Follicular Epithelial Cell Hypertrophy Induced by Chronic Oral Administration of 2,3,7,8-Tetrachlorodibenzo-p-Dioxin in Female Harlan Sprague—Dawley Rats

Metolachlor (2-chloro- N-(2-ethyl-6-methylphenyl)- N-(2-methoxy-1-methylethyl) acetamide) is widely used internationally as a corn and cotton herbicide. The metolachlor effects noted in rats during testing for U.S. pesticide registration include increased liver weight and hepatocarcinogenicity associated with eosinophilic foci. These properties, plus nongenotoxicity, are also characteristic of the prototypical rat liver tumor promoter, phenobarbital. Phenobarbital induces hepatic cytochrome P450s CYP2B1/2 and CYP3A1/2 and thyroxine (T4)-UDP-glucuronosyltransferase (T4-UGT), which enhances thyroxine clearance and thus indirectly increases thyroid gland activity. Because other chloroacetanilide herbicides are known to similarly affect rat thyroid gland, this study tested the hypothesis that metolachlor would have these additional phenobarbital-like effects on liver, especially that of T4-UGT induction with consequential stimulation of thyroid gland. Effects of metolachlor, fed to male Sprague-Dawley rats for 14 days at the carcinogenic dose of 3000 ppm, were compared to those of equimolar phenobarbital. Liver microsomal CYP2B1/2 and CYP3A1/2 were probed by immunoblotting and T4-UGT was measured enzymat-ically. Serum T4, triiodothyronine (T3), and thyroid-stimulating hormone (TSH) and thyroid follicular epithelial cell morphology and proliferation were used to assess thyroid gland activity. Metolachlor induced CYP2B1/2 and CYP3A1/2 proteins, but unlike phenobarbital, did not affect T4-UGT activity. In agreement, serum T4, T3, or TSH were unaffected by metolachlor. Also, no significant effects of metolachlor on thyroid gland morphology or follicular epithelial cell height or proliferation were observed. These data demonstrate that metolachlor is an inducer of hepatic CYP2B1/2 activity. But unlike the prototypical CYP2B1/2 inducer phenobarbital, metolachlor does not cause an increase in T4-glucuronidation and thyroid gland activation.

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Comparison of liver tumor frequencies after intermittent oral administration of different doses of N-nitrosopyrrolidine in Sprague-Dawley rats

Cancer Letters ◽

10.1016/0304-3835(85)90175-2 ◽

1985 ◽

Vol 26 (1) ◽

pp. 77-82

Author(s):

A. Hoos ◽

M. Habs ◽

D. Schmähl

Keyword(s):

Oral Administration ◽

Liver Tumor ◽

Sprague Dawley ◽

Sprague Dawley Rats ◽

Different Doses

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Basal Autophagy Deficiency Causes Thyroid Follicular Epithelial Cell Death in Mice

Endocrinology ◽

10.1210/en.2019-00312 ◽

2019 ◽

Vol 160 (9) ◽

pp. 2085-2092 ◽

Cited By ~ 3

Author(s):

Tomomi Kurashige ◽

Yasuyo Nakajima ◽

Mika Shimamura ◽

Mutsumi Matsuyama ◽

Masanobu Yamada ◽

...

Keyword(s):

Cell Death ◽

Epithelial Cell ◽

Gene Knockout ◽

Tissue Degeneration ◽

Serum T4 ◽

Follicular Epithelial Cell ◽

Thyroid Morphology ◽

And Function ◽

Cellular Components ◽

Follicular Epithelial

Abstract Autophagy is a catabolic process that involves the degradation of cellular components through the lysosomal machinery, relocating nutrients from unnecessary processes to more pivotal processes required for survival. It has been reported that systemic disruption of the Atg5 or Atg7 gene, a component of autophagy, is lethal and that its tissue-specific disruption causes tissue degeneration in several organs. However, the functional significance of autophagy in the thyroid glands remains unknown. Our preliminary data imply the possible involvement of dysfunctional autophagy in radiation-induced thyroid carcinogenesis. Therefore, we evaluated the effect of Atg5 gene knockout (KO) on thyroid morphology and function. To this end, Atg5flox/flox mice were crossed with TPO-Cre mice, yielding the thyroid follicular epithelial cell (thyrocyte)‒specific ATG5-deficient mice (Atg5thyr-KO/KO). Atg5 gene KO was confirmed by a lack of ATG5 expression, and disruption of autophagy was demonstrated by a decrease in microtubule-associated protein 1 light chain 3–II puncta and an increase in p62. Atg5thyr-KO/KO mice were born normally, and thyroid morphology, thyroid weights, and serum T4 and TSH levels were almost normal at 4 months. However, at 8 and 12 months, a decrease in the number of thyrocytes and an increase in TUNEL+-thyrocytes were observed in Atg5thyr-KO/KO mice even though thyroid function was still normal. The number of irregularly shaped (gourd-shaped) follicles was also increased. Excess oxidative stress was indicated by increased 8-hydroxy-2′-deoxyguanosine and 53BP1 foci in Atg5thyr-KO/KO mice. These data demonstrate that thyrocytes gradually undergo degradation/cell death in the absence of basal levels of autophagy, indicating that autophagy is critical for the quality control of thyrocytes.

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