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Male autism spectrum disorder is linked to brain aromatase disruption by prenatal BPA in multimodal investigations and 10HDA ameliorates the related mouse phenotype (BPA)

ABSTRACT: Pregannt Cyp19-EGFP mice (maintained on a soybean free mouse chow diet) were treated with either 50μg/kg/day Bsiphenol A or vehicle (ethinol in peanut oil) between gestational days (GD) 10.5-14.5. On GD15.5, fetuses were dissected and sex determined by SRY genotyping. Fetuses were obtained from different dams.

ORGANISM(S): Mus musculus

PROVIDER: GSE266401 | GEO | 2024/05/08

REPOSITORIES: GEO

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Project description:Although the effects of thyroid hormones (TH) on the brain development have been extensively studied perinatally, effects of TH of maternal origin on the fetal brain development have been largely unexplored. We applied a high throughput study on the mouse models with aberrant TH levels on gestation day (GD) 16, before the onset of fetal thyroid function. Although 3 day treatment with methimazole (MMI) and perchlorate significantly decreased TH levels in fetal cerebral cortex, few changes in the abundance of mRNA were revealed by the microarray analysis. Injection TH to dams 12 hours before sacrifice on GD 16 induced 161 genes significantly changed in fetal cortex. Nine out of 10 selected genes were confirmed with RT-PCR, including known TH responsive gene Klf9 and other novel TH responsive genes such as Appbp2, Ppap2b and Fgfr1op2. TH regulation of the expression of these genes was also confirmed with cultured N2a? cells. Thyroid responsive elements (TREs) in the promoters of these genes were identified using electrophoresis mobility shift assay. TH effect on microRNA (miRNA) expression in developing cortex on GD 16 and postnatal day (PND) 15 was investigated with microarray and RT-PCR. Some of miRNAs and precursors decreased in fetal cortex from the dams injected with TH on GD 16, including miR-16 and miR-106. Using 3’ untranslate region reporter vector, we identified Klf9 is one of the target genes of miR-106, while Ppap2b is the target of miR-16. These results indicated that TH regulation on gene expression could through TR-TRE interaction and through regulating target miRNA expression. This study is the first report to identify TH responsive genes and miRNAs genome wide in the early fetal brain; it provides evidence to further understand the mechanism of TH effect on brain development. Timed-pregnant C57BL/6 mice (n=20; Harlan, Indianapolis, IN) arrived on gestational day (GD) 11 and were housed individually in plastic cages under a 12:12 light cycle (0600 h–1800 h) with food available ad libitum. Mice were divided randomly into one of 4 groups (control, hypo, hypo+ and hyper; 5 per group) . Mice in the control and hyper groups were provided with fresh drinking water containing 2% sucrose from GD 13 to GD 16 until sacrifice. Mice in hypo and hypo+ were provided with fresh drinking water daily containing 1% Perchlorate (Per) and 0.025% Methimazole (MMI) supplemented with 2% sucrose (to mask bitterness) from GD 13 to sacrifice on GD 16. Twelve hours prior to sacrifice on GD 16 all mice received a single subcutaneous injection. Control and hypo mice received vehicle (0.9% saline in 100 µl volume); the hypo+ group received 25.0 µg/100g body weight thyroxine (T4) with 2.5 µg/100g body weight T3 to restore a physiological level of TH; the hyper group received 100.0 µg/100g body weight T4 with 10.0 µg/100g body weight T3 to model hyperthyroidism. Dams were killed by exposure to CO2. Fetuses were dissected from the uterine horn and embryonic membranes then frozen on pulverized dry ice. Tissue samples were taken from the fetuses to determine sex using PCR for SRY (Yang J and RT Zoeller, 2002). Fetal cerebral cortices were removed from each mouse and used for microarray and RT-PCR analysis. Total RNA was extracted from half cortices of individual female fetuses using RNeasy Lipid tissue Mini kits (Qiagen, Germantown, MD) according to the manufacturer's instructions. The quality of total RNA was evaluated by A260/A280 ratio (found to be at least 1.8 for each sample) and by electrophoresis on the Agilent Bioanalyzer. The Yale Center for the Neuroscience Microarray Consortium carried out the Affymetrix microarray analysis using The GeneChip Rat Genome 230 2.0 Array. Preparation of labeled cRNA for hybridization onto Affymetrix GeneChips followed the recommended Affymetrix protocol. Control versus each of the three treatment groups: hyper, hypo, and hypo+. 1 of 20 samples removed due to poor quality.

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Male autism spectrum disorder is linked to brain aromatase disruption by prenatal BPA in multimodal investigations and 10HDA ameliorates the related mouse phenotype (BPA)

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