ATHENA – Assays for the identification of Thyroid Hormone axis-disrupting chemicals: Elaborating Novel Assessment strategies

Start date: 01 January 2019
End date: 31 December 2023
Project Coordinator: Prof. Dr. Andreas Kortenkamp (Brunel University)
Project Leader VU-Environment and Health: Dr. Timo Hamers

Funding: EU H2020 (Grant Agreement no. 825161)

INTRODUCTION TO THE RESEARCH PROJECT

ATHENA focuses on substances that disturb the thyroid hormone system. Apart from regulating many body functions in adult life, thyroid hormones are essential for healthy brain development during pregnancy and after birth. They control the division of neuronal cells, their proper development and migration. If the delivery of thyroid hormones to the baby’s brain is insufficient or disturbed, irreversible brain damage (manifesting as e.g. low IQ scores) may be the consequence. During the key stages of brain development, the foetus cannot yet produce thyroid hormones and is therefore entirely dependent on sufficient supply from the mother. However, some mothers are deficient in thyroid hormones, due to medical problems or to undersupply of iodine, a key component of thyroid hormones. Certain chemicals can also diminish the uptake of iodine into the thyroid (e.g. thiocyanates in cigarette smoke), whereas others can block hormone synthesis in the thyroid gland or displace the hormone from distributor proteins in the blood (e.g. flame retardant chemicals). If this happens during pregnancy, development of the baby’s brain may be compromised.

It is therefore essential that chemicals capable of disrupting thyroid hormone supply are detected before damage occurs. There are however serious gaps in our arsenal of test methods for identifying such chemicals. In particular, there is a lack of methods for finding chemicals that adversely affect brain development. Much is also to be done for method development to pinpoint disruption of thyroid hormone transport from the mother to the baby.

The ATHENA consortium will close these gaps by developing new methods for incorporation into existing international (OECD) test guidelines.

Read a more detailed background on the ATHENA project.

MAIN OBJECTIVES
The ATHENA project focuses on tests that can capture the consequences of maternal thyroid hormone deficiency on the developing brain. The main objectives are:

  1. To provide new test methods for chemicals that interfere with the delivery of thyroid hormones to the foetus across the placenta, the blood brain barrier and the blood brain cerebrospinal fluid barrier.
  2. To develop predictive methods (quantitative structure-activity relationships; QSARs) for the screening of large compound libraries and methods for capturing disruption of the local supply of thyroid hormone by inhibition of deiodinases, dehalogenases and cell membrane transporters.
  3. To construct networks of pathways for adverse neurodevelopmental effects. Based on such networks, we will deliver a comprehensive testing strategy that can protect from chemicals harmful to brain development in foetal life.
  4. To conceive strategies for the international harmonisation of screening, testing and hazard identification for thyroid hormone axis disrupting chemicals. ATHENA comprises world-leading endocrinologists, experts in endocrine disruption and experts in modelling brain function ex vivo who collectively will deliver a step change in thyroid disruptor testing.

DETAILS
VU is specifically involved in several tasks regarding test method development for transmembrane transport of thyroid hormones across the blood-cerebrospinal fluid barrier. In these tasks we collaborate with colleagues from Erasmus MC who study transmembrane transporters in other barriers, i.e. the placenta and the blood-brain barrier. VU’s specific tasks are:
  • To develop high-throughput-adaptive cell-based bioassays for transmembrane thyroid hormone transport
  • To identify the most important transcellular thyroid hormone transporters in the blood-cerebrospinal-fluid-barrier
  • To explore the role and importance of transthyretin in transport of thyroid hormone and thyroid hormone system disruptors across the placenta and the blood-cerebrospinal-fluid-barrier
Read more about ATHENA

COLLABORATIONS
The ATHENA project is carried out in collaboration with Andreas Kortenkamp, Olwenn Martin, Martin Scholze, Luigi Margiotta-Casaluci (Brunel University London, UK), Terje Svingen, Marta Axelstad, Eva Bay Wedeby, Sofie Christiansen (Danish Technical University, DK), Josef Köhrle, Kostja Renko, Harald Stachelscheid, Philipp Mergenthaler (Charité Universitätsmedizin Berlin, DE), Barbara Demeneix, Jean-Baptiste Fini, Sylvie Remaud (Centre National de la Recherche Scientifique (CNRS), FR), Robin Peeters, Henning Tiemeier, Tim Korevaar, Jan Danser, Edwin Visser, Marcel Meima (Erasmus University Medical Centre, NL), Thomas Zoeller, Ake Bergman (Örebro University, SE), David Du Pasquier, Andrew Tindall (Watchfrog, FR), Carl-Gustaf Bornehag (Karlstad University, SE), Johan Lindberg, Björn Platzack (RISE, SE).

STAFF INVOLVED IN THIS PROJECT
  • Dr. Timo Hamers (timo.hamers@vu.nl)
  • Prof. Dr. Majorie van Duursen
  • Prof. Dr. Marja Lamoree
  • Fabian Wagenaars (MSc)
  • Peter Cenijn