Thyroid follicular cells

Hurley, P. M., Hill, R, N., and W hiting, R. ]. (1998). Mode of carcinogenic action of pesticides inducing thyroid follicular cell tumors in rodents. Environ. Health Terspect. 106(8), 437-445. 

Figure 42-11. Model of iodide metabolism in the thyroid follicle. A follicular cell is shown facing the follicular lumen (top) and the extracellular space (at bottom). Iodide enters the thyroid primarily through a transporter (bottom left). Thyroid hormone synthesis occurs in the follicular space through a series of reactions, many of which are peroxidase-mediated. Thyroid hormones, stored in the colloid in the follicular space, are released from thyroglobulin by hydrolysis inside the thyroid cell. (Tgb, thyroglobulin MIT, monoiodotyrosine DIT, diiodotyro-sine Tj, triiodothyronine T4, tetraiodothyronine.) Asterisks indicate steps or processes that are inherited enzyme deficiencies which cause congenital goiter and often result in hypothyroidism.

Thyroid hormones. Internally, the thyroid consists of follicles, which are spherical structures with walls formed by a single layer of epithelial cells called follicular cells. The center of each follicle contains a homogenous gel referred to as colloid. Thyroid hormones are stored here as a component of the larger molecule, thyroglobulin. The amount of thyroid hormones stored within the colloid is enough to supply the body for 2 to 3 months. 

Inhibits, by acting as a competitor, the accumulation of 1 in thyroid follicular cells... 

Triiodothyronine is not classified as a thyroid inhibitor it is an amino acid derivative of thyronine and results from the oxidative coupling of monoiodotyrosyl and diiodotyrosyl residues. Iodine 131, the most often used radioisotope of I, is rapidly absorbed by the thyroid and is deposited in follicular colloid. Prom the site of its deposition, Bll causes fibrosis of the thyroid subsequent to pyknosis and necrosis of the follicular cells. 

The thyroid hormones thyroxine (T4) and triiodothyronine (T3) are formed on thyroglobulin, a large glycoprotein synthesized within the thyroid cell. Inorganic iodide enters the thyroid follicular cell and is oxidized by thyroid peroxidase and covalently bound (organified) to tyrosine residues of thyroglobulin. 

TCDD also causes thyroid tumours in male rats. This has been shown to proceed through a mechanism that involves altered thyroid hormone metabolism and consequent increases in feedback mechanisms, TSH (thyroid stimulating hormone), which results in a chronic proliferative stimulation of thyroid follicular cells. 

Hepatocellular neoplasia in mice Thyroid follicular-cell neoplasia in rats... 

Thyroxine synthesis begins when iodide (I-) is transferred from the blood stream to the thyroid follicle cell by an active ATP-driven membrane pump mechanism this process is stimulated by cAMP following TSH stimulation of the gland. Iodide is transported through the follicular cell and secreted into the lumen of the follicle where it is oxidized to iodine and incorporated in to tyrosine residues by the enzyme thyroid peroxidase (TPO). 

When the thyroid gland is stimulated to secrete thyroxine, a small piece of iodinated Tgb is taken from the lumen into a follicular cell, where the hormones are released from the protein. Both T3 and T4 are secreted from the vesicle directly into the bloodstream but the plasma concentration of T4 is substantially higher than that of T3. In contrast, T3 has a higher biological activity than T4 and conversion of T4 to T3 occurs at the target site. 

Osborne-Mendel rats were fed technical-grade heptachlor (73%) males received TWA doses of 1.94 and 3.9 mg/kg/day and females received TWA doses of 1.28 and 2.56 mg/kg/day for 80 weeks (NCI 1977). The results of this study showed a statistically significant increase in follicular cell neoplasms in the thyroid (adenomas and carcinomas) in females fed the high dose compared to controls. This finding was discounted by the investigators, however, because the incidence rates were low and are known to be variable in the control rat population. Rates of tumor incidences in males were not increased. 

Fig. 1 Thyroid hormone synthesis in a thyroid follicular cell. NIS and TPO (organification and coupling reaction) have been marked in red dashed line as the two main targets for direct thyroid gland function disrupters. DEHALl iodotyrosine dehalogenase 1, DIT diiodotyrosine, DUOX2 dual oxidase 2, MIT monoiodotyrosine, Na/K-ATPase sodium-potassium ATPase, NIS sodium-iodide symporter, PSD pendrin, TG thyroglobulin, TPO thyroperoxidase. Reprinted from [7] with permission from Elsevier...

There is no information existing about the exact stage when NIS and TPO, the two main targets for direct TGFD, become functional in zebrafish follicular cells. The presence of T4 in the first thyroid follicle at about 72 hpf suggests that both mechanisms are likely to be functional by that time. Moreover, exposing 48 hpf larvae... 

Spontaneous thyroid tumors derived from the thyroid follicular cell occur in l%-3% of laboratory rats (adenomas and carcinomas combined in a variety of strains of rats aged 2 or more years). 

In animal studies aldrin induced an increased incidence of hepatocellular carcinoma at two dietary doses in male mice the tumors showed a significant dose-response trend and were statistically significant at the high dose. Follicular cell tumors of the thyroid and adrenal cortical cell adenomas were increased in female rats in the low-dose group but not in the high-dose group the results could not be clearly associated with treatment. ... 

At dosages above 30mg/kg in the diet, chlordane interfered with reproduction in rats and mice, but this effect was reversible after exposure ceased." Pre- and postnatal exposures to chlordane altered the development of the immune system in rodents. A dose-related increase in the incidence of hepatocellular carcinomas was found in male and female mice fed approximately 60mg/k chlordane for 80 weeks. In rats, increases in the incidences of thyroid follicular cell neoplasms were observed. ... 

A recent study confirmed that ethylene thiourea was carcinogenic in male and female rats as shown by increased incidences of thyroid follicular cell neoplasms after treatment of up to 250 ppm in the diet for 2 years. In mice, concentrations ranging from 100 to 1000 ppm for 2 years caused liver and pituitary tumors in addition to thyroid tumors. Perinatal exposure up to 8 weeks followed by a control diet for 2 years was not carcinogenic in rats or mice. Combined perinatal-adult ETU exposures produced the same carcinogenic effects as adult-only exposures. 

Chronic oral exposure of rats and mice to MDA and its dihydrochloride is carcinogenic. Treatment-related increases in the incidences of thyroid follicular cell adenomas and hepatocellular neoplasms were observed in mice after chronic ingestion of MDA in drinking water. In rats, increases in the incidences of thyroid follicular cell carcinoma and hepatic nodules were observed in males and thyroid follicular cell ademonas occurred in females. Although not statistically significant, certain uncommon tumors such as bile duct adenomas, papillomas of the urinary bladder, and granulosa cell tumors of the ovary also were reported. These tumors are of low incidence in historical controls. In another report, MDA acted as a promoter of thyroid tumors in rats. °... 

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