Thyroid-Disrupting Chemicals: Interpreting Upstream Biomarkers of Adverse Outcomes

Abstract

BackgroundThere is increasing evidence in humans and in experimental animals for a relationship between exposure to specific environmental chemicals and perturbations in levels of critically important thyroid hormones (THs). Identification and proper interpretation of these relationships are required for accurate assessment of risk to public health.ObjectivesWe review the role of TH in nervous system development and specific outcomes in adults, the impact of xenobiotics on thyroid signaling, the relationship between adverse outcomes of thyroid disruption and upstream causal biomarkers, and the societal implications of perturbations in thyroid signaling by xenobiotic chemicals.Data sourcesWe drew on an extensive body of epidemiologic, toxicologic, and mechanistic studies.Data synthesisTHs are critical for normal nervous system development, and decreased maternal TH levels are associated with adverse neuropsychological development in children. In adult humans, increased thyroid-stimulating hormone is associated with increased blood pressure and poorer blood lipid profiles, both risk factors for cardiovascular disease and death. These effects of thyroid suppression are observed even within the “normal” range for the population. Environmental chemicals may affect thyroid homeostasis by a number of mechanisms, and multiple chemicals have been identified that interfere with thyroid function by each of the identified mechanisms.ConclusionsIndividuals are potentially vulnerable to adverse effects as a consequence of exposure to thyroid-disrupting chemicals. Any degree of thyroid disruption that affects TH levels on a population basis should be considered a biomarker of adverse outcomes, which may have important societal outcomes.

Early weaning PCB 95 exposure alters the neonatal endocrine system: thyroid adipokine dysfunction

“…Collectively, results reported by many authors (Crofton & Zoeller 2005, Miller et al 2009, Patrick 2009, Grimm et al 2013 indicate the following mechanisms to be involved in the impairment of thyroid function by PCBs: i) PCBs may reduce the ability of THs to bind to the transport proteins (transthyretin) in the bloodstream; ii) PCBs may impair the proteolysis of thyroglobulin; iii) PCBs may activate the aryl hydrocarbon receptors (AhRs), resulting in the elevation of the concentrations of several hepatic enzymes, including uridine diphosphate glucuronyl transferases and sulfotransferases; iv) PCBs may activate phase II conjugation of T 4 (formation of T 4 -glucuronide (T 4 -G)), resulting in the elevation of biliary excretion of T 4 -G and reduction in the circulating concentration of T 4 , leading to hypothyroidism; v) PCBs may inhibit or upregulate the production of deiodinases that allow T 4 to be converted to T 3 ; and vi) PCBs may act as either an agonist or an antagonist at the site of the cellular TR, where they induce a partial dissociation of TR/retinoid X receptor (RXR) heterodimer complex from the TRE, resulting in the suppression of gene transcription. Although it is not clear which among these potential mechanisms are most important for mediating the effects of PCBs on the circulating concentrations of THs, it is likely that all are important to some extent in experimental models.…”

Waterborne exposure to PFOS causes disruption of the hypothalamus–pituitary–thyroid axis in zebrafish larvae

“…Given the key role of THs in normal development and physiological functions in vertebrates, it is important to identify environmental chemicals that may adversely affect thyroid function and/or TH signaling, and to evaluate their risk to animals and humans (Brucker-Davis, 1998). As such, several groups of chemicals, including polychlorinated biphenyls (PCBs) and their metabolites, dioxins, brominated flame retardants, phenols, phthalates and pesticides, have the potential for disturbing thyroid hormone homeostasis in fish, amphibians and mammals (reviewed by Boas et al, 2006;Miller et al, 2009).…”

Increased Risk for Obesity and Diabetes with Neurodegeneration in Developing Countries

“…Chronic diseases such as gall bladder disease and hypothyroidism has increased with the metabolic syndrome and gall bladder removal now closely related to NAFLD [157,158]. The slow metabolism of xenobiotics in individuals with insulin resistance [159] may lead to dysfunction of the thyroid and hypothyroidism is now involved with the progression to obesity and diabetes [160][161][162].…”