples using AllPrep DNA/RNA Mini Kit (Qiagen, CA, USA) as described by the manufacturer. Three high quality sample per condition were chosen to the mRNA enrichment using KAPA Stranded mRNA-Seq Kit Illumina® Platforms (Kapa Biosystems). Transcriptomic profiles were generated by deep sequencing using Illumina TruSeq SBS Kit v3-HS (pair-ended; 2x76bp) on a HiSeq2000 sequencing system. Images analysis, base calling and quality scoring of the run were processed using the manufacturer’s software Real Time Analysis (RTA 1.13.48) and followed by generation of FASTQ sequence files by CASAVA. Statistical analysis: RNA-seq reads were aligned to the D. rerio reference genome (GRCz10) using STAR version 2.5.1b . Genes annotated in GRCz10.84 were quantified using RSEM version 1.2.28 with default parameters. Differential expression analysis between all BPA conditions was performed with the DESeq2 (v.1.10.1) R package with the Likelihood ratio test option. ANOVA-PLS was performed on the normalized data using the lmdme package in R (v. 1.0.136, R Core Team). Results: We generated on average 40 million paired-end reads for each sample and identified aproximatelly 25000 transcripts. 2539 differentially expressed genes (DEGs) were detected which could be divided in 3 clusters including 960, 1132 and 447 genes, respectively. Affected metabolic pathways were analyzed from the DEGs: liver development, lipid transport, lysosome and protein glycosylation, metabolic pathways for lipids, glutathione, retinol, and steroid hormones, and cytochrome P450-mediated metabolism in adittion to protein ubiquitination and glycolysis/gluconeogenesis pathways' were down or upregulated. Conclusions: The results suggest the interaction of BPA with different signaling pathways, being the estrogenic and retinoid receptors two likely BPA targets. We concluded that our analysis allowed us the identification of underlying molecular mechanisms occurring simultaneously at the exposed animals. While this approach is very useful to analyze the effects of compounds, like BPA, able to interact with different cellular targets, we believe that it can be also applied to the characterization of the different toxic components present in complex natural mixtures.

Dataset Information

Low-dose exposure to bisphenol A and replacement bisphenol S induces precocious hypothalamic neurogenesis in embryonic zebrafish.

Publications

Low-dose exposure to bisphenol A and replacement bisphenol S induces precocious hypothalamic neurogenesis in embryonic zebrafish.

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