Associations among exposure to methylmercury, reduced Reelin expression, and gender in the cerebellum of developing mice

Filippo Biamonte, Laura Latini, Filippo S ean Giorgi, Maria Zingariello, Ramona Marino, Roberto De Luca, Sonia D'Ilio, Costanza Majorani, Francesco Petrucci, Nicola Violante, Oreste Senofonte, Marco Molinari, Flavio Keller

Research output: Contribution to journalArticle

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.

Original languageEnglish
Pages (from-to)67-80
Number of pages14
JournalNeuroToxicology
Volume45
DOIs
Publication statusPublished - Dec 1 2014

Fingerprint

Purkinje Cells
Cerebellum
Autistic Disorder
Drinking Water
Dams
Animals
Ultrasonics
Mitochondria
Calpain
Poisons
Cytochromes
Mercury
Genotype
Rigidity
Neurologic Mutant Mice
Phenotype
Environmental Exposure
Rodentia
Cell Count
Parturition

Keywords

  • Autism
  • Cerebellum
  • Mercury
  • Reelin
  • Social novelty

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Biamonte, F., Latini, L., Giorgi, F. S. E., Zingariello, M., Marino, R., De Luca, R., ... Keller, F. (2014). Associations among exposure to methylmercury, reduced Reelin expression, and gender in the cerebellum of developing mice. NeuroToxicology, 45, 67-80. https://doi.org/10.1016/j.neuro.2014.09.006

Associations among exposure to methylmercury, reduced Reelin expression, and gender in the cerebellum of developing mice. / Biamonte, Filippo; Latini, Laura; Giorgi, Filippo S ean; Zingariello, Maria; Marino, Ramona; De Luca, Roberto; D'Ilio, Sonia; Majorani, Costanza; Petrucci, Francesco; Violante, Nicola; Senofonte, Oreste; Molinari, Marco; Keller, Flavio.

In: NeuroToxicology, Vol. 45, 01.12.2014, p. 67-80.

Research output: Contribution to journalArticle

Biamonte, F, Latini, L, Giorgi, FSE, Zingariello, M, Marino, R, De Luca, R, D'Ilio, S, Majorani, C, Petrucci, F, Violante, N, Senofonte, O, Molinari, M & Keller, F 2014, 'Associations among exposure to methylmercury, reduced Reelin expression, and gender in the cerebellum of developing mice', NeuroToxicology, vol. 45, pp. 67-80. https://doi.org/10.1016/j.neuro.2014.09.006
Biamonte, Filippo ; Latini, Laura ; Giorgi, Filippo S ean ; Zingariello, Maria ; Marino, Ramona ; De Luca, Roberto ; D'Ilio, Sonia ; Majorani, Costanza ; Petrucci, Francesco ; Violante, Nicola ; Senofonte, Oreste ; Molinari, Marco ; Keller, Flavio. / Associations among exposure to methylmercury, reduced Reelin expression, and gender in the cerebellum of developing mice. In: NeuroToxicology. 2014 ; Vol. 45. pp. 67-80.
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