Disruption in Thyroid Signaling Pathway: A Mechanism for the Effect of Endocrine-Disrupting Chemicals on Child Neurodevelopment

Abstract

Thyroid hormones are crucial in normal brain development. Transient and mild thyroid hormone insufficiency in pregnancy is also associated with impaired neurodevelopment in the offspring (e.g., 3–4 IQ score loss in association with maternal free thyroxine in the lowest fifth percentile). While inadequate iodine intake remains the most common underlying cause of mild thyroid hormone insufficiency in vulnerable populations including pregnant women, other factors such as exposure to environmental contaminants have recently attracted increasing attention, in particular in interaction with iodine deficiency. Endocrine-disrupting chemicals (EDCs) are natural and synthetic substances with ubiquitous exposure in children and adults including pregnant women. EDCs interfere, temporarily or permanently, with hormonal signaling pathways in the endocrine system by binding to hormone receptors and modifying gene expression. Other mechanisms involve alterations in production, metabolism, and transfer of hormones. Experimental studies have shown that exposures to EDCs affect various brain processes such as neurogenesis, neural differentiation and migration, as well as neural connectivity. Neuroimaging studies confirm brain morphological abnormalities (e.g., cortical thinning) consistent with neurodevelopmental impairments as a result of EDC exposures at standard use levels. In this review, we provide an overview of present findings from toxicological and human studies on the anti-thyroid effect of EDCs with a specific attention to fetal and early childhood exposure. This brief overview highlights the need for additional multidisciplinary studies with a focus on thyroid disruption as an underlying mechanism for developmental neurotoxicity of EDC, which can provide insight into modifiable risk factors of developmental delays in children.

Occurrence of chemicals with known or suspected endocrine disrupting activity in drinking water, groundwater and surface water, Austria 2017/2018

“…There is growing evidence that EDCs can disrupt thyroid homeostasis, even though the most important knowledge on this topic derives from animal studies, while clinical studies are still few and controversial (Gore et al, 2015). All the substance groups investigated are suspected of having anti-thyroid effects in some way, with specific attention to fetal and early childhood exposure, potentially affecting various brain processes such as neurogenesis, neural differentiation and migration, as well as neural connectivity, leading to morphological brain abnormalities (e.g., cortical thinning) consistent with neurodevelopmental impairment.…”

“…All the substance groups investigated are suspected of having anti-thyroid effects in some way, with specific attention to fetal and early childhood exposure, potentially affecting various brain processes such as neurogenesis, neural differentiation and migration, as well as neural connectivity, leading to morphological brain abnormalities (e.g., cortical thinning) consistent with neurodevelopmental impairment. Ghassabian and Trasande (2018) describe the following in a review: a) Experimental studies have shown that PBDEs, at environmentally relevant doses, bind to receptors, inhibit binding of triiodothyronine (T3) to thyroid hormone receptors (TRs) and suppress T3 actions; b) In vivo, bisphenol A can impair thyroid hormone action by antagonizing T3-induced TR activation (TRα1 and TRβ1) and by suppressing its transcriptional activity in a dose-dependent manner; c) Triclosan affects thyroid hormone-dependent metamorphosis in animals; d) Urinary phthalates are crosssectionally associated with lower free thyroxine (fT4) and higher thyroid stimulating hormone (TSH); e) PFASs interfere with binding of thyroid hormone to transthyretin and upregulate deiodinase in the thyroid gland. Thyroid disruption is of particular interest because several EDCs interfere with thyroid function in a sex-specific manner, which might explain the sexual dimorphism in the brain effect of EDCs (de Cock et al, 2014).…”

Decoding the multimorbidities among psychiatric disorders and cognitive functioning

“…This is epitomized by hypo and hyperthyroidism, where altered thyroid hormone supplies cause changes in brain functioning, leading to psychiatric disorders (e.g. SCZ, BD, anxiety and depression) 27,40 . Interestingly, we found common pathways associated with thyroid hormone functioning (e.g.…”

“…thyroid hormone signalling pathway) across all six phenotypes. Dysregulation and imbalanced gene expression within this pathway may be associated with impaired neurodevelopment 40 .…”

Possible consequences of early exposure to endocrine disruptors

“…PCB-u) te nekim metalima (olovo, živa) utječe na razvoj neuroendokrinog sustava (3,41), što su pokazala istraživanja na životinjama. Kod djece se također povezuje izloženost ED-u s poremećajima kognitivnih sposobnosti i poremećajima ponašanja, primjerice smanjenim kvocijentom inteligencije, smanjenim pamćenjem, pojavom poremećaja iz autističnog spektra ili poremećaja pozornosti s hiperaktivnošću (4,8,42). Fitoestrogeni iz soje ili iz sojinog mlijeka mogu utjecati na neuroendokrini razvoj (38).…”