Cefic-lri Programme | European Chemical Industry Council

EMSG59 – Developing a quantitative AOP for liver-mediated thyroid modulation after prenatal exposure to a xenobiotic compound in the rat

Principal Investigator

Pr Aldert Piersma
RIVM National Institute for Public Health and the Environment
Leeuwenhoeklaan 9
3720BA Bilthoven
The Netherlands
Tel. +31302742526


Manon Beekhuijzen, Charles River Laboratories, Den Bosch, NL, manon.beekhuijzen@crl.com

Dr Timo Hamers, Vrije Universiteit Amsterdam, NL, timo.hamers@vu.nl

Dr Anita Boelen, Amsterdam UMC, NL, a.boelen@amc.uva.nl


This project aims at understanding the consequences of chemical-induced changes in liver physiology on thyroid hormone balance and related adverse health effects. The project will focus on prenatal exposure and development of the foetus and new-born in the rat as the model species.

Many natural and synthetic chemicals are able to induce elevations in hepatic metabolism, typically manifesting as increased expression and activities of phase I and phase II enzymes.  In addition to increased metabolism of xenobiotics, such increases in hepatic enzyme activities may also result in elevated clearance of endogenous substances, including thyroid hormones.  This is particularly relevant for toxicology, as changes in thyroid hormone levels may subsequently lead to adverse effects in the thyroid itself and in a number of target tissues including the developing brain.

This project will concentrate on characterizing dose-response profiles for liver enzyme induction, thyroid hormones, and thyroid-related effects, in the rat model using Pregnenolone-16α-carbonitril (PCN), an anti-androgen that causes thyroid toxicity through a secondary, hepatic, mode of action. Exposure will be from gestation day 6 to 20 in the rat, fetal parameters will be measured on gestation day 21, and maternal and pup parameters will be monitored on postnatal day 21. We will use a wide dosage range in order to be able to compare dose-response profiles of all relevant parameters in detail. This information will be used to describe a quantitative adverse outcome pathway for liver-mediated thyroid toxicity. It will help us to understand what changes in liver metabolism should be considered relevant in terms of thyroid toxicity and downstream adverse health effects. A wealth of relevant tissues will be collected for further analysis in part 2 of the project. Besides blood, liver and thyroid, we will collect brain tissues, in order in part 2 to enable study of brain developmental effects that may be caused by disrupted thyroid homeostasis during pregnancy.

Timeline: March 2019 > August 2020

LRI funding: € 600 000

Cefic-Lri Programme Responsible Care

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