A possible mechanism for the decrease in serum thyroxine level by a 2,3,7,8-tetrachlorodibenzo-p-dioxin-like...

Area of Science:

• Environmental Toxicology
• Endocrinology
• Pharmacology

Background:

• Polychlorinated biphenyls (PCBs) are environmental contaminants with known toxic effects.
• Thyroxine (T4) is a crucial thyroid hormone regulating metabolism.
• Differential sensitivity to toxic compounds exists between mouse strains.

Purpose of the Study:

• To investigate the mechanism by which 3,3',4,4',5-pentachlorobiphenyl (CB126) affects serum thyroxine (T4) levels.
• To compare the effects of CB126 on T4 metabolism in TCDD-sensitive and TCDD-resistant mice.

Main Methods:

• Administration of CB126 to C57BL/6 (TCDD-sensitive) and DBA/2 (TCDD-resistant) mice.
• Measurement of serum total and free T4 levels.
• Assay of hepatic T4-UDP-glucuronosyltransferase (T4-UGT) activity.
• Analysis of biliary excretion and serum clearance of radiolabeled T4.
• Assessment of liver weight and hepatic T4 accumulation.

Main Results:

• CB126 significantly decreased serum T4 levels in C57BL/6 mice but not in DBA/2 mice.
• Hepatic T4-UGT activity and T4 glucuronidation were significantly increased by CB126 in C57BL/6 mice.
• CB126 enhanced serum T4 clearance and biliary excretion of T4 glucuronide in C57BL/6 mice.
• Liver hypertrophy was observed in CB126-treated C57BL/6 mice, leading to increased hepatic T4 accumulation.

Conclusions:

• CB126-induced decrease in serum T4 is mediated by increased hepatic T4-UGT activity and enhanced T4 metabolism.
• Liver hypertrophy contributes to the altered T4 homeostasis observed in CB126-exposed sensitive mice.
• Mouse strain sensitivity plays a critical role in the toxicological response to CB126 regarding thyroid hormone disruption.