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

Abstract

12Epidemiological and experimental studies have raised questions as to whether the insecticide 13 pyriproxyfen (PPF) could be implicated in the increased incidence of microcephaly associated 14 with ZIKA infection during pregnancy. This pesticide is documented as a thyroid hormone (TH) 15 disrupting chemical. We investigated whether environmentally relevant amounts of its main 16 metabolite, 4'-OH-pyriproxyfen (4'-OH-PPF), modified TH signaling and early neuronal 17 development. First, an in silico study revealed strong affinity of 4'-OH-PPF to fit the ligand 18 binding pocket of TH receptors (TRs). Further, in vitro assays on human cell lines showed 4'OH-19 PPF (> 3 mg/L ) to act as a TR antagonist. Next, using a transgenic Xenopus TH-sensitive 20 reporter system, Tg(thibz:GFP) tadpoles showed that 4'OH-PPF (> 10 -7 mg/L) displayed TH-21 disruptive activity and reduced tadpole mobility (> 10 -1 mg/L). Exposure to 4'OH-PPF 22 significantly reduced Xenopus head size at levels equivalent to the maximum recommended daily 23 intake of PPF (3x 10 -1 mg/L). Most strikingly, in both the Xenopus system in vivo and in mouse 24 neurosphere cultures, environmentally relevant concentrations of 4'OH-PPF increased expression 25 of the gene encoding an RNA-binding protein that enables ZIKA replication: Musashi-1 (msi1) in 26 neurogenic brain areas. We conclude that first, the PPF metabolite, 4'OH-PPF, disrupts thyroid 27 signaling, neuronal development and behavior in Xenopus embryos, and second, that it increases 28 Musashi-1 levels in neurogenic zones of both mouse and Xenopus, creating the potential to 29 enhance viral replication. As PPF is used in areas with high microcephaly incidence and is 30 readily broken down to 4'OH-PPF, these findings provide a plausible mechanism whereby PPF 31 could, through modulating expression of Musashi-1, exacerbate the effects of ZIKA virus 32 infection. 33

Pyriproxyfen Exposure Impairs Cognitive Parameters and Alters Cortisol Levels in Zebrafish

“…Despite its broad use, pyriproxyfen has been shown to affect the central nervous system. The main pyriproxyfen metabolite, 4'OH-pyriproxyfen, alters gene expression in mouse neurospheres cultures, indicating possible consequences on neurogenesis and brain morphology (Spirhanzlova et al, 2018). Moreover, rat pups chronically exposed to pyriproxyfen showed arhinencephaly and reduced brain weight (Evans et al, 2016).…”

Possible teratogenic and adults abnormalities induced by insecticide pyriproxyfen on non-target organisms

“…It is generally known that amphibian tadpoles are the most famous developmental stage for ecotoxicological contaminants among terrestrial amphibian adults (Yan et al, 2012). However, PPF is recognized as an interfering agent with thyroid hormones essential for amphibians' development and signaling (Spirhanzlova et al, 2018;Wegner and Stolt, 2005). Additionally, Ose et al, (2017) reported that there were no observed mortality rate and other adverse symptoms through recorded daily actions through the Nieuwkoop and Faber stage 51 of African clawed frog, Xenopus laevis, exposed to pure PPF.…”

“…Additionally, Ose et al, (2017) reported that there were no observed mortality rate and other adverse symptoms through recorded daily actions through the Nieuwkoop and Faber stage 51 of African clawed frog, Xenopus laevis, exposed to pure PPF. Spirhanzlova et al, (2018) claimed that low affinity binding activities of PPF to TRα1 on transgenic Tg (thibz:GFP) X. laevis tadpoles triggering the impacts of ecologically relevant concentrations of PPF and its primary metabolite (4′-OH-Pyr) on thyroid hormone signaling and early brain development exhibited their abnormalities. Lajmanovich et al, (2019) investigated the impacts on enzymatic activities, hormone levels, and behavioral activity of PPF on premetamorphic tadpoles, after their exposure to 0.1 mg PPF/L and 0.01 mg/L of PPF for 22 days.…”