Recent developments in the investigation of thyroid regulation and thyroid carcinogenesis.

Abstract

This review covers new mechanistic information spanning the past 10 years relevant to normal and abnormal thyroid growth and function that may assist in the risk assessment of chemicals inducing thyroid follicular cell neoplasia. Recent studies have shown that thyroid regulation occurs via a complex interactive network mediated through several different messenger systems. Increased thyroid-stimulating hormone (TSH) levels activate the signal transduction pathways to stimulate growth and differentiation of the follicular cell. The important role of TSH in growth as well as in function helps to explain how disruptions in the thyroid-pituitary axis may influence thyroid neoplasia in rodents. New investigations that couple mechanistic studies with information from animal cancer bioassays (e. g., sulfamethazine studies) confirm the linkage between prolonged disruption of the thyroid-pituitary axis and thyroid neoplasia. New initiation/promotion studies in rodents also support the concept that chronic stimulation of the thyroid induced by goitrogens can result in thyroid tumors. Some of these studies confirm previous suggestions regarding the importance of chemically induced thyroid peroxidase inhibition and the inhibition of 3,3',5, 5'-tetraiodothyronine (T4, thyroxine) deiodinases on disruption of the thyroid-pituitary axis leading to thyroid neoplasia. Some comparative physiologic and mechanistic data highlight certain differences between rodents and humans that could be expected to confer an increased vulnerability of rodents to chronic hypersecretion of TSH. New data from epidemiologic and molecular genetic studies in humans contribute further to an understanding of thyroid neoplasia. Acute exposure to ionizing radiation, especially in childhood, remains the only verified cause of thyroid carcinogenesis in humans. Iodine deficiency studies as a whole remain inconclusive, even though several new studies in humans examine the role of dietary iodine deficiency in thyroid cancer. Specific alterations in gene expression have been identified in human thyroid neoplasia, linked to tumor phenotype, and thus oncogene activation and tumor-suppressor gene inactivation may also be factors in the development and progression of thyroid cancer in humans. An analysis by the U.S. EPA Risk Assessment Forum, prepared as a draft report in 1988 and completed in 1997, focused on the use of a threshold for risk assessment of thyroid follicular tumors. New studies, involving several chemicals, provide further support that there will be no antithyroid activity until critical intracellular concentrations are reached. Thus, for chemically induced thyroid neoplasia linked to disruptions in the thyroid-pituitary axis, a practical threshold for thyroid cancer would be expected. More information on thyroid autoregulation, the role of oncogene mutations and growth factors, and studies directly linking persistently high TSH levels with the sequential cellular development of thyroid follicular cell neoplasia would provide further confirmation.

Aberrant activation of ubiquitin D at G₂ phase and apoptosis by carcinogens that evoke cell proliferation after 28-day administration in rats

“…The hypothyroidismrelated mechanism of SDM involves a decrease in the serum levels of thyroid hormone causing suppression of negative feedback through the pituitary and an increase in serum thyroid-stimulating hormone (TSH) in rats (Imai et al, 2004). TSH then stimulates thyroid functions, including growth and proliferation of follicular cells as a link to carcinogenesis (Hard, 1998). PEITC activates cell proliferation of the urothelium early after administration due to cytotoxic oxidative DNA damage (Akagi et al, 2003).…”

Obesity and thyroid cancer

“…In addition to the association between TSH and BMI, there is a clinical association between higher serum TSH levels and an increased risk of malignancy in human thyroid nodules (Fiore & Vitti 2012) and advanced stage of the disease (McLeod et al 2013). As TSH is the major stimulator of thyrocyte proliferation, this hormone could be directly involved in thyroid carcinogenesis in obese subjects (Hard 1998). In fact, the binding of TSH to its receptor (TSHR) increases the intracellular levels of cAMP and activates proliferation pathways, including PI3K-AKT and RAS-BRAF pathways (Takada et al 1990, Xing 2013.…”

“…TSH also interacts with other growth factors such as insulin (Rapp et al 2006). In IR, a clinical condition frequently present in obesity, insulin stimulates TSH production promoting proliferation of thyroid cancer cells (Hard 1998, Hursting et al 2008. Based on the important role of TSH in thyroid cell proliferation, a recent study has evaluated the serum TSH levels in two mouse groups that spontaneously develop thyroid cancer: one fed on a high-fat diet and another on a low-fat diet.…”

Risk factors for thyroid cancer: A prospective cohort study

“…However, given that the incidence of thyroid cancer is consistently higher in women than in men 3,4 and the finding that estrogen receptors are present in papillary and follicular thyroid carcinomas (the 2 major histologic subtypes of thyroid cancer), 4 it has been hypothesized that hormonal factors may be involved in the etiology of thyroid cancer. Furthermore, there is experimental evidence that elevated thyroid-stimulating hormone (TSH) levels may play a role in the development of thyroid carcinomas [5][6][7][8][9] and epidemiologic evidence that smoking [10][11][12][13] and alcohol consumption 14 may be inversely associated with TSH production, which suggests that they might be inversely associated with thyroid cancer risk.…”