title: Associations among exposure to methylmercury, reduced Reelin expression, and gender in the cerebellum of developing mice.
abstract: Genetic risk factors acting during pregnancy or early after birth have been proposed to account for the exponential increase of autism diagnoses in the past 20 years. In particular, a potential link with exposure to environmental mercury has been suggested. Male sex constitutes a second risk factor for autism. A third potential genetic risk factor is decreased Reelin expression. Male heterozygous reeler (rl(+/-)) mice show an autism-like phenotype, including Purkinje cells (PCs) loss and behavioral rigidity. We evaluated the complex interactions between 3 risk factors, i.e. genetic status, sex, and exposure to methylmercury (MeHg), in rl(+/-) mice. Mice were exposed to MeHg during the prenatal and early postnatal period, either at a subtoxic dose (2 ppm in Dams' drinking water), or at a toxic dose (6 ppm Dams' drinking water), based on observations in other rodent species and mice strains. We show that: (a) 2 ppm MeHg does not cause PCs loss in the different animal groups, and does not enhance PCs loss in rl(+/-) males; consistent with a lack of overt neurotoxicity, 2 ppm MeHg per se does not cause behavioral alterations (separation-induced ultrasonic calls in newborns, or sociability and social preference in adults); (b) in stark contrast, 6 ppm MeHg causes a dramatic reduction of PCs number in all groups, irrespective of genotype and sex. Cytochrome C release from mitochondria of PCs is enhanced in 6 ppm MeHg-exposed groups, with a concomitant increase of μ-calpain active subunit. At the behavioral level, 6 ppm MeHg exposure strongly increases ultrasonic vocalizations in all animal groups. Notably, 6 ppm MeHg significantly decreases sociability in rl(+/-) male mice, while the 2 ppm group does not show such as decrease. At a subtoxic dose, MeHg does not enhance the autism-like phenotype of male rl(+/-) mice. At the higher MeHg dose, the scenario is more complex, with some "autism-like" features (loss of sociability, preference for sameness) being evidently affected only in rl(+/-) males, while other neuropathological and behavioral parameters being altered in all groups, independently from genotype and sex. Mitochondrial abnormalities appear to play a crucial role in the observed effects.
authors.affiliation: Laboratory of Developmental Neuroscience and Neural Plasticity, University Campus Biomedico, Via A. del Portillo 21, 00198 Rome, Italy.
authors.forename: Filippo
authors.initials: F
authors.lastname: Biamonte
authors.affiliation: Santa Lucia Foundation, I.R.C.C.S., Via del Fosso di Fiorano 64, 00143 Rome, Italy.
authors.forename: Laura
authors.initials: L
authors.lastname: Latini
authors.affiliation: Section of Neurology, Department of Clinical and Experimental Medicine, University of Pisa, Via Roma 67, 56126 Pisa, Italy.
authors.forename: Filippo Sean
authors.initials: FS
authors.lastname: Giorgi
authors.affiliation: Laboratory of Histology, University Campus Biomedico, Rome, Italy.
authors.forename: Maria
authors.initials: M
authors.lastname: Zingariello
authors.affiliation: Laboratory of Developmental Neuroscience and Neural Plasticity, University Campus Biomedico, Via A. del Portillo 21, 00198 Rome, Italy.
authors.forename: Ramona
authors.initials: R
authors.lastname: Marino
authors.affiliation: Laboratory of Developmental Neuroscience and Neural Plasticity, University Campus Biomedico, Via A. del Portillo 21, 00198 Rome, Italy.
authors.forename: Roberto
authors.initials: R
authors.lastname: De Luca
authors.affiliation: Istituto Superiore di Sanità, Centro Nazionale Sostanze Chimiche, Viale Regina Elena 299, Rome, Italy.
authors.forename: Sonia
authors.initials: S
authors.lastname: D'Ilio
authors.affiliation: Istituto Superiore di Sanità, Dipartimento di Ambiente e Prevenzione Primaria, Viale Regina Elena 299, Rome, Italy.
authors.forename: Costanza
authors.initials: C
authors.lastname: Majorani
authors.affiliation: Istituto Superiore di Sanità, Dipartimento di Ambiente e Prevenzione Primaria, Viale Regina Elena 299, Rome, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Petrucci
authors.affiliation: Istituto Superiore di Sanità, Dipartimento di Ambiente e Prevenzione Primaria, Viale Regina Elena 299, Rome, Italy.
authors.forename: Nicola
authors.initials: N
authors.lastname: Violante
authors.affiliation: Istituto Superiore di Sanità, Dipartimento di Ambiente e Prevenzione Primaria, Viale Regina Elena 299, Rome, Italy.
authors.forename: Oreste
authors.initials: O
authors.lastname: Senofonte
authors.affiliation: Santa Lucia Foundation, I.R.C.C.S., Via del Fosso di Fiorano 64, 00143 Rome, Italy. Electronic address: m.molinari@hsantalucia.it.
authors.forename: Marco
authors.initials: M
authors.lastname: Molinari
authors.affiliation: Laboratory of Developmental Neuroscience and Neural Plasticity, University Campus Biomedico, Via A. del Portillo 21, 00198 Rome, Italy. Electronic address: f.keller@unicampus.it.
authors.forename: Flavio
authors.initials: F
authors.lastname: Keller
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D015816:Cell Adhesion Molecules, Neuronal / Q000235:genetics*; D002452:Cell Count; D002531:Cerebellum / Q000187:drug effects* / Q000378:metabolism; D002659:Child Development Disorders, Pervasive / Q000139:chemically induced* / Q000235:genetics; D004195:Disease Models, Animal; D016326:Extracellular Matrix Proteins / Q000235:genetics*; D005260:Female; D006579:Heterozygote; D008297:Male; D008767:Methylmercury Compounds / Q000008:administration & dosage / Q000032:analysis / Q000633:toxicity*; D051379:Mice; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D009043:Motor Activity / Q000187:drug effects; D009419:Nerve Tissue Proteins / Q000235:genetics*; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects; D011689:Purkinje Cells / Q000187:drug effects / Q000648:ultrastructure; D000091042:Reelin Protein; D012307:Risk Factors; D012697:Serine Endopeptidases / Q000235:genetics*; D012737:Sex Factors; D012919:Social Behavior; D014828:Vocalization, Animal / Q000187:drug effects
chemical_list: D015816:Cell Adhesion Molecules, Neuronal; D016326:Extracellular Matrix Proteins; D008767:Methylmercury Compounds; D009419:Nerve Tissue Proteins; D000091042:Reelin Protein; C000717128:Reln protein, mouse; D012697:Serine Endopeptidases
keywords: Autism; Cerebellum; Mercury; Reelin; Social novelty