TCDD (2,3,7,8-tetrachlorodibenzo-p-dioxin) induces depression-like phenotype

Abstract

The etiology of major depressive disorder (MDD) remains poorly understood. Our previous studies suggest a role for the aryl hydrocarbon receptor (AhR) in depression. 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) is a toxic environmental contaminant, with a high AhR binding affinity, and an established benchmark for assessing AhR activity. Therefore, this study examined the effect of TCDD on depression-like behaviors. Female mice were fed standard chow or a high-fat diet (HFD) for 11 weeks, and their weight was recorded. Subsequently, they were tested for baseline sucrose preference and splash test grooming. Then, TCDD (0.1 µg/kg/day) or vehicle was administered orally for 28 days, and mice were examined for their sucrose preference and performances in the splash test, forced swim test (FST), and Morris water maze (MWM) task. TCDD significantly decreased sucrose preference, increased FST immobility time, and decreased groom time in chow-fed mice. HFD itself significantly reduced sucrose preference. However, TCDD significantly increased FST immobility time and decreased groom time in HFD-fed mice. A small decrease in bodyweight was observed only at the fourth week of daily TCDD administration in chow-fed mice, and no significant effects of TCDD on bodyweights were observed in HFD-fed mice. TCDD did not have a significant effect on spatial learning in the MWM. Thus, this study demonstrated that TCDD induces a depression-like state, and the effects were not due to gross lethal toxicity. This study further suggests that more studies should examine a possible role for AhR and AhR-active environmental pollutants in precipitating or worsening MDD.

Keywords: Aryl hydrocarbon receptor (AhR); Environmental pollutant; Major depression; Spatial learning.

Fig 1.. Illustrations of the experimental design.

HFD = high fat deit; SPT = sucrose preference test; Spl = Splash test; MWM = Morris water maze; FST = forced swim test.

Fig 2.. Effects on weight.

Female mice were fed for 11 weeks with regular chow diet or HFD before the start of the experiment. Weights were recorded weekly during the pre-feeding period and daily during the experimental period. There was a robust effect of HFD on weight, but very minimal effect of TCDD. A three-way repeated ANOVA revealed significant effects of diet (F(1, 28)=229.935, p<0.001) and time (F(10, 280)=75.719, p<0.001), and significant interactions between time and diet (F(10, 280)=37.107, p<0.01, and time and TCDD (F(10, 280)=2.159, p<0.05). (*) Bonferroni post hoc contrast indicates a significant difference from the Chow Vehicle experimental group (p<0.05); (ϕ) Bonferroni post hoc contrast indicates a significant difference from the HFD Vehicle experimental group (p<0.05); Results are presented as mean ± SEM.

Fig 3.. TCDD-induced depression-like behaviors.

Chow- and HFD-fed mice were administered with TCDD or vehicle. Depression-like behaviors were examined prior (BL = Baseline) following TCDD administration. (A) Sucrose preference: A three-way repeated ANOVA revealed significant effects of diet (F(1, 28)=40.701, p<0.001), TCDD (F(1, 28)=22.769, p<0.001), and time (F(2, 56)=7.307, p<0.01), and significant interactions between diet and TCDD (F(1, 28)=6.365, p<0.05), and time and TCDD (F(2, 56)=3.168, p<0.05). (B) Splash Test: A three-way repeated ANOVA revealed significant effects of diet (F(1, 28)=15.671, p<0.001), TCDD (F(1, 28)=20.569, p<0.001), and time (F(1,28)=59.747, p<0.001), and significant interactions between time and diet (F(1, 28)=29.206, p<0.001), and time and TCDD (F(1, 28)=41.946, p<0.001). (C) FST: A two-way ANOVA revealed significant effects of diet (F(1, 27)=10.860, p<0.01) and TCDD (F(1, 27)=138.223, p<0.001). (*) Bonferroni post hoc contrast indicates a significant difference from the Chow Vehicle experimental group (p<0.05); (ϕ) Bonferroni post hoc contrast indicates a significant difference from the HFD Vehicle experimental group (p<0.05); Results are presented as mean ± SEM. Circles, triangles, and diamonds are results from individual mouse.

Fig 4.. No significant effects of TCDD on spatial learning in the MWM task.

Chow-fed (A) and HFD-fed (B) mice were administered with TCDD or vehicle. Mice were examined for the time to locate a hidden platform on experimental days 15–19 and 24–25. A three-way repeated ANOVA revealed only a significant effects of time (F(6, 168)=57.997, p<0.001). Results are presented as mean ± SEM.