The PI3K/Akt and ERK pathways elevate thyroid hormone receptor β1 and TRH receptor to decrease thyroid hormones after...

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.