Evaluating thyroid hormone disruption: investigations of long-term neurodevelopmental effects in rats after perinatal exposure to perfluorohexane sulfonate (PFHxS)

Abstract

Thyroid hormones are critical for mammalian brain development. Thus, chemicals that can affect thyroid hormone signaling during pregnancy are of great concern. Perfluorohexane sulfonate (PFHxS) is a widespread environmental contaminant found in human serum, breastmilk, and other tissues, capable of lowering serum thyroxine (T4) in rats. Here, we investigated its effects on the thyroid system and neurodevelopment following maternal exposure from early gestation through lactation (0.05, 5 or 25 mg/kg/day PFHxS), alone or in combination with a mixture of 12 environmentally relevant endocrine disrupting compounds (EDmix). PFHxS lowered thyroid hormone levels in both dams and offspring in a dose-dependent manner, but did not change TSH levels, weight, histology, or expression of marker genes of the thyroid gland. No evidence of thyroid hormone-mediated neurobehavioral disruption in offspring was observed. Since human brain development appear very sensitive to low T4 levels, we maintain that PFHxS is of potential concern to human health. It is our view that current rodent models are not sufficiently sensitive to detect adverse neurodevelopmental effects of maternal and perinatal hypothyroxinemia and that we need to develop more sensitive brain-based markers or measurable metrics of thyroid hormone-dependent perturbations in brain development.

Thyroid Disrupting Effects of Old and New Generation PFAS

“…On the other hand, a study performed on dams exposed to PFHxS reported no statistically significant effects on thyroid gland weights and histopathology ( 54 ).…”

Hyperthyroidism in pregnancy: evidence and hypothesis in fetal programming and development

“…For example, the placentas of humans and rats show anatomical similarities with a discoid shape and hemochorial type of fetal-maternal interface, however, disparities exist regarding the histological structure and the function of the yolk sac ( 31 ). Finally, important considerations are on the assessment of brain development in humans and in experimental animals, respectively ( 32 ).…”

“…maze) can be evaluated ( Table 1 ). However, no measure of brain development in an experimental animal directly translates to IQ in humans ( 32 ). Furthermore, it is important to notice that many methodological considerations exist when the role of maternal thyroid disease in relation to fetal brain development is assessed in humans and in an experimental design.…”

“…Furthermore, it is important to notice that many methodological considerations exist when the role of maternal thyroid disease in relation to fetal brain development is assessed in humans and in an experimental design. In humans, the risk of confounding is a particular concern in observational designs ( 7 ), and in experimental animals it has recently been discussed that the currently available models may not be sensitive enough to detect the neurodevelopmental abnormalities associated with different degrees of abnormal maternal thyroid function ( 32 ).…”

Best Achievements in Translational and Basic Thyroidology in 2020

“…Chemicals that can affect thyroid hormone signaling during pregnancy are an important issue in this field [ 17 ], since thyroid hormones play a critical role in fetal development. Ramhoj et al [ 18 ] studied the effects of perfluorohexane sulfonate (PFHxS), a widely used environmental chemical found in breast milk, on fetal brain development. PFHxS has been proven to lower serum thyroxine in a rat model [ 19 ].…”