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Author Spotlight: In Vivo Assessment of Thyroid Hormone Disruption Using the THAI Mouse Model
Published on: October 6, 2023
The PI3K/Akt and ERK pathways elevate thyroid hormone receptor β1 and TRH receptor to decrease thyroid hormones after
Changjiang Liu1, Lianbing Li2, Mei Ha3
1MOE Key Lab of Environment and Health, Department of Occupational and Environmental Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, PR China; Key Lab of Birth Defects and Reproductive Health of National Health and Family Planning Commission, Chongqing Population and Family Planning Science and Technology Research Institute, Chongqing 400020, PR China.
Abstract:
PCBs and DDT cause the disturbance of thyroid hormone (TH) homeostasis in humans and animals. To test the hypothesis that the PI3K/Akt and MAPK pathways would play significant roles in TH imbalance caused by PCBs and DDT, Sprague-Dawley rats were dosed with PCB153 and p,p'-DDE intraperitoneally for 5 consecutive days, and human thyroid follicular epithelial (Nthy-ori 3-1 cell line) were treated with PCB153 and p,p'-DDE for different time. Results showed that serum total thyroxine (TT4), free thyroxine (FT4), total triiodothyronine (TT3) and thyroid stimulating hormone (TSH) were decreased, whereas serum free triiodothyronine (FT3) and thyrotropin releasing hormone (TRH) were not changed. The PI3K/Akt and ERK pathways were activated in vivo and in vitro after the treatment with PCB153 and p,p'-DDE. Moreover, TH receptor β1 (TRβ1) was elevated after the activation of the PI3K/Akt pathway and was depressed after the inhibition of the PI3K/Akt pathway; TRH receptor (TRHr) was increased after the activation of the ERK pathway and was decreased after the inhibition of the ERK pathway. Though TH receptor α1 (TRα1) level was increased in the hypothalamus, TRα1 and TSHr were not influenced by the status of signaling pathways in in vitro study. Taken together, after exposure to PCB153 and p,p'-DDE, activated PI3K/Akt and ERK pathways disrupt the hypothalamic-pituitary-thyroid (HPT) axis via TRβ1 and TRHr and then decrease TH levels, and that would be a potential mechanism by which PCBs and DDT disturb TH homeostasis.
Insights
Polychlorinated biphenyls (PCBs) and DDT disrupt thyroid hormone (TH) homeostasis by activating PI3K/Akt and ERK pathways. These pathways alter TH receptors, disrupting the hypothalamic-pituitary-thyroid axis and lowering TH levels.
Area of Science:
- Environmental Toxicology
- Endocrinology
- Molecular Biology
Background:
- PCBs and DDT are environmental contaminants known to disrupt thyroid hormone (TH) homeostasis in humans and animals.
- The precise molecular mechanisms underlying TH imbalance induced by these pollutants are not fully understood.
- Signaling pathways like PI3K/Akt and MAPK are implicated in cellular responses to environmental stressors.
Purpose of the Study:
- To investigate the role of PI3K/Akt and MAPK pathways in TH imbalance caused by PCB153 and p,p'-DDE exposure.
- To elucidate the molecular mechanisms by which these signaling pathways mediate the disruption of the hypothalamic-pituitary-thyroid (HPT) axis.
Main Methods:
- Sprague-Dawley rats were administered PCB153 and p,p'-DDE intraperitoneally for five consecutive days.
- Human thyroid follicular epithelial cells (Nthy-ori 3-1) were treated with PCB153 and p,p'-DDE in vitro.
- Serum levels of thyroid hormones (TT4, FT4, TT3, FT3) and pituitary/hypothalamic hormones (TSH, TRH) were measured.
- Activation of PI3K/Akt and ERK pathways, and expression of TH receptors (TRβ1, TRα1) and TRH receptor (TRHr) were analyzed.
Main Results:
- Exposure to PCB153 and p,p'-DDE decreased serum TT4, FT4, TT3, and TSH levels.
- The PI3K/Akt and ERK pathways were activated both in vivo and in vitro following exposure.
- Activated PI3K/Akt pathway led to elevated TRβ1, while activated ERK pathway increased TRHr expression.
- Inhibition of PI3K/Akt decreased TRβ1, and inhibition of ERK decreased TRHr, confirming pathway involvement.
Conclusions:
- Activated PI3K/Akt and ERK signaling pathways are key mediators in the disruption of the HPT axis by PCBs and DDT.
- These pathways influence TH homeostasis by modulating the expression of TRβ1 and TRHr.
- The findings suggest a potential molecular mechanism for how PCBs and DDT disturb thyroid hormone balance.
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