title: Prenatal exposure to sodium valproate alters androgen receptor expression in the developing cerebellum in a region and age specific manner in male and female rats.
abstract: Valproic acid (VPA) is an anti-epileptic drug with teratogenicity activity that has been related to autism. In rodents, exposure to VPA in utero leads to brain abnormalities similar than those reported in the autistic brain. Particularly, VPA reduces the number of Purkinje neurons in the rat cerebellum parallel to cerebellar abnormalities found in autism. Thus, we injected pregnant females on embryonic day 12 either with VPA (600mg/kg, i.p.) or 0.9% saline solution and obtained the cerebellum from their offspring at different postnatal time points. Testosterone has been linked to autism and plays an important role during brain development. Therefore, we identified and analyzed the androgen receptor (AR) by immunohistochemistry and densitometry, respectively. We found VPA decreases AR density in the superficial Purkinje layer only in cerebellar lobule 8 at PN7, but increased it at PN14 compared to control in males. In females, VPA decreased AR density in the superficial Purkinje layer in cerebellar lobule 6 at PN14, but increased it in lobule 9 at the same time point. No differences were found in the deep Purkinje layer of any cerebellar lobule in terms of AR density neither in males nor females. We additionally found a particular AR density decreasing in both superficial and deep regions across development in the majority of cerebellar lobules in males, but in all cerebellar lobules in females. Thus, our results indicate that VPA disrupts the AR ontogeny in the developing cerebellum in an age and region specific manner in male and female rats. Future epigenetic studies including the evaluation of histone deacetylases (HDAC's) might shed light these results as HDAC's are expressed by Purkinje neurons, interact with the AR and are VPA targets. This work contributes to the understanding of the cerebellar development and it might help to understand the role of the cerebellum in neurodevelopmental disorders such as autism.
authors.affiliation: Centro de Investigaciones Cerebrales, Universidad Veracruzana, Xalapa, Ver, Mexico. Electronic address: mpouchoulen@som.umaryland.edu.
authors.forename: Miguel
authors.initials: M
authors.lastname: Perez-Pouchoulen
authors.affiliation: Area de Psicobiologia, Universidad Jaume I, Castellon de la Plana, Spain. Electronic address: miquel@uji.es.
authors.forename: Marta
authors.initials: M
authors.lastname: Miquel
authors.affiliation: Centro de Investigaciones Cerebrales, Universidad Veracruzana, Xalapa, Ver, Mexico. Electronic address: paulsaft@uaem.edu.mx.
authors.forename: Paul
authors.initials: P
authors.lastname: Saft
authors.affiliation: Centro de Investigaciones Cerebrales, Universidad Veracruzana, Xalapa, Ver, Mexico. Electronic address: brug_@hotmail.com.
authors.forename: Brenda
authors.initials: B
authors.lastname: Brug
authors.affiliation: Centro de Investigaciones Cerebrales, Universidad Veracruzana, Xalapa, Ver, Mexico. Electronic address: rtoledo@uv.mx.
authors.forename: Rebeca
authors.initials: R
authors.lastname: Toledo
authors.affiliation: Centro de Investigaciones Cerebrales, Universidad Veracruzana, Xalapa, Ver, Mexico. Electronic address: elenahernandez@uv.mx.
authors.forename: Maria Elena
authors.initials: ME
authors.lastname: Hernandez
authors.affiliation: Centro de Investigaciones Cerebrales, Universidad Veracruzana, Xalapa, Ver, Mexico. Electronic address: jmanzo@uv.mx.
authors.forename: Jorge
authors.initials: J
authors.lastname: Manzo
mesh_terms: D000367:Age Factors; D000704:Analysis of Variance; D000818:Animals; D000831:Animals, Newborn; D000927:Anticonvulsants / Q000633:toxicity*; D002531:Cerebellum / Q000187:drug effects / Q000254:growth & development / Q000378:metabolism; D003720:Densitometry; D005260:Female; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects*; D006655:Histone Deacetylases / Q000378:metabolism; D008297:Male; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology; D051381:Rats; D017208:Rats, Wistar; D011944:Receptors, Androgen / Q000378:metabolism*; D012727:Sex Characteristics; D014635:Valproic Acid / Q000633:toxicity*
chemical_list: D000927:Anticonvulsants; D011944:Receptors, Androgen; D014635:Valproic Acid; D006655:Histone Deacetylases
keywords: Neurodevelopmental disorders; Purkinje neuron; Sex differences; Teratogen; Vermis