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

Abstract

BACKGROUND: 2,3,7,8-tetrachlorodibenzo-p-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. OBJECTIVES: 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. METHODS: Throughout gestation, pregnant C57BL/6J mice were fed a diet containing a low dose of TCDD (9 ng 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. RESULTS: 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. DISCUSSION: Exposure to 9 ng 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.

Proper modulation of AHR signaling is necessary for establishing neural connectivity and oligodendrocyte precursor cell development in the embryonic zebrafish brain

“…Prior studies identified oligodendrocytes as possible targets of developmental and adult TCDD toxicity in the hippocampus, cerebellum, and medulla oblongata ( Fernández et al, 2010 ; Rosińczuk et al, 2015 ; Gileadi et al, 2021 ). These studies were limited to gene expression data from homogenized tissues and analysis of histological sectioning.…”

“…Epidemiological studies examining the adverse effects of contaminant-induced AHR activation on brain health have been corroborated by laboratory investigations using animal models to understand the impact of AHR agonist exposure on brain development and behavior. Studies in multiple model organisms have demonstrated that developmental exposure to AHR agonists produces functional changes in the nervous system ( Dubovický et al, 2008 ; Chen et al, 2012 ; Knecht et al, 2017 ; Gileadi et al, 2021 ; Holloway et al, 2021 ). In rats, exposure to the AHR agonist benzo[a]pyrene (BaP) during critical postnatal periods of development resulted in impaired learning and memory with deficiencies being persistent and exacerbated with age ( Chen et al, 2012 ).…”

“…TCDD exposure in adult mice impairs neurogenesis and neuronal differentiation in the hippocampus as well as hippocampal-dependent contextual memory ( Latchney et al, 2013 ). Low-dose, gestational TCDD exposure in mice was found to induce motor and learning deficits in juvenile females ( Gileadi et al, 2021 ) and, in zebrafish, embryonic BaP exposure has been reported to produce larval hyperactivity as well impaired learning in adult fish ( Knecht et al, 2017 ). However, under different exposure paradigms and testing parameters, BaP exposure was also reported to produce hypoactivity in zebrafish ( Holloway et al, 2021 ).…”

Progress in magnetic resonance imaging of autism model mice brain

“…Prenatal and postnatal exposure can cause neurodevelopmental delay and cognitive impairment in children (Ames et al, 2019). Gileadi et al (2021) explored the effect of TCDD exposure during pregnancy on brain structure in mouse offspring. MRI of the offspring exposed to TCDD during pregnancy revealed that the volume of ventral hippocampus, hypothalamus, cerebellum, and other brain regions were increased, while the crus I and papillary bodies of the cerebellar hemisphere were decreased.…”

Alterations in Regional Brain Regional Volume Associated with Dioxin Exposure in Men Living in the Most Dioxin-Contaminated Area in Vietnam: Magnetic Resonance Imaging (MRI) Analysis Using Voxel-Based Morphometry (VBM)

“…We found that opposing effects were associated with high dioxin levels, observing both volume increases and volume decreases. Previous animal studies suggested that the effects of persistent organic pollutants (POPs), including dioxins, might be nonmonotonic: POPs exert both promoting and suppressing effects on neuronal dendritic growth, depending on their dose and the brain region, which may lead to brain volume increases and decreases, respectively [22][23][24].…”