Autism is a neurodevelopmental disorder characterized by impaired social and communicative skills and repetitive behaviors with a male-female ratio of 4:1. The etiology of autism results from complex interaction between multiple genes and diverse environmental contaminants. Chlorpyrifos (CPF) is a widely diffused organophosphate insecticide. Recent epidemiological studies indicate that environmentally prenatal exposure to CPF in children can alter the morphology of some brain areas involved in cognitive and behavioural processes. Several rodent studies have confirmed that CPF developmental exposure influences serotonergic neurotransmission and neuroendocrine markers in hypothalamic and amygdaloidal regions in a sex-dimorphic fashion. In the present study we analyzed the effects of low-dose developmental exposure to CPF in a mouse model of autism-spectrum disorders, the BTBR T+tf/J mouse strain, which displays several behavioral traits relevant to autism. To this aim, pregnant BTBR mice were administered from gestational day 14-17 with either vehicle or CPF at a dose of 6 mg/kg/bw by oral gavages. Offspring of both sexes underwent early assessment of sensorimotor milestones and ultrasound emission. At adulthood, the social responses of females were assessed in a free social interaction test with a same-sex companion, whereas the courtship behavior of adult males with a sexually receptive female was analyzed. Our findings evidenced significant effects of CPF on neonatal motor patterns and ultrasound emission, in the male offspring. At adulthood, CPF males showed an abnormal pattern of social investigation of the receptive female, associated to marked increase in the rate of ultrasonic vocalizations emitted during the courtship. Analysis of mRNA expression in hypothalamus and amygdala evidenced in CPF males a significant decrease of vasopressin receptor 1A in the hypothalamus and ERα in the amygdala, and a diminished expression of ERβ and oxytocin precursor in the hypothalamus. These findings open the way for future experimental studies on the interaction among vulnerable gene backgrounds and environmental neurotoxicants in the etiology of sex-biased neurodevelopmental disorders. Supported by: Project Italy/US 11US/11 and Italian Ministry of Health Grant (GR3), Young Researcher 2008, “Non-invasive tools for early detection of Autism Spectrum Disorders”.
Sex-dimorphic behavioral and neuroendocrine effects of the organophosphate chlorpyrifos in a mouse model of autism spectrum disorders / DE FELICE, Alessia; M. L., Scattoni; S., Tait; L., Ricceri; G., Calamandrei. - (2013). ( 14th International Neurotoxicology Association Meeting Egmond aan Zee, Olanda. 9-13 Giugno).
Sex-dimorphic behavioral and neuroendocrine effects of the organophosphate chlorpyrifos in a mouse model of autism spectrum disorders.
DE FELICE, ALESSIA;
2013
Abstract
Autism is a neurodevelopmental disorder characterized by impaired social and communicative skills and repetitive behaviors with a male-female ratio of 4:1. The etiology of autism results from complex interaction between multiple genes and diverse environmental contaminants. Chlorpyrifos (CPF) is a widely diffused organophosphate insecticide. Recent epidemiological studies indicate that environmentally prenatal exposure to CPF in children can alter the morphology of some brain areas involved in cognitive and behavioural processes. Several rodent studies have confirmed that CPF developmental exposure influences serotonergic neurotransmission and neuroendocrine markers in hypothalamic and amygdaloidal regions in a sex-dimorphic fashion. In the present study we analyzed the effects of low-dose developmental exposure to CPF in a mouse model of autism-spectrum disorders, the BTBR T+tf/J mouse strain, which displays several behavioral traits relevant to autism. To this aim, pregnant BTBR mice were administered from gestational day 14-17 with either vehicle or CPF at a dose of 6 mg/kg/bw by oral gavages. Offspring of both sexes underwent early assessment of sensorimotor milestones and ultrasound emission. At adulthood, the social responses of females were assessed in a free social interaction test with a same-sex companion, whereas the courtship behavior of adult males with a sexually receptive female was analyzed. Our findings evidenced significant effects of CPF on neonatal motor patterns and ultrasound emission, in the male offspring. At adulthood, CPF males showed an abnormal pattern of social investigation of the receptive female, associated to marked increase in the rate of ultrasonic vocalizations emitted during the courtship. Analysis of mRNA expression in hypothalamus and amygdala evidenced in CPF males a significant decrease of vasopressin receptor 1A in the hypothalamus and ERα in the amygdala, and a diminished expression of ERβ and oxytocin precursor in the hypothalamus. These findings open the way for future experimental studies on the interaction among vulnerable gene backgrounds and environmental neurotoxicants in the etiology of sex-biased neurodevelopmental disorders. Supported by: Project Italy/US 11US/11 and Italian Ministry of Health Grant (GR3), Young Researcher 2008, “Non-invasive tools for early detection of Autism Spectrum Disorders”.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
