Fetal exposure to 2,3,7,8‐tetrachlorodibenzo‐p‐dioxin transactivates aryl hydrocarbon receptor‐responsive element III in the tyrosine hydroxylase immunoreactive neurons of the mouse midbrain

Abstract

Fetal exposure to dioxins and related compounds is known to disrupt normal development of the midbrain dopaminergic system, which regulates behavior, cognition and emotion. The toxicity of these chemicals is mediated mainly by aryl hydrocarbon receptor (AhR) signaling. Previously, we identified a novel binding motif of AhR, the AhR-responsive element III (AHRE-III), in vitro. This motif is located upstream from the gene encoding tyrosine hydroxylase (TH), the rate-limiting enzyme of dopamine biosynthesis. To provide in vivo evidence, we investigated whether 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) could regulate AHRE-III transcriptional activity in midbrain dopaminergic neurons. We produced transgenic mice with inserted constructs of the AHRE-III enhancers, TH gene promoter and the c-myc-tagged luciferase gene. Single oral administrations of TCDD (0-2000 ng kg⁻¹ body weight) to the transgenic dams markedly enhanced TH-immunoreactive (ir) intensity in the A9, A10 and A8 areas of their offspring at 3 days and 8 weeks of age. The offspring of dams treated with 200 ng kg⁻¹ TCDD exhibited significant increases in the numbers of TH- and double (TH and c-myc)-ir neurons in area A9 compared with controls at 8 weeks. These results show that fetal exposure to TCDD upregulates TH expression and increases TH-ir neurons in the midbrain. Moreover, the results suggest that TCDD directly transactivates the TH promoter via the AhR-AHRE-III-mediated pathway in area A9. Fetal exposure to TCDD caused stable upregulation of TH via the AhR-AHRE-III signaling pathway and overgrowth of TH-ir neurons in the midbrain, implying possible involvement in the etiology of neurodevelopmental disorders such as attention-deficit/hyperactivity disorder (ADHD).

Insight into the Mechanism of Reproductive Dysfunction Caused by Neonicotinoid Pesticides

“…9) Moreover, fetal exposure to TCDD caused stable upregulation of tyrosine hydroxylase (TH) via a novel binding motif of aryl hydrocarbon receptor (AhR), AhR-responsive element III (AHRE-III), which we identified via the signaling pathway and overgrowth of TH-immunoreactive (ir) neurons in the midbrain, implying possible involvement in the etiology of neurodevelopmental disorders such as attention-deficit/hyperactivity disorder (ADHD). 10,11) Thus, our data could serve as a basis for future follow-up investigations in the field of EDCs.…”

Delayed effects of developmental exposure to low levels of the aryl hydrocarbon receptor agonist 3,3′,4,4′,5-pentachlorobiphenyl (PCB126) on adult zebrafish behavior

“…Early exposure of zebrafish embryos to environmentally relevant concentrations of dioxin resulted in reduced brain volume and decreased expression of neurodevelopmental genes in larvae (Hill et al, 2003). In rodents, gestational exposure to dioxin causes AHR-dependent abnormal development in a number of areas in the brain, including the cerebellum, hippocampus, the midbrain and the early region of the forebrain that matures to control advanced brain functions (Collins et al, 2008, Latchney et al, 2013, Tanida et al, 2014, Williamson et al, 2005). These abnormalities often involve changes in neuronal development and establishment of neuron cell fate (Gohlke et al, 2009, Hays et al, 2002, Latchney et al, 2013, Nguyen et al, 2013b).…”

Endocrine-disrupting actions of PCBs on brain development and social and reproductive behaviors

“…Alternatively, cells throughout the striatum, cortex, and hippocampus express estrogen and androgen receptors, and therefore could be sites of direct action of NDL PCBs. Midbrain dopaminergic cells also express AhR, making them a direct target of DL congeners [100]. These sensitivities could serve to alter cellular function or even induce neurotoxic effects [101,102].…”