title: Executive function deficits and social-behavioral abnormality in mice exposed to a low dose of dioxin in utero and via lactation.
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.
authors.affiliation: Laboratory of Environmental Health Sciences, Center for Disease Biology and Integrative Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
authors.forename: Toshihiro
authors.initials: T
authors.lastname: Endo
authors.forename: Masaki
authors.initials: M
authors.lastname: Kakeyama
authors.forename: Yukari
authors.initials: Y
authors.lastname: Uemura
authors.forename: Asahi
authors.initials: A
authors.lastname: Haijima
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Okuno
authors.forename: Haruhiko
authors.initials: H
authors.lastname: Bito
authors.forename: Chiharu
authors.initials: C
authors.lastname: Tohyama
mesh_terms: D000679:Amygdala / Q000187:drug effects / Q000378:metabolism; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects*; D003598:Cytoskeletal Proteins / Q000378:metabolism; D004785:Environmental Pollutants / Q000494:pharmacology*; D056344:Executive Function / Q000187:drug effects*; D005260:Female; D007774:Lactation; D051379:Mice; D009419:Nerve Tissue Proteins / Q000378:metabolism; D000072317:Polychlorinated Dibenzodioxins / Q000494:pharmacology*; D017397:Prefrontal Cortex / Q000187:drug effects / Q000378:metabolism; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects; D012919:Social Behavior; D013239:Stereotyped Behavior / Q000187:drug effects
chemical_list: D003598:Cytoskeletal Proteins; D004785:Environmental Pollutants; D009419:Nerve Tissue Proteins; D000072317:Polychlorinated Dibenzodioxins; C092069:activity regulated cytoskeletal-associated protein