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. 2015 Jul 28;10(7):e0134565.
doi: 10.1371/journal.pone.0134565. eCollection 2015.

Lipopolysaccharide Exposure Induces Maternal Hypozincemia, and Prenatal Zinc Treatment Prevents Autistic-Like Behaviors and Disturbances in the Striatal Dopaminergic and mTOR Systems of Offspring

Thiago Berti Kirsten  1 , Gabriela P Chaves-Kirsten  2 , Suene Bernardes  3 , Cristoforo Scavone  2 , Jorge E Sarkis  4 , Maria Martha Bernardi  5 , Luciano F Felicio  6
Affiliations

Lipopolysaccharide Exposure Induces Maternal Hypozincemia, and Prenatal Zinc Treatment Prevents Autistic-Like Behaviors and Disturbances in the Striatal Dopaminergic and mTOR Systems of Offspring

Thiago Berti Kirsten et al. PLoS One. .

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.

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Conflict of interest statement

Competing Interests: The authors have declared that no competing interests exist.

Figures

Fig 1
Fig 1. T-maze spontaneous alternation of the offspring.
The effects of prenatal LPS (100 μg/kg) and zinc (ZnSO4; 2 mg/kg) exposure at gestational day 9.5 on T-maze spontaneous alternation in young male rat offspring (PND 29). Five-session scores: 0, no alternations; 1, one alternation; 2, two alternations; 3, three alternations; and 4, four alternations. SAL+SAL, prenatal saline injection and another saline injection 1 h later; LPS+SAL, prenatal LPS injection and a saline injection 1 h later; LPS+Zn, prenatal LPS injection and a zinc injection 1 h later (n = 10 rats/group). **p < 0.01 compared with the SAL+SAL group; # p < 0.05 compared with the LPS+Zn group (Kruskal-Wallis test followed by Dunn’s test). The data are expressed as the median (minimum and maximum).
Fig 2
Fig 2. Play behaviors in the offspring.
The effects of prenatal LPS (100 μg/kg) and zinc (ZnSO4; 2 mg/kg) exposure at gestational day 9.5 on play behaviors in young male rat offspring (PND 30). SAL+SAL, prenatal saline injection and another saline injection 1 h later; LPS+SAL, prenatal LPS injection and a saline injection 1 h later; LPS+Zn, prenatal LPS injection and a zinc injection 1 h later (n = 10 rats/group). **p < 0.01 and ***p < 0.0001 compared with the SAL+SAL group; # p < 0.01 and ### p < 0.0001 compared with the LPS+Zn group (one-way ANOVA followed by the Bonferroni test). The data are expressed as the mean ± SEM.
Fig 3
Fig 3. TH and mTOR expression in the offspring.
The effects of prenatal LPS (100 μg/kg) and zinc (ZnSO4; 2 mg/kg) exposure at gestational day 9.5 on the TH and mTOR levels in the striatum and substantia nigra (normalized optical density/Beta-actin ratio, western blotting) in young male rat offspring (PND 30). (A) striatal TH levels; (B) substantia nigra TH levels; (C) striatal mTOR levels; (D) substantia nigra mTOR levels. SAL+SAL, prenatal saline injection and another saline injection 1 h later; LPS+SAL, prenatal LPS injection and a saline injection 1 h later; LPS+Zn, prenatal LPS injection and a zinc injection 1 h later (n = 6–7 rats/group). *p < 0.05 and **p < 0.01 compared with the SAL+SAL group; ### p < 0.0001 compared with the LPS+Zn group (one-way ANOVA followed by the Bonferroni test). The data are expressed as the mean ± SEM.
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Grants and funding

This research was supported by the São Paulo Research Foundation (FAPESP grant 2012/07007-8, 2013/01610-7 and thematic grant 2009/51886-3) and the Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES/Prêmio). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.