Polybrominated Diphenyl Ethers, Thyroid Hormones, and Risk of Papillary Thyroid Cancer
Thyroid cancer is the most common cancer of the endocrine system. The incidence of thyroid cancer has increased worldwide for decades in the general populations and in the US military personnel. Although emerging evidence indicates that exposure to polybrominated diphenyl ethers (PBDEs) is related to disruption of thyroid hormone homeostasis, the association between exposure to PBDEs and risk of thyroid cancer is still unclear. Additionally, mutations in genes coding for enzymes involved in regulation, metabolism, or functional activation of PBDEs and thyroid hormones could modify the PBDEs and thyroid hormones related risk of thyroid carcinogenesis. Using data from a nested case-control study including 742 pairs of papillary thyroid cancer (PTC) cases and individually matched controls with pre-diagnostic serum concentrations of PBDEs and thyroid hormones from the Department of Defense Serum Repository (DoDSR), we tested the hypothesis that exposure to elevated PBDEs increases the risk of PTC and the increased risk posed by PBDEs is through the disruption of thyroid hormones. We also investigated the effects of genetic variants in genes involved in metabolism/detoxification of PBDEs and thyroid hormones on the association between PBDEs, thyroid hormones, and risk of PTC. Results from this study suggested that exposure to BDE-28 and dysregulate serum levels of thyroid stimulating hormone (TSH) were associated with increased risk of PTC. This study also observed significantly nonmonotonic relationships between serum concentrations of BDE-153 and 2,2’,4,4’,5,5’-hexabromobiphenyl (BB-153) and serum levels of total triiodothyronine (TT3) and total thyroxine (TT4) in PTC cases, and between BDE-47, -100, and -153 in relation to free T4 (FT4) level in controls. However, results from the causal mediation analysis did not support the hypothesis that thyroid carcinogenesis of PBDEs is mainly operated through disruption of thyroid hormone homeostasis. Investigation on the genetic polymorphisms and gene-environment interactions suggested significant interactions between BDE-28 and single nucleotide variants (SNVs) on CYP2E1 rs7092584 and DIO2 rs12885300. Serum level of TSH also interacted with UGT1A rs1875263, DIO2 rs1288530, and UGT1A rs2011404. Findings of this study provides evidence to the link between exposure to PBDEs and risk of PTC, , which will promote further regulations on production and application of PBDEs. Also, there could be significant clinical implications to monitor and regulate thyroid hormone levels among the most susceptible populations. Results from the gene-environment interaction analysis provide novel evidence to understand the basis of the molecular biology behind the initiation and promotion of PTC. With further understanding the pathogenesis of PTC, as well as implementing appropriate regulation and intervention, it should be pursued to decrease the incidence of PTC in the public, and to reduce the health and economic burdens caused by thyroid cancer.