Towards a science-based testing strategy to identify maternal thyroid hormone imbalance and neurodevelopmental effects in the progeny—part III: how is substance-mediated thyroid hormone imbalance in pregnant/lactating rats or their progeny related to neurodevelopmental effects?

Prenatal test cohort of a modified rat comparative thyroid assay adding brain thyroid hormone measurements and histology but lowering group size appears able to detect disruption by sodium phenobarbital

“…Therefore, it apparently recommends separate blood collection from male and female offspring. However, previous reports demonstrated that no sex differences were detected at basal TH concentrations and chemical-induced suppressions in the serum and brain TH concentrations ( Gilbert and Sui, 2008 , O’Shaughnessy et al, 2018 , Marty et al, 2022 , Ford et al, 2023 ). Especially, this is likely in fetuses at an early gestation period because the majority of fetal TH comes from the dams via the placenta ( Bárez-López and Guadaño-Ferraz, 2017 ).…”

“…Overall, the present study suggests that lowering group size to 10 from 20 animals per group per cohort in the CTA appears able to detect TH disruption (approximately 20–30 % reduction) if fetal serum and brain TH concentrations are assessed. Such power should be acceptable based on the previous reports by Crofton in which a 50–60 % decrease in circulating T4 was needed to significantly impact hearing function in rats ( Crofton, 2004 ), and also a recent review ( Marty et al, 2022 ) that reported that thresholds of >60 %/>50 % (at top-/lower-dose groups) offspring serum T4 reduction indicate an increased likelihood for statistically significant neurodevelopmental effects based on analyses reported in many publications, including with amitrole ( Ramhøj et al, 2021 ), perchlorate ( Gilbert and Sui, 2008 ), perfluorohexane sulfonate ( Ramhøj et al, 2020 , Gilbert et al, 2021 ), Aroclor 1254 ( Crofton et al, 2000 ), and others.…”

“…In the present study with NaPB, no additional value of brain measurements over serum alone was observed for T4 assessment in GD20 fetuses (i.e., high correlation between serum T4 and brain T4 concentrations, consistent with the findings of control fetuses in a previous study ( Hassan et al, 2017 )), however, T3 assessment by brain measurement was improved (Supplemental Table 4), as the group size required to detect a 25 % reduction should be greater than 10 animals for serum and less than 10 animals for brain ( Table 3 ). Again, a recent review ( Marty et al, 2022 ) reported that thresholds of >20 % and statistically significant offspring serum T3 reduction indicate an increased likelihood for statistically significant neurodevelopmental effects based on analysis of many publications described above. On the other hand, there was a correlation between fetal brain T3 and T4 concentrations in the NaPB study, so it may not be necessary to measure fetal brain T3 concentrations when measuring brain T4.…”

Comparison of the sensitivity of histopathological and immunohistochemical analyses and blood hormone levels for early detection of antithyroid effects in rats treated with thyroid peroxidase inhibitors

“…Disturbance of thyroid hormone homeostasis is closely associated with adverse health effects. Exposure to thyroid hormone disruptors in humans contributes to an increased incidence of thyroid neoplasm (Foster et al, 2021; Macedo et al, 2023; Zimmermann & Galetti, 2015), and maternal hypothyroidism can alter brain structure and function in the offspring of humans and rats (Gilbert et al, 2022; Marty et al, 2022; Willoughby et al, 2014). Many chemicals act as thyroid hormone disruptors, including environmental chemicals such as perchlorates and phthalates and pharmaceuticals such as amiodarone and interferon (Calsolaro et al, 2017; Rizzo et al, 2017).…”

New approach methods to improve human health risk assessment of thyroid hormone system disruption–a PARC project

“…Deficiency in THs during these events can thus have profound and irreversible effects on the developing brain. Worryingly, many environmental chemicals have been shown to act as TH system disruptors and can thus potentially affect brain development with significant consequences for life-long cognition ( Gilbert et al, 2020 ; Marty et al, 2022 ). In this context, it is also important to consider the regulatory networks that finetune TH action in complex organisms.…”