bioRxiv Science⌕ Search
Home/Archive/bioRxiv

bioRxiv · 10.1101/048538

A Possible Link Between Pyriproxyfen and Microcephaly

Dan Evans·Fred Nijhout·Raphael Parens·Alfredo J. Morales·Yaneer Bar-Yam
View original source ↗Export metadata ↓

Abstract

The Zika virus is the primary suspect in the large increase in microcephaly cases in 2015-6 in Brazil, however its role is unconfirmed despite individual cases of viral infections found in neural tissue. Here we consider the alternative that the insecticide pyriproxyfen, used in Brazilian drinking water for mosquito control, may actually be the cause. Pyriproxifen is an analog of juvenile hormone, which corresponds in mammals to regulatory molecules including retinoic acid, a vitamin A metabolite, with which it has cross-reactivity and whose application during development causes microcephaly. Methoprene, another juvenile hormone analog approved as an insecticide has metabolites that bind to the retinoid X receptor, and causes developmental disorders in mammals. Isotretinoin is another example of a retinoid causing microcephaly in human babies via activation of the retinoid X receptor. Moreover, tests of pyriproxyfen by the manufacturer, Sumitomo, widely quoted as giving no evidence for developmental toxicity, actually found some evidence for such an effect, including low brain mass and arhinencephaly--incomplete formation of the anterior cerebral hemispheres--in rat pups. Finally, the pyriproxyfen use in Brazil is unprecedented--it has never before been applied to a water supply on such a scale. Claims that it is not being used in Recife, the epicenter of microcephaly cases, do not distinguish the metropolitan area of Recife, where it is widely used, and the municipality, where it is not. Given this combination of information we strongly recommend that the use of pyriproxyfen in Brazil be suspended pending further investigation.

Source connections

Explore related subjects

Pharmacology and ToxicologyPreprint

Keep this discovery

BibTeXRIS

Dan Evans, Fred Nijhout, Raphael Parens, Alfredo J. Morales, Yaneer Bar-Yam. 2016-04-13. A Possible Link Between Pyriproxyfen and Microcephaly. https://doi.org/10.1101/048538

Cite the original work for its findings. Save a collection to share your selection of sources.

KEEP EXPLORING

Related preprints

bioRxiv2016

Harnessing Big Data for Systems Pharmacology

Systems pharmacology aims to holistically understand genetic, molecular, cellular, organismal, and environmental mechanisms of drug actions through developing mechanistic or predictive models. Data-driven modeling plays a central role in systems pharmacology, and has already enabled biologists to generate novel hypotheses. However, more is needed. The drug response is associated with genetic/epigenetic variants and environmental factors, is coupled with molecular conformational dynamics, is affected by possible off-targets, is modulated by the complex interplay of biological networks, and is dependent on pharmacokinetics. Thus, in order to gain a comprehensive understanding of drug actions, systems pharmacology requires integration of models across data modalities, methodologies, organismal hierarchies, and species. This imposes a great challenge on model management, integration, and translation. Here, we discuss several upcoming issues in systems pharmacology and potential solutions to them using big data technology. It will allow systems pharmacology modeling to be findable, accessible, interoperable, reusable, reliable, interpretable, and actionable.

Pharmacology and Toxicology↗
bioRxiv2016

Insights into the binding mode of MEK type-III inhibitors. A step towards discovering and designing allosteric kinase inhibitors across the human kinome

Protein kinases are critical drug targets for treating a large variety of human diseases. Type-I and type-II kinase inhibitors frequently exhibit off-target toxicity or lead to mutation acquired resistance. Two highly specific allosteric type-III MEK-targeted drugs, Trametinib and Cobimetinib, offer a new approach. Thus, understanding the binding mechanism of existing type-III kinase inhibitors will provide insights for designing new type-III kinase inhibitors. In this work we have systematically studied the binding mode of MEK-targeted type-III inhibitors using structural systems pharmacology and molecular dynamics simulation. Our studies provide detailed sequence, structure, interaction-fingerprint, pharmacophore and binding-site information on the binding characteristics of MEK type-III kinase inhibitors. We propose that the helix-folding activation loop is a hallmark allosteric binding site for type-III inhibitors. Subsequently we screened and predicted allosteric binding sites across the human kinome, suggesting other kinases as potential targets suitable for type-III inhibitors. Our findings will provide new insights into the design of potent and selective kinases inhibitors.\n\nAuthor SummaryHuman protein kinases represent a large protein family relevant to many diseases, especially cancers, and have become important drug targets. However, developing the desired selective kinase-targeted inhibitors remain challenging. Kinase allosteric inhibitors provide that opportunity, but, to date, few have been designed other than MEK inhibitors. To more efficiently develop kinase allosteric inhibitors, we systematically studied the binding mode of the MEK type-III allosteric kinase inhibitors using structural system pharmacology and molecular dynamics approaches. New insights into the binding mode and mechanism of type-III inhibitors were revealed that may facilitate the design of new prospective type-III kinase inhibitors.

Pharmacology and Toxicology↗
bioRxiv2016

Clinically-weighted transcriptomic signatures for protein kinase inhibitor associated cardiotoxicity

Cardiotoxicity (CT) involving diminished cardiac contractility and heart failure is a major adverse event associated with otherwise efficacious protein kinase inhibitors (KIs). Here, we sought to develop clinically-weighted transcriptomic signatures to predict risk of CT and to better understand the biological processes associated with CT risk. We obtained transcriptome-wide response profiles in four human primary cardiomyocyte cell lines that were treated with 22 different KIs using mRNA sequencing with 3 digital gene expression. The FDA Adverse Event Reporting System was used to derive relative risk scores for four types of CT for different KIs. We used elastic net regression to associate these transcriptomic profiles with KI-associated risk scores for CT subtypes to obtain clinically-weighted transcriptomic signatures, which showed good predictive properties (cross-validation R2 >0.87). Our clinically-weighted transcriptomic signatures for KI-associated CT may be of relevance in early drug development for the prediction of KI-associated CT.

Pharmacology and Toxicology↗