title: Lipopolysaccharide Exposure Induces Maternal Hypozincemia, and Prenatal Zinc Treatment Prevents Autistic-Like Behaviors and Disturbances in the Striatal Dopaminergic and mTOR Systems of Offspring.
abstract: Autism is characterized by social deficits, repetitive behaviors, and cognitive inflexibility. The risk factors appear to include genetic and environmental conditions, such as prenatal infections and maternal dietary factors. Previous investigations by our group have demonstrated that prenatal exposure to lipopolysaccharide (LPS), which mimics infection by gram-negative bacteria, induces autistic-like behaviors. To understand the causes of autistic-like behaviors, we evaluated maternal serum metal concentrations, which are involved in intrauterine development and infection/inflammation. We identified reduced maternal levels of zinc, magnesium, selenium and manganese after LPS exposure. Because LPS induced maternal hypozincemia, we treated dams with zinc in an attempt to prevent or ease the impairments in the offspring. We evaluated the social and cognitive autistic-like behaviors and brain tissues of the offspring to identify the central mechanism that triggers the development of autism. Prenatal LPS exposure impaired play behaviors and T-maze spontaneous alternations, i.e., it induced autistic-like behaviors. Prenatal LPS also decreased tyrosine hydroxylase levels and increased the levels of mammalian target of rapamycin (mTOR) in the striatum. Thus, striatal dopaminergic impairments may be related to autism. Moreover, excessive signaling through the mTOR pathway has been considered a biomarker of autism, corroborating our rat model of autism. Prenatal zinc treatment prevented these autistic-like behaviors and striatal dopaminergic and mTOR disturbances in the offspring induced by LPS exposure. The present findings revealed a possible relation between maternal hypozincemia during gestation and the onset of autism. Furthermore, prenatal zinc administration appears to have a beneficial effect on the prevention of autism.
authors.affiliation: Department of Pathology, School of Veterinary Medicine, University of Sao Paulo, São Paulo, Brazil; Environmental and Experimental Pathology, Paulista University, Sao Paulo, Brazil.
authors.forename: Thiago Berti
authors.initials: TB
authors.lastname: Kirsten
authors.affiliation: Department of Pharmacology, Institute of Biomedical Science, University of São Paulo, Sao Paulo, Brazil.
authors.forename: Gabriela P
authors.initials: GP
authors.lastname: Chaves-Kirsten
authors.affiliation: Institute of Physics, University of São Paulo, Sao Paulo, Brazil.
authors.forename: Suene
authors.initials: S
authors.lastname: Bernardes
authors.affiliation: Department of Pharmacology, Institute of Biomedical Science, University of São Paulo, Sao Paulo, Brazil.
authors.forename: Cristoforo
authors.initials: C
authors.lastname: Scavone
authors.affiliation: Institute for Energy and Nuclear Research/IPEN, University of São Paulo, Sao Paulo, Brazil.
authors.forename: Jorge E
authors.initials: JE
authors.lastname: Sarkis
authors.affiliation: Environmental and Experimental Pathology, Paulista University, Sao Paulo, Brazil.
authors.forename: Maria Martha
authors.initials: MM
authors.lastname: Bernardi
authors.affiliation: Department of Pathology, School of Veterinary Medicine, University of Sao Paulo, São Paulo, Brazil.
authors.forename: Luciano F
authors.initials: LF
authors.lastname: Felicio
mesh_terms: D000818:Animals; D001321:Autistic Disorder / Q000209:etiology / Q000517:prevention & control* / Q000523:psychology; D001522:Behavior, Animal / Q000187:drug effects*; D004298:Dopamine / Q000378:metabolism*; D005260:Female; D008070:Lipopolysaccharides / Q000009:adverse effects*; D017072:Neostriatum / Q000187:drug effects* / Q000473:pathology; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects / Q000188:drug therapy; D051381:Rats; D017208:Rats, Wistar; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*; D015032:Zinc / Q000008:administration & dosage* / Q000172:deficiency*
chemical_list: D008070:Lipopolysaccharides; C546845:mTOR protein, rat; D058570:TOR Serine-Threonine Kinases; D015032:Zinc; D004298:Dopamine