Dataset Information

Long term transcriptional and behavioral effects in mice developmentally exposed to a mixture of endocrine disruptors associated with delayed human neurodevelopment.

ABSTRACT: Accumulating evidence suggests that gestational exposure to endocrine disrupting chemicals (EDCs) may interfere with normal brain development and predispose for later dysfunctions. The current study focuses on the exposure impact of mixtures of EDCs that better mimics the real-life situation. We herein describe a mixture of phthalates, pesticides and bisphenol A (mixture N1) detected in pregnant women of the SELMA cohort and associated with language delay in their children. To study the long-term impact of developmental exposure to N1 on brain physiology and behavior we administered this mixture to mice throughout gestation at doses 0×, 0.5×, 10×, 100× and 500× the geometric mean of SELMA mothers' concentrations, and examined their offspring in adulthood. Mixture N1 exposure increased active coping during swimming stress in both sexes, increased locomotion and reduced social interaction in male progeny. The expression of corticosterone receptors, their regulator Fkbp5, corticotropin releasing hormone and its receptor, oxytocin and its receptor, estrogen receptor beta, serotonin receptors (Htr1a, Htr2a) and glutamate receptor subunit Grin2b, were modified in the limbic system of adult animals, in a region-specific, sexually-dimorphic and experience-dependent manner. Principal component analysis revealed gene clusters associated with the observed behavioral responses, mostly related to the stress axis. This integration of epidemiology-based data with an experimental model increases the evidence that prenatal exposure to EDC mixtures impacts later life brain functions.

SUBMITTER: Repouskou A

PROVIDER: S-EPMC7283331 | biostudies-literature | 2020 Jun

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Long term transcriptional and behavioral effects in mice developmentally exposed to a mixture of endocrine disruptors associated with delayed human neurodevelopment.

Repouskou Anastasia A Papadopoulou Anastasia-Konstantina AK Panagiotidou Emily E Trichas Panagiotis P Lindh Christian C Bergman Åke Å Gennings Chris C Bornehag Carl-Gustaf CG Rüegg Joëlle J Kitraki Efthymia E Stamatakis Antonios A

Scientific reports 20200609 1

Accumulating evidence suggests that gestational exposure to endocrine disrupting chemicals (EDCs) may interfere with normal brain development and predispose for later dysfunctions. The current study focuses on the exposure impact of mixtures of EDCs that better mimics the real-life situation. We herein describe a mixture of phthalates, pesticides and bisphenol A (mixture N1) detected in pregnant women of the SELMA cohort and associated with language delay in their children. To study the long-ter ...[more]

PMID: 32518293

Similar Datasets

Project description:Environmental reproductive health focuses on the effect of exposure to contaminants considered as endocrine disruptors. Developmental testis is considered as target of these compounds affecting testicular functions in adults and suspected implications in tumor etiology. Comparative analysis of gene expression in mouse testis exposed to five disruptors, three different dosages and three accumulative developmental stages shown defined signature profiles of gene deregulation for MEHP (monoethyl phthalate) and zearalenone (a phytoestrogen) and different to 17β-estradiol exposure. The effects are even detected in postpuberal male offspring from premating exposed mothers. Oxidative stress response, protein ubiquitination and oxidative phosphorylation are the most representative pathways affected. Animal Exposure CD-1 mice were in vivo exposed to several doses of EDs following a defined protocol: mothers were exposed two weeks before mating (exposure A); the same exposure and dose were maintained during pregnancy (exposure B) and four weeks after birth (exposure C). In all exposures, male offspring were sacrificed to obtain the testes. The compounds were administrated in drinking water to a final concentration of: E2(mg/l) BPA(mg/l) Zea(mg/l) MEHP(mg/l) Lindane(mg/l) Dose (1) 0.02 0.5 4 27.85 50 Dose (2) 0.04 50 12 139.17 100 Dose (3) 0.16 200 20 278.34 200 Ethanol was used as vehicle for E2, BPA and Zea and DMSO was for MEHP and Lindane. Control testes were obtained from animals exposed to solvents of EDs: Ethanol and DMSO. Animal care and sacrifice were made following regulations from the CSIC Bioethics Committee. RNA preparation Total RNA from testes of exposed animals and controls was extracted using TRIzol reagent (Invitrogen), according to the manufacturer’s standard protocol. RNA samples were spectrophotometrically quantified using NanoDrop (NanoDrop Technologies). To minimize the effect of inter-individual expression variability we made pools of RNA from at least 3 individual RNA samples from each experimental condition (same quantity of total RNA per sample). Pools of RNA were checked for quality performing Experion analysis (Bio-Rad Laboratories). Total RNA from testes of unexposed four weeks old animals was also extracted with the purpose of making pools to assess the variability at the expression level of the mouse strain used (Ctr). Microarray Processing Starting with total RNA from pools described above, full length cDNAs were synthesized from oligo(dT) primers bearing a T7 promoter. These cDNAs were used as template for in vitro transcription by T7-RNA-Polymerase to amplify the mRNAs; following the Amino Allyl MessageAmp™ aRNA Kit (Ambion, Inc.) protocol. The amplified mRNAs (aRNA) were labeled either with Cy3 or Cy5 dyes, using Amersham CyDye Post-Labeling Reactive Dyes (Amersham Biosciences). The incorporated dye was spectrophotometrically quantified using NanoDrop (NanoDrop Technologies). The same dye signal quantities of labeled experimental and control aRNAs were mixed and hybridized to Mouse Oligoset v3 (OPERON) arrays from Genomics facility-University of Cincinnati (USA). The slides contained 31,769 spotted probes (70 mer oligonucleotides) corresponding to 24,878 expressed or predicted mouse genes. Hybridization and washes of microarrays were performed according to Genomics facility-University of Cincinnati instructions. Dye-Swap replicates were performed: one slide hybridized with experimental and control targets labeled with Cy3 and Cy5, respectively; and the second slide with the same type of targets but inversely labeled. Target refers to labeled aRNA while probe refers to the oligonucleotides spotted on the microarray platform. Imaging and data generation were carried out using a GenePix 4000B (Axon Instruments) and associated software from Axon Instruments, Inc. The microarray slides were scanned with dual lasers with wavelength frequencies to excite Cy3 and Cy5. Images were captured in TIFF files. Information extraction for a given spot was based on the median value for the signal pixels minus the median value for the background pixels to produce a gene set data file for all the DNA spots. The Cy3 and Cy5 fluorescence signal intensities were normalized.

Dataset Information

Long term transcriptional and behavioral effects in mice developmentally exposed to a mixture of endocrine disruptors associated with delayed human neurodevelopment.

Publications

Long term transcriptional and behavioral effects in mice developmentally exposed to a mixture of endocrine disruptors associated with delayed human neurodevelopment.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets