title: Early methyl donor deficiency alters cAMP signaling pathway and neurosteroidogenesis in the cerebellum of female rat pups.
abstract: Early deficiency of the methyl donors folate and vitamin B12 produces hyperhomocysteinemia and cognitive and motor disorders in 21-day-old rat pups from dams fed a diet deficient in methyl donors during gestation and lactation. These disorders are associated with impaired neurogenesis and altered synaptic plasticity in cerebellum. We aimed to investigate whether these disorders could be related to impaired expression of neurosteroidogenesis-associated proteins, key regulator receptors, and some steroid content in the cerebellum. The methyl donor deficiency produced a decreased concentration of folate and vitamin B12, along with accumulation of homocysteine in Purkinje cells in both sexes, whereas the S-adenosylmethionine/S-adenosylhomocysteine ratio was reduced only in females. The transcription level and protein expression of StAR, aromatase, ERα, ERβ, and LH receptors were decreased only in females, with a marked effect in Purkinje cells, as shown by immunohistochemistry. Consistently, reduced levels of estradiol and pregnenolone were measured in cerebellar extracts of females only. The decreased expression levels of the transcriptional factors CREB, phospho-CREB, and SF-1, the lesser increase of cAMP concentration, and the lower level of phospho-PKC in the cerebellum of deficient females suggest that the activation of neurosteroidogenesis via cAMP-mediated signaling pathways associated with LHR activation would be altered. In conclusion, a gestational methyl donor deficiency impairs neurosteroidogenesis in cerebellum in a sex-dependent manner.
authors.affiliation: Institut National de la Sante et de la Recherche Medicale, U-954, Nutrition-Génétique et Exposition Aux Risques Environnementaux, Faculté de Médecine, Université de Lorraine, Vandoeuvre les Nancy, France.
authors.forename: Sarah
authors.initials: S
authors.lastname: El Hajj Chehadeh
authors.affiliation: Institut National de la Sante et de la Recherche Medicale, U-954, Nutrition-Génétique et Exposition Aux Risques Environnementaux, Faculté de Médecine, Université de Lorraine, Vandoeuvre les Nancy, France.
authors.forename: Natacha
authors.initials: N
authors.lastname: Dreumont
authors.affiliation: Institut National de la Sante et de la Recherche Medicale, U-954, Nutrition-Génétique et Exposition Aux Risques Environnementaux, Faculté de Médecine, Université de Lorraine, Vandoeuvre les Nancy, France.
authors.forename: Jérèmy
authors.initials: J
authors.lastname: Willekens
authors.affiliation: Institut National de la Sante et de la Recherche Medicale, U-954, Nutrition-Génétique et Exposition Aux Risques Environnementaux, Faculté de Médecine, Université de Lorraine, Vandoeuvre les Nancy, France.
authors.forename: Laetitia
authors.initials: L
authors.lastname: Canabady-Rochelle
authors.affiliation: Institut National de la Sante et de la Recherche Medicale, U-954, Nutrition-Génétique et Exposition Aux Risques Environnementaux, Faculté de Médecine, Université de Lorraine, Vandoeuvre les Nancy, France.
authors.forename: Elise
authors.initials: E
authors.lastname: Jeannesson
authors.affiliation: Institut National de la Sante et de la Recherche Medicale, U-954, Nutrition-Génétique et Exposition Aux Risques Environnementaux, Faculté de Médecine, Université de Lorraine, Vandoeuvre les Nancy, France.
authors.forename: Jean-Marc
authors.initials: JM
authors.lastname: Alberto
authors.affiliation: Institut National de la Sante et de la Recherche Medicale, U-954, Nutrition-Génétique et Exposition Aux Risques Environnementaux, Faculté de Médecine, Université de Lorraine, Vandoeuvre les Nancy, France.
authors.forename: Jean-Luc
authors.initials: JL
authors.lastname: Daval
authors.affiliation: Institut National de la Sante et de la Recherche Medicale, U-954, Nutrition-Génétique et Exposition Aux Risques Environnementaux, Faculté de Médecine, Université de Lorraine, Vandoeuvre les Nancy, France.
authors.forename: Jean-Louis
authors.initials: JL
authors.lastname: Guéant
authors.affiliation: Institut National de la Sante et de la Recherche Medicale, U-954, Nutrition-Génétique et Exposition Aux Risques Environnementaux, Faculté de Médecine, Université de Lorraine, Vandoeuvre les Nancy, France Brigitte.Leininger@univ-lorraine.fr.
authors.forename: Brigitte
authors.initials: B
authors.lastname: Leininger-Muller
mesh_terms: D000818:Animals; D002531:Cerebellum / Q000378:metabolism*; D000242:Cyclic AMP / Q000502:physiology*; D004958:Estradiol / Q000378:metabolism; D005260:Female; D005494:Folic Acid Deficiency / Q000378:metabolism*; D008861:Microsomes / Q000378:metabolism; D008928:Mitochondria / Q000378:metabolism; D018377:Neurotransmitter Agents / Q000096:biosynthesis*; D010750:Phosphoproteins / Q000096:biosynthesis / Q000235:genetics; D011284:Pregnenolone / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction / Q000502:physiology*; D014158:Transcription, Genetic / Q000235:genetics / Q000502:physiology; D014806:Vitamin B 12 Deficiency / Q000378:metabolism*; D000098682:Steroidogenic Acute Regulatory Protein
chemical_list: D018377:Neurotransmitter Agents; D010750:Phosphoproteins; D000098682:Steroidogenic Acute Regulatory Protein; D004958:Estradiol; D011284:Pregnenolone; D000242:Cyclic AMP
keywords: cerebellum development; cyclic AMP signaling cascade; early methyl donor deficiency; neurosteroids