Mixtures measured in human, disrupt thyroid hormone signaling and behavior in Xenopus laevis
Résumé
Endocrine disrupting chemicals (EDCs) harm human health both as single
molecules and as mixtures. Most research on EDCs is done on individual
chemicals whereas we are exposed to mixtures of numerous and possibly
interacting molecules. This discrepancy presents a dilemma for risk assessment
and legislation. Thyroid hormones are essential for normal brain development
where they influence, through specific embryonic and post-natal periods all the
steps of brain development. In adults, TH roles are essential to brain function and
to general metabolism (thermogenesis, fat burning, etc.). As number of
compounds produced by chemical industries increased by 300 fold since the
70’s, and many reports in the scientific literature show that many of these
chemicals are potential Endocrine disruptors (EDCs) we questioned the thyroid
hormone disrupting effect of common chemicals. We hypothesized that this axis
could be a key target for disruption and hence alter normal brain development. To
test this hypothesis, we used a thyroid disruptor screening assay, the Xenopus
Embryonic Thyroid Assay (XETA), RT-qPCR on brain tissue, and behavior
analysis. We used to independent strategies with different mixtures from human
data. First we recreated m a mixture of 15 compounds commonly found in Human
beings and tested them at the concentration meassured in amniotic fluid and study
the effects on thyroid hormone signaling and adverse effects on our tadpole
model. Second, a novel approach, developed within the European project, EDCMixRisk, was to classify adverse mixtures of chemicals found in population based
on epidemiological studies and test their EDC potential with both in vivo and
in vitro assays. Samples from about 2,000 pregnant women were examined and
retrospective analysis on offspring identified a chemical mixture for which
embryonic exposure was associated with language delay, an indication for
neurodevelopmental delay. Results on the two kind of mixtures show significant
modification of TH availability (XETA assay) at the actual mixture concentration
found in fluids of pregnant women. Second, mRNA levels of key genes involved
the TH-signaling pathway showed significant alteration of TH-dependent genes at
the accrual exposure level. Finally, mixtures were found to alter tadpoles’mobility
behavior. Taken together, these results show advantages of using different
strategies and necessity to take into consideration mixture in both experimental
studies and risk assessment.