Most thyroid hormone system-disrupting chemicals cause T4 decreases without corresponding TSH changes in rodent modelsChemicals May Disrupt Thyroid Function in Ways Current Tests Miss

IntroductionIdentification of thyroid hormone system-disrupting chemicals (THSDC) requires a solid understanding of the mechanisms by which exposure leads to adverse outcomes in the thyroid hormone system (THS). MethodsIn this systematic review, we present the results from our extensive evidence mapping of thyroid hormone (TH) and thyroid stimulating hormone (TSH) patterns in serum or plasma, after exposure to various THSDCs in adult rodents. Following PRISMA guidelines, we systematically searched PubMed, Web of Sciences and Scopus for relevant studies. Eligible studies were selected according to predefined inclusion and exclusion criteria.ResultsOur review of 234 peer-reviewed studies revealed that only a small group of compounds induced changes in T4 and TSH consistent with the canonical view of the hypothalamic-pituitary-thyroid (HPT) negative feedback loop, whilst the most frequent pattern was a decrease in T4 without TSH changes. The lack of a TSH response may have been due to T4 decreases not being sufficient to change HPT feedback. However, risk of bias analysis also identified deficits in TH/TSH analytical methodology, including the timepoints of TH measurements, possibly explaining discrepancies between studies. We further compared T4/TSH patterns to mechanism-of-action information and other THS-related outcomes and found that THSDCs frequently affected TH synthesis, induced hepatic enzymes involved in TH metabolism, and exhibited other differences in pharmacokinetic properties. Given the diverse chemical nature of the various THSDCs and variety of molecular targets in the THS, there is likely no single explanation for the different patterns observed.ConclusionOur compilation of T4/TSH patterns observed after different chemical exposures demonstrated that it is important to not solely rely on the canonical serum hormonal patterns to determine adversity of chemical exposures. Chemicals with different responses should be carefully considered, as current regulatory criteria may fail to identify them as being harmful to human health.Systematic review registrationhttps://zenodo.org/records/5528557, identifier doi.org/10.5281/zenodo.5528557.