The larvicide pyriproxyfen blamed during the Zika virus outbreak does not cause microcephaly in zebrafish embryos

Dzieciolowska, Stefania; Larroque, Anne-Laure; Kranjec, Elizabeth-Ann; Drapeau, Pierre; Samarut, Éric

doi:10.1038/srep40067

Cited by 39 publications

(23 citation statements)

References 42 publications

(51 reference statements)

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“…Our experiments show that cells treated with PPF alone do not readily form EVs (Figs. 2cii, iii and iv) and it is possible that PPF exposure by itself does not affect normal cellular functions [27]. However, an unusual behavior was observed when PPF-exposed cells were infected with VSV.…”

Section: Discussionmentioning

confidence: 99%

Impact of pyriproxyfen on virus behavior: implications for pesticide-induced virulence and mechanism of transmission

Waziry

Raja

Salmon

et al. 2020

Virol J

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Background: More than 3 years since the last Zika virus (ZIKV) outbreak in Brazil, researchers are still deciphering the molecular mechanisms of neurovirulence and vertical transmission, as well as the best way to control spread of ZIKV, a flavivirus. The use of pesticides was the main strategy of mosquito control during the last ZIKV outbreak. Methods: We used vesicular stomatitis virus (VSV) tagged with green fluorescent protein (GFP) as our prototypical virus to study the impact of insecticide pyriproxyfen (PPF). VZV-GFP infected and uninfected Jurkat, HeLa and trophoblast cells were treated with PPF and compared to untreated cells (control). Cell viability was determined by the MTT assay. Cell morphology, presence of extracellular vesicles (EVs), virus infection/GFP expression as well as active mitochondrial levels/localization were examined by confocal microscopy. Results: PPF, which was used to control mosquito populations in Brazil prior to the ZIKV outbreak, enhances VSV replication and has cell membrane-altering properties in the presence of virus. PPF causes enhanced viral replication and formation of large EVs, loaded with virus as well as mitochondria. Treatment of trophoblasts or HeLa cells with increasing concentrations of PPF does not alter cell viability, however, it proportionately increases Jurkat cell viability. Increasing concentrations of PPF followed by VSV infection does not interfere with HeLa cell viability. Both Jurkats and trophoblasts show proportionately increased cell death with increased concentrations of PPF in the presence of virus. Conclusions: We hypothesize that PPF disrupts the lipid microenvironment of mammalian cells, thereby interfering with pathways of viral replication. PPF lowers viability of trophoblasts and Jurkats in the presence of VSV, implying that the combination renders immune system impairment in infected individuals as well as enhanced vulnerability of fetuses towards viral vertical transmission. We hypothesize that similar viruses such as ZIKV may be vertically transmitted via EV-to-cell contact when exposed to PPF, thereby bypassing immune detection. The impact of pesticides on viral replication must be fully investigated before large scale use in future outbreaks of mosquito borne viruses.

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Section: Discussionmentioning

confidence: 99%

Impact of pyriproxyfen on virus behavior: implications for pesticide-induced virulence and mechanism of transmission

Waziry

Raja

Salmon

et al. 2020

Virol J

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“…Only two studies, both using Zebrafish, have addressed the question of whether PPF could be implicated in microcephaly, each producing contradictory results (Dzieciolowska et al, 2017; Truong et al, 2016). One study (Truong et al, 2016) demonstrated that PPF induces adverse morphological changes including craniofacial defects in zebrafish at 5.2 μM (1.66 mg/L) - EC50.…”

Section: Discussionmentioning

confidence: 99%

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

Špirhanzlová

Wejaphikul

et al. 2018

Preprint

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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

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“…Furthermore, researchers have theorized that these birth defects could be because a new chemical, larvicide, was being used as a pesticide in Brazil's water supply beginning in 2015 to prevent the spread of mosquitoes. Research done on zebrafish has shown that this chemical is not the cause of microcephaly; although it is lethal in large doses, it does not cause any brain malformations (Dzieciolowska, 2017) This pesticide despite this conclusion on zebra fish may still be a possible reason on why the microcephaly problem is occurring most significantly in Brazil.…”

Section: The Brazilian Problemmentioning

confidence: 93%

Divergent Co-mordibidites of Zika Virus and Microcephaly in Latin America

Smerdon

Courage²,

Danielson-Francios³

2017

J Stud Res

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Since 2015, a major problem in our society has been the spread of the Zika virus, formally known as ZIKV. ZIKV, originally of African origins, in recent years has spread its way across the Pacific with minor outbreaks before landing in Latin America. The most significant change in ZIKV from discovery is its increasing neurological effects, unique to this disease family. Data has suggested that a pregnant mother having been diagnosed with ZIKV that the child will be subject to congenital disorders as well as Guillain-Barre syndrome. Most notably has been the diagnosis of microcephaly, where a baby is born with an abnormally small head. Some data has suggested a significant increase of rates of microcephaly, but the limitation of small sample sizes and not all populations having been studied prevents a definite conclusion on the effect size of this diagnosis. Therefore, I decided to preform a meta-analysis on existing data sets to determine the likelihood that a child would develop microcephaly, hypothesizing a positive association. My odds ratio did result in a value confirming this confirmation, but because they were statistically insignificant, I had to reject the hypothesis that a pregnant mother’s child would develop microcephaly. I presented alternative hypotheses that there is no association because of genomic changes in the virus or not all of Latin American is feeling the effects of microcephaly at the same extent, with Brazil feeling the effects of the virus the strongest, skewing the data and making researchers overestimate the effects of microcephaly. I hypothesized that Brazil has been assumed to be hardest hit because of possible lack of evaluation on past rates of microcephaly, addition of a pesticide to the water, and the Brazilian population being more genetically susceptible to microcephaly. Further research should study genomic changes in the virus strain and testing the Brazilian population original risk of genetic microcephaly.

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The larvicide pyriproxyfen blamed during the Zika virus outbreak does not cause microcephaly in zebrafish embryos

Cited by 39 publications

References 42 publications

Impact of pyriproxyfen on virus behavior: implications for pesticide-induced virulence and mechanism of transmission

Impact of pyriproxyfen on virus behavior: implications for pesticide-induced virulence and mechanism of transmission

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

Divergent Co-mordibidites of Zika Virus and Microcephaly in Latin America

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