Developmental origin of abnormal dendritic growth in the mouse brain induced by in utero disruption of aryl hydrocarbon receptor signaling

Abstract

Increased prevalence of mental disorders cannot be solely attributed to genetic factors and is considered at least partly attributable to chemical exposure. Among various environmental chemicals, in utero and lactational dioxin exposure has been extensively studied and is known to induce higher brain function abnormalities in both humans and laboratory animals. However, how the perinatal dioxin exposure affects neuromorphological alterations has remained largely unknown. Therefore, in this study, we initially studied whether and how the over-expression of aryl hydrocarbon receptor (AhR), a dioxin receptor, would affect the dendritic growth in the hippocampus of the developing brain. Transfecting a constitutively active AhR plasmid into the hippocampus via in utero electroporation on gestational day (GD) 14 induced abnormal dendritic branch growth. Further, we observed that 14-day-old mice born to dams administered with 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD; dose: 0, 0.6, or 3.0 μg/kg) on GD 12.5 exhibited disrupted dendritic branch growth in both the hippocampus and amygdala. Finally, we observed that 16-month-old mice born to dams exposed to perinatal TCDD as described above exhibited significantly reduced spine densities. These results indicated that abnormal micromorphology observed in the developing brain may persist until adulthood and may induce abnormal higher brain function later in life.

Excessive activation of AhR signaling disrupts neuronal migration in the hippocampal CA1 region in the developing mouse

“…This observation is in agreement with our previous study (Kimura et al, 2015) that demonstrated abnormal dendritic morphology in the CA-AhRtransfected pyramidal neurons of the hippocampus in the developing mice from the same littermates as used in the present study. Thus, it is likely that disruption of neuronal migration induces abnormal dendritic morphology in the developing hippocampus.…”

“…AhR deletion mutant that lacks part of the ligand-binding domain functions as a CA-AhR that induces Cyp1a1 expression (Kimura et al, 2015). This CA-AhR cDNA fragment was amplified by PCR using the specific primers 5′-CTCGAGGCGGGCACCATGAGCAGCGGCGCCA -3′ and 5′-CTCGAGTCAACTCTGCACCTTGCT-3′ and pQCXIN-CA-AhR-EGFP (a kind gift from Dr. Yoshiaki Fujii-Kuriyama, then at the University of Tsukuba and Dr. Tomohiro Ito at the National Institute for Environmental Studies) as a template.…”

“…Pregnant mice underwent surgery and embryo manipulation in utero as previously described (Kimura et al, 2015;Nakajima, 2001, 2008;Tomita et al, 2011). Briefly, on gestational day (GD) 14, pregnant C57BL/6N mice were anesthetized with sodium pentobarbital (50 mg/kg b.w., ip) and laparotomized to expose the uterine horns.…”

“…Thus, it is reasonable to speculate that the disruption of AhR signaling impairs the molecular mechanisms that control neural circuit formation during development, which leads to behavioral abnormalities in adulthood. We previously reported that in utero and lactational TCDD exposure induces the expression of Class 3 Semaphorin genes, which regulate neurite outgrowth in the developing mammalian brain, and causes abnormal dendritic morphology in the developing mouse brain (Kimura et al, 2015(Kimura et al, , 2016. Additionally, CA-AhR transfected pyramidal neurons showed abnormal dendritic morphology in the hippocampal CA1 region (Kimura et al, 2015).…”

“…We previously reported that in utero and lactational TCDD exposure induces the expression of Class 3 Semaphorin genes, which regulate neurite outgrowth in the developing mammalian brain, and causes abnormal dendritic morphology in the developing mouse brain (Kimura et al, 2015(Kimura et al, , 2016. Additionally, CA-AhR transfected pyramidal neurons showed abnormal dendritic morphology in the hippocampal CA1 region (Kimura et al, 2015). However, the effect of AhR disruption on neuronal migration in the hippocampus remains unclear.…”