Impact of Thyroid Hormone System Disrupting Chemicals on Brain Development

Impact of Thyroid Hormone System Disrupting Chemicals on Brain Development: A Multi-Omics Approach in Pregnant Rats and Their Offspring

N. Clavel Rolland 1*, Sonia Dagnino 2, P.-M. Vaysse 1, B. Gangadharan 1, C. Jaussely 1, F. Schorsch 1, T. Pourcher 2, O. Blanck 1

1 Bayer SAS, Sophia Antipolis, France,

2 Université Nice Côte d'Azur, Commissariat à l’Energie Atomique, Nice, France

*Corresponding author: nais.clavelrolland@bayer.com

Thyroid hormones (TH) play a crucial role in brain development, particularly during gestation and neonatal period. Thyroid Hormone System Disrupting Chemicals (THSDC), of natural or synthetic origin, can interfere with multiple molecular targets and alter key biological processes such as synthesis, regulation, or action of TH. These disruptions can lead to hormonal imbalances that may affect brain development 1. Exposure to these compounds raises major public health concerns for pregnant women and their offspring 2.

To improve our understanding of the mechanisms underlying thyroid disruption, this study investigates the effects of two compounds administered to pregnant rats from gestational day 6 to postnatal day 21:

• 5-propyl-2-thiouracil (PTU, 2.4 mg/kg/day), a well-characterized inhibitor of thyroid peroxidase and deiodinase I, enzymes essential for TH synthesis and regulation.

• pregnenolone-16α-carbonitrile (PCN, 300 mg/kg/day), a hepatic inducer of UDP-glucuronosyltransferases involved in TH metabolism.

The effects of these compounds were assessed through the analysis of parameters, including circulating and brain TH levels, hepatic enzyme activities, and histopathological alterations in dams and their offspring.

Our goal was to apply integrative multi-omics approaches (proteomics, metabolomics, and spatial transcriptomics) to key target organs (thyroid gland, liver, and brain). This strategy aimed to comprehensively characterize molecular perturbations and identify potential biomarkers of developmental neurotoxicity associated with thyroid disruption.

This study showed PTU treatment induced significant decrease in TH levels in dams and pups’ plasma. In pups, follicular cell hypertrophy in the thyroid was observed as well as specific brain lesions (periventricular heterotopia, persistence of external granular layer in cerebellum). PCN treatment induced no TH variation, but a TSH increase in dams. It also induced hepatic enzyme activity increase, and no toxic lesions in the pups’ brain. Comparative omics analysis of PTU and PCN exposure revealed distinct yet overlapping statistically significant omics signatures suggesting both shared and compound-specific mechanisms of toxicity.

References:

1. Alcaide Martin, A. & Mayerl, S. Local Thyroid Hormone Action in Brain Development. Int. J. Mol. Sci. 24, 12352 (2023).

2. Thompson, W. et al. Maternal thyroid hormone insufficiency during pregnancy and risk of neurodevelopmental disorders in offspring: A systematic review and meta‐analysis. Clin. Endocrinol. (Oxf.) 88, 575–584 (2018).

Keywords: Thyroid disruption, Neurodevelopmental toxicity, Multi-omics integration, Biomarkers, System-level toxicology