title: Hydrocephalus and arthrogryposis in an immunocompetent mouse model of ZIKA teratogeny: A developmental study.
abstract: The teratogenic mechanisms triggered by ZIKV are still obscure due to the lack of a suitable animal model. Here we present a mouse model of developmental disruption induced by ZIKV hematogenic infection. The model utilizes immunocompetent animals from wild-type FVB/NJ and C57BL/6J strains, providing a better analogy to the human condition than approaches involving immunodeficient, genetically modified animals, or direct ZIKV injection into the brain. When injected via the jugular vein into the blood of pregnant females harboring conceptuses from early gastrulation to organogenesis stages, akin to the human second and fifth week of pregnancy, ZIKV infects maternal tissues, placentas and embryos/fetuses. Early exposure to ZIKV at developmental day 5 (second week in humans) produced complex manifestations of anterior and posterior dysraphia and hydrocephalus, as well as severe malformations and delayed development in 10.5 days post-coitum (dpc) embryos. Exposure to the virus at 7.5-9.5 dpc induces intra-amniotic hemorrhage, widespread edema, and vascular rarefaction, often prominent in the cephalic region. At these stages, most affected embryos/fetuses displayed gross malformations and/or intrauterine growth restriction (IUGR), rather than isolated microcephaly. Disrupted conceptuses failed to achieve normal developmental landmarks and died in utero. Importantly, this is the only model so far to display dysraphia and hydrocephalus, the harbinger of microcephaly in humans, as well as arthrogryposis, a set of abnormal joint postures observed in the human setting. Late exposure to ZIKV at 12.5 dpc failed to produce noticeable malformations. We have thus characterized a developmental window of opportunity for ZIKV-induced teratogenesis encompassing early gastrulation, neurulation and early organogenesis stages. This should not, however, be interpreted as evidence for any safe developmental windows for ZIKV exposure. Late developmental abnormalities correlated with damage to the placenta, particularly to the labyrinthine layer, suggesting that circulatory changes are integral to the altered phenotypes.
authors.affiliation: Brazilian Biosciences National Laboratory, LNBio, Rua Giuseppe Máximo Scolfaro, 10.000, Polo II de Alta Tecnologia de Campinas, Campinas, SP, Brazil.
authors.forename: Jose
authors.initials: J
authors.lastname: Xavier-Neto
authors.affiliation: Brazilian Biosciences National Laboratory, LNBio, Rua Giuseppe Máximo Scolfaro, 10.000, Polo II de Alta Tecnologia de Campinas, Campinas, SP, Brazil.
authors.forename: Murilo
authors.initials: M
authors.lastname: Carvalho
authors.affiliation: Brazilian Biosciences National Laboratory, LNBio, Rua Giuseppe Máximo Scolfaro, 10.000, Polo II de Alta Tecnologia de Campinas, Campinas, SP, Brazil.
authors.forename: Bruno Dos Santos
authors.initials: BD
authors.lastname: Pascoalino
authors.affiliation: Brazilian Biosciences National Laboratory, LNBio, Rua Giuseppe Máximo Scolfaro, 10.000, Polo II de Alta Tecnologia de Campinas, Campinas, SP, Brazil.
authors.forename: Alisson Campos
authors.initials: AC
authors.lastname: Cardoso
authors.affiliation: Brazilian Biosciences National Laboratory, LNBio, Rua Giuseppe Máximo Scolfaro, 10.000, Polo II de Alta Tecnologia de Campinas, Campinas, SP, Brazil.
authors.forename: Ângela Maria Sousa
authors.initials: ÂM
authors.lastname: Costa
authors.affiliation: Brazilian Biosciences National Laboratory, LNBio, Rua Giuseppe Máximo Scolfaro, 10.000, Polo II de Alta Tecnologia de Campinas, Campinas, SP, Brazil.
authors.forename: Ana Helena Macedo
authors.initials: AH
authors.lastname: Pereira
authors.affiliation: Brazilian Biosciences National Laboratory, LNBio, Rua Giuseppe Máximo Scolfaro, 10.000, Polo II de Alta Tecnologia de Campinas, Campinas, SP, Brazil.|Department of Cell and Developmental Biology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, SP, Brazil.
authors.forename: Luana Nunes
authors.initials: LN
authors.lastname: Santos
authors.affiliation: Brazilian Biosciences National Laboratory, LNBio, Rua Giuseppe Máximo Scolfaro, 10.000, Polo II de Alta Tecnologia de Campinas, Campinas, SP, Brazil.
authors.forename: Ângela
authors.initials: Â
authors.lastname: Saito
authors.affiliation: Brazilian Biosciences National Laboratory, LNBio, Rua Giuseppe Máximo Scolfaro, 10.000, Polo II de Alta Tecnologia de Campinas, Campinas, SP, Brazil.
authors.forename: Rafael Elias
authors.initials: RE
authors.lastname: Marques
authors.affiliation: Brazilian Biosciences National Laboratory, LNBio, Rua Giuseppe Máximo Scolfaro, 10.000, Polo II de Alta Tecnologia de Campinas, Campinas, SP, Brazil.
