Abstract
An increasing prevalence of mental health problems has been partly ascribed to abnormal brain development that is induced upon exposure to environmental chemicals. However, it has been extremely difficult to detect and assess such causality particularly at low exposure levels. To address this question, we here investigated higher brain function in mice exposed to dioxin in utero and via lactation by using our recently developed automated behavioral flexibility test and immunohistochemistry of neuronal activation markers Arc, at the 14 brain areas. Pregnant C57BL/6 mice were given orally a low dose of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) at a dose of either 0, 0.6 or 3.0 µg/kg on gestation day 12.5. When the pups reached adulthood, they were group-housed in IntelliCage to assess their behavior. As a result, the offspring born to dams exposed to 0.6 µg TCDD/kg were shown to have behavioral inflexibility, compulsive repetitive behavior, and dramatically lowered competitive dominance. In these mice, immunohistochemistry of Arc exhibited the signs of hypoactivation of the medial prefrontal cortex (mPFC) and hyperactivation of the amygdala. Intriguingly, mice exposed to 3.0 µg/kg were hardly affected in both the behavioral and neuronal activation indices, indicating that the robust, non-monotonic dose-response relationship. In conclusion, this study showed for the first time that perinatal exposure to a low dose of TCDD in mice develops executive function deficits and social behavioral abnormality accompanied with the signs of imbalanced mPFC-amygdala activation.
Highlights
The development of the brain is highly sensitive to be perturbed by various kinds of environmental factors including chemical exposure [1,2,3,4]
We found that in utero and lactational exposure to a low dose of TCDD, which corresponds to approximately 1/300th of the LD50 and is comparable to the dose from which was used to derive a tolerable daily intake level in humans [48], perturbs executive functions and induce low competitive dominance for limited sources of water reward after water deprivation of offspring, and that such behavioral alterations are consistent with altered signs of neuronal activity in the medial prefrontal cortex (mPFC) and amygdala
Using our recently developed behavioral task for group-housed mice, we investigated how a low dose of perinatal dioxin exposure affects executive function and social-emotional behavior in adulthood and analyzed immediate early gene products to determine the neurobiological basis of the observed behavioral alterations
Summary
The development of the brain is highly sensitive to be perturbed by various kinds of environmental factors including chemical exposure [1,2,3,4]. Dioxins are a group of chemicals unintentionally produced in combustion processes or byproducts of manufacturing certain kinds of herbicides Due to their persistency in the environment, humans have been exposed to non-negligible amounts of dioxins mainly through daily food [10]. Mitsuhashi and associates [28] showed that in utero exposure of mice to TCDD impairs histogenesis of the neocortex, albeit at a high dose corresponding to approximately one-ninth of its 50% lethal dose (LD 50) [29]. It is largely unknown whether and how exposure to dioxin, at a low dose, affects higher brain function
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