The pyriproxyfen metabolite 4’OH- pyriproxyfen disrupts thyroid hormone signaling and enhances Musashi-1 levels in neuroprogenitors

Spirhanzlova, P.; Le Mevel, S.; Wejaphikul, K.; Mughal, B.; Gothie, J.-D.; Sebillot, A.; Butruille, L.; Leemans, M.; Visser, T.; Remaud, S.; Fini, J.-B.; Demeneix, B.

doi:10.1101/352088

bioRxiv · 10.1101/352088

The pyriproxyfen metabolite 4’OH- pyriproxyfen disrupts thyroid hormone signaling and enhances Musashi-1 levels in neuroprogenitors

Spirhanzlova, P.·Le Mevel, S.·Wejaphikul, K.·Mughal, B.·Gothie, J.-D.·Sebillot, A.·Butruille, L.·Leemans, M.·Visser, T.·Remaud, S.·Fini, J.-B.·Demeneix, B.

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Abstract

Epidemiological and experimental studies have raised questions as to whether the insecticide pyriproxyfen (PPF) could be implicated in the increased incidence of microcephaly associated with ZIKA infection during pregnancy. This pesticide is documented as a thyroid hormone (TH) disrupting chemical. We investigated whether environmentally relevant amounts of its main metabolite, 4-OH-pyriproxyfen (4-OH-PPF), modified TH signaling and early neuronal development. First, an in silico study revealed strong affinity of 4-OH-PPF to fit the ligand binding pocket of TH receptors (TRs). Further, in vitro assays on human cell lines showed 4OH-PPF (> 3 mg/L) to act as a TR antagonist. Next, using a transgenic Xenopus TH-sensitive reporter system, Tg(thibz:GFP) tadpoles showed that 4OH-PPF (> 10-7 mg/L) displayed TH-disruptive activity and reduced tadpole mobility (> 10-1 mg/L). Exposure to 4OH-PPF significantly reduced Xenopus head size at levels equivalent to the maximum recommended daily intake of PPF (3x 10-1 mg/L). Most strikingly, in both the Xenopus system in vivo and in mouse neurosphere cultures, environmentally relevant concentrations of 4OH-PPF increased expression of the gene encoding an RNA-binding protein that enables ZIKA replication: Musashi-1 (msi1) in neurogenic brain areas. We conclude that first, the PPF metabolite, 4OH-PPF, disrupts thyroid signaling, neuronal development and behavior in Xenopus embryos, and second, that it increases Musashi-1 levels in neurogenic zones of both mouse and Xenopus, creating the potential to enhance viral replication. As PPF is used in areas with high microcephaly incidence and is readily broken down to 4OH-PPF, these findings provide a plausible mechanism whereby PPF could, through modulating expression of Musashi-1, exacerbate the effects of ZIKA virus infection.\n\n\n\nO_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=167 SRC=\"FIGDIR/small/352088_ufig1.gif\" ALT=\"Figure 1\">\nView larger version (23K):\norg.highwire.dtl.DTLVardef@12f397borg.highwire.dtl.DTLVardef@166bbdforg.highwire.dtl.DTLVardef@1b83665org.highwire.dtl.DTLVardef@fb5a30_HPS_FORMAT_FIGEXP M_FIG C_FIG

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Spirhanzlova, P., Le Mevel, S., Wejaphikul, K., Mughal, B., Gothie, J.-D., Sebillot, A., Butruille, L., Leemans, M., Visser, T., Remaud, S., Fini, J.-B., Demeneix, B.. 2018-06-27. The pyriproxyfen metabolite 4’OH- pyriproxyfen disrupts thyroid hormone signaling and enhances Musashi-1 levels in neuroprogenitors. https://doi.org/10.1101/352088

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