authors.forename: Juliana Helena Costa
authors.initials: JH
authors.lastname: Smetana
authors.affiliation: Brazilian Biosciences National Laboratory, LNBio, Rua Giuseppe Máximo Scolfaro, 10.000, Polo II de Alta Tecnologia de Campinas, Campinas, SP, Brazil.
authors.forename: Silvio Roberto
authors.initials: SR
authors.lastname: Consonni
authors.affiliation: Department of Cell and Developmental Biology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, SP, Brazil.
authors.forename: Carla
authors.initials: C
authors.lastname: Bandeira
authors.affiliation: Laboratório de Imunofarmacologia, Departamento de Bioquímica e Imunologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Avenida Antônio Carlos, 6627, Belo Horizonte, MG, Brazil.
authors.forename: Vivian Vasconcelos
authors.initials: VV
authors.lastname: Costa
authors.affiliation: Brazilian Biosciences National Laboratory, LNBio, Rua Giuseppe Máximo Scolfaro, 10.000, Polo II de Alta Tecnologia de Campinas, Campinas, SP, Brazil.
authors.forename: Marcio Chaim
authors.initials: MC
authors.lastname: Bajgelman
authors.affiliation: Brazilian Biosciences National Laboratory, LNBio, Rua Giuseppe Máximo Scolfaro, 10.000, Polo II de Alta Tecnologia de Campinas, Campinas, SP, Brazil.
authors.forename: Paulo Sérgio Lopes
authors.initials: PSL
authors.lastname: de Oliveira
authors.affiliation: CPqAM-Fiocruz. Federal University of Pernambuco, Av. Professor Moraes Rego s/n, Cidade Universitária, Recife, PE, Brazil.
authors.forename: Marli Tenorio
authors.initials: MT
authors.lastname: Cordeiro
authors.affiliation: CPqAM-Fiocruz. Federal University of Pernambuco, Av. Professor Moraes Rego s/n, Cidade Universitária, Recife, PE, Brazil.
authors.forename: Laura Helena Vega
authors.initials: LH
authors.lastname: Gonzales Gil
authors.affiliation: Brazilian Biosciences National Laboratory, LNBio, Rua Giuseppe Máximo Scolfaro, 10.000, Polo II de Alta Tecnologia de Campinas, Campinas, SP, Brazil.
authors.forename: Bianca Alves
authors.initials: BA
authors.lastname: Pauletti
authors.affiliation: Brazilian Biosciences National Laboratory, LNBio, Rua Giuseppe Máximo Scolfaro, 10.000, Polo II de Alta Tecnologia de Campinas, Campinas, SP, Brazil.
authors.forename: Daniela Campos
authors.initials: DC
authors.lastname: Granato
authors.affiliation: Brazilian Biosciences National Laboratory, LNBio, Rua Giuseppe Máximo Scolfaro, 10.000, Polo II de Alta Tecnologia de Campinas, Campinas, SP, Brazil.
authors.forename: Adriana Franco
authors.initials: AF
authors.lastname: Paes Leme
authors.affiliation: Brazilian Biosciences National Laboratory, LNBio, Rua Giuseppe Máximo Scolfaro, 10.000, Polo II de Alta Tecnologia de Campinas, Campinas, SP, Brazil.
authors.forename: Lucio
authors.initials: L
authors.lastname: Freitas-Junior
authors.affiliation: Brazilian Biosciences National Laboratory, LNBio, Rua Giuseppe Máximo Scolfaro, 10.000, Polo II de Alta Tecnologia de Campinas, Campinas, SP, Brazil.
authors.forename: Carolina Borsoi Moraes
authors.initials: CB
authors.lastname: Holanda de Freitas
authors.affiliation: Laboratório de Imunofarmacologia, Departamento de Bioquímica e Imunologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Avenida Antônio Carlos, 6627, Belo Horizonte, MG, Brazil.
authors.forename: Mauro Martins
authors.initials: MM
authors.lastname: Teixeira
authors.affiliation: Department of Cell and Developmental Biology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, SP, Brazil.
authors.forename: Estela
authors.initials: E
authors.lastname: Bevilacqua
authors.affiliation: Brazilian Biosciences National Laboratory, LNBio, Rua Giuseppe Máximo Scolfaro, 10.000, Polo II de Alta Tecnologia de Campinas, Campinas, SP, Brazil.
authors.forename: Kleber
authors.initials: K
authors.lastname: Franchini
mesh_terms: D000818:Animals; D001176:Arthrogryposis / Q000196:embryology / Q000276:immunology / Q000473:pathology / Q000821:virology*; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D006849:Hydrocephalus / Q000196:embryology / Q000276:immunology / Q000473:pathology / Q000821:virology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010920:Placenta / Q000002:abnormalities / Q000276:immunology / Q000821:virology; D011247:Pregnancy; D011251:Pregnancy Complications, Infectious / Q000276:immunology / Q000473:pathology / Q000821:virology*; D013723:Teratogens / Q000032:analysis; D000071244:Zika Virus / Q000502:physiology*; D000071243:Zika Virus Infection / Q000196:embryology / Q000276:immunology / Q000473:pathology / Q000821:virology*
chemical_list: D013723:Teratogens