Journal Article

Effects of Low-Dose Gestational TCDD Exposure on Behavior and on Hippocampal Neuron Morphology and Gene Expression in Mice

Lundebye, Anne-Katrine, Stockinger, Brigitta, Lerch, Jason P., Horswell, Stuart, Mohan, Conor, Ellegood, Jacob, Hogstrand, Christer, Fernandes, Cathy, Gileadi, Talia E., Swamy, Abhyuday K., Giese, K. Peter, Mizuno, Keiko, Hore, Zoe, Basson, M. Albert

2021

Overview

2,3,7,8-tetrachlorodibenzo- -dioxin (TCDD) is a persistent and toxic environmental pollutant. Gestational exposure to TCDD has been linked to cognitive and motor deficits, and increased incidence of autism spectrum disorder (ASD) traits in children. Most animal studies of these neurodevelopmental effects involve acute TCDD exposure, which does not model typical exposure in humans. The aim of the study was to establish a dietary low-dose gestational TCDD exposure protocol and performed an initial characterization of the effects on offspring behavior, neurodevelopmental phenotypes, and gene expression. Throughout gestation, pregnant C57BL/6J mice were fed a diet containing a low dose of TCDD ( TCDD/kg body weight per day) or a control diet. The offspring were tested in a battery of behavioral tests, and structural brain alterations were investigated by magnetic resonance imaging. The dendritic morphology of pyramidal neurons in the hippocampal Cornu Ammonis (CA)1 area was analyzed. RNA sequencing was performed on hippocampi of postnatal day 14 TCDD-exposed and control offspring. TCDD-exposed females displayed subtle deficits in motor coordination and reversal learning. Volumetric difference between diet groups were observed in regions of the hippocampal formation, mammillary bodies, and cerebellum, alongside higher dendritic arborization of pyramidal neurons in the hippocampal CA1 region of TCDD-exposed females. RNA-seq analysis identified 405 differentially expressed genes in the hippocampus, enriched for genes with functions in regulation of microtubules, axon guidance, extracellular matrix, and genes regulated by SMAD3. Exposure to TCDD/kg body weight per day throughout gestation was sufficient to cause specific behavioral and structural brain phenotypes in offspring. Our data suggest that alterations in SMAD3-regulated microtubule polymerization in the developing postnatal hippocampus may lead to an abnormal morphology of neuronal dendrites that persists into adulthood. These findings show that environmental low-dose gestational exposure to TCDD can have significant, long-term impacts on brain development and function. https://doi.org/10.1289/EHP7352.

• Publisher: National Institute of Environmental Health Sciences,Environmental Health Perspectives
• Subject: Animal cognition / Animals / Autism / Axon guidance / Behavior / Behavior, Animal - drug effects / Body weight / Brain / Brain diseases / Breastfeeding & lactation / Cerebellum / Children & youth / Cognition disorders / Cognitive ability / Dendrites / Dendritic branching / Dendritic structure / Diet / Dioxin / Dioxins / Dosage / Dose-response relationship (Biochemistry) / Environmental aspects / Exposure / Extracellular matrix / Female / Females / Food contamination & poisoning / Gene expression / Gene Expression - drug effects / Gene regulation / Gene sequencing / Genes / Gestation / Health aspects / Hippocampus / Hippocampus - drug effects / Hydrocarbons / Ligands / Magnetic resonance imaging / Medical research / Medicine, Experimental / Memory / Mice / Mice, Inbred C57BL / Microtubules / Morphology / Motor skill learning / Neuroimaging / Neurons / Neurons - drug effects / Nutrient deficiency / Offspring / PCB / Persistent organic pollutants / Phenotypes / Pollutants / Polychlorinated biphenyls / Polychlorinated Dibenzodioxins - administration & dosage / Polychlorinated Dibenzodioxins - toxicity / Postpartum period / Pregnancy / Prenatal Exposure Delayed Effects / Prenatal influences / Pyramidal cells / Reversal learning / Ribonucleic acid / Risk factors / RNA / Rodents / TCDD