## 4 Discussion
### Global and Regional Brain Volume Alterations Associated with Estimated Perinatal Dixxin Exposure  
Our results indicate that perinatal dioxin exposure, which was estimated on the basis of the mother's residency in Bien Hoa during pregnancy, was significantly associated with increased global gray matter volume, total brain volume, and total intracranial volume. To our knowledge, no previous study has investigated the effects of perinatal dioxin exposure on structural brain changes in humans. Although some previous animal studies reported reduced cortical thickness in several brain areas and changes in cortical cell numbers and cell distributions in TCDD-exposed rats [29; 30], recent animal studies suggest that dioxins in low doses may lead to neuronal dendritic overgrowth [22; 24], which may in turn lead to increases in brain volume.  
Our previous study found that perinatal TCDD exposure increased autistic traits in Vietnamese children [5]. It was also reported that Vietnamese children perinatally exposed to dioxin showed disturbed mirror neuron activity [31], which is one of the social cognitive deficits present in autism. Moreover, extensive studies have reported brain enlargement in children [32; 33; 34], adolescents, and adults with autism [35; 36]. In a VBM study of 833 children and adults, [PERSON] et al. (2017) recognized higher total brain volume and gray matter volume of approximately 1-2% in the ASD group compared with the typically-developing group [11]. Consistently, an animal model of autism showed dendritic overgrowth [37]. These similar results (increased brain volume) suggest that perinatal dioxin exposure and autism may share a similar pathogenesis: dendritic overgrowth could be a cause of pathogenesis resulting in brain enlargement and cognitive deficits.  
Additionally, to identify regional gray matter abnormalities in men subjected to perinatal dioxin exposure, we applied VBM analysis. After adjusting for total intracranial volume and age, this analysis showed regional gray matter volume reduction in the left IFG pars orbitalis compared with a group without such exposure. The IFG pars orbitalis is important in the comprehension of emotional signals and semantic communication in humans [38]. [PERSON] et al. (2003) reported abnormality of orbitofrontal cortical volume in adolescents with ASD [39]. Furthermore, we also reported that dioxin exposure was associated with attention deficit hyperactivity disorder (ADHD) traits in Vietnamese children [40]. Several studies in ADHD children also demonstrated reduced gray matter volume in the left orbitofrontal cortex relative to healthy children [41; 42]. Volume reduction of the left IFG pars orbitalis may be associated with symptoms of inattention and/or impulsivity in ADHD [42]. Taking these findings together, perinatal dioxin exposure may increase total gray matter volume as well as total brain volume, and may also decrease gray matter volume in the IFG pars orbitalis, suggesting that perinatal dioxin exposure affects cognitive and social functions by altering global and local brain development, leading to adverse neurodevelopment and traits, such as ASD and ADHD.