Gender Related Changes in Gene Expression Induced by Valproic Acid in A Mouse Model of Autism and the Correction by S-adenosyl Methionine. Does It Explain the Gender Differences in Autistic Like Behavior?

Abstract

In previous studies we produced autism like behavioral changes in mice by Valproic acid (VPA) with significant differences between genders. S-adenosine methionine (SAM) prevented the autism like behavior in both genders. The expression of 770 genes of pathways involved in neurophysiology and neuropathology was studied in the prefrontal cortex of 60 days old male and female mice using the NanoString nCounter. In females, VPA induced statistically significant changes in the expression of 146 genes; 71 genes were upregulated and 75 downregulated. In males, VPA changed the expression of only 19 genes, 16 were upregulated and 3 downregulated. Eight genes were similarly changed in both genders. When considering only the genes that were changed by at least 50%, VPA changed the expression of 15 genes in females and 3 in males. Only Nts was similarly downregulated in both genders. SAM normalized the expression of most changed genes in both genders. We presume that genes that are involved in autism like behavior in our model were similarly changed in both genders and corrected by SAM. The behavioral and other differences between genders may be related to genes that were differently affected by VPA in males and females and/or differently affected by SAM.

Prenatal S-Adenosine Methionine (SAMe) Induces Changes in Gene Expression in the Brain of Newborn Mice That Are Prevented by Co-Administration of Valproic Acid (VPA)

“…Similar to our previous findings of sex-specific VPA-induced differences in gene expression in adult mice [46], we found that newborn mice prenatally treated with SAMe demonstrated significant sex differences in the expression of genes in the brain, thus the data were analyzed for males and for females separately. The full list of the genes with significant changes in their expression is detailed in the Supplementary Table S1 and Figure S1.…”

“…We did not find any external malformations in the offspring in any of the groups. The weight gain of the offspring during the first 30 postnatal days was similar in all groups (Figure 1A-C) There were no differences in the developmental milestones between the control and SAMe-treated animals until the age of one month (Weinstein-Fudim L et al [46]).…”

“…In our previous studies [46], we found behavioral abnormalities and multiple changes in gene expression in the prefrontal cortex of adult male and female mice exposed to VPA on postnatal day 4. This period is parallel to the third trimester of human pregnancy and a time of rapid maturation of the brain.…”

S-Adenosine Methionine (SAMe) and Valproic Acid (VPA) as Epigenetic Modulators: Special Emphasis on their Interactions Affecting Nervous Tissue during Pregnancy

“…Co-administration of VPA with SAMe normalized almost all gene expression changes produced by SAMe alone. Thus, an antagonistic action (interaction) between SAMe and VPA was demonstrated with prenatal treatment as well as with early postnatal treatment [131]. Interestingly, the main pathway affected by SAMe administration was the Vegfa (vascular endothelial growth factor a) pathway with 13 out of 26 genes significantly changed in males and 9 out of 26 genes in the Vegfa pathway changed in females.…”

SAMe, Choline, and Valproic Acid as Possible Epigenetic Drugs: Their Effects in Pregnancy with a Special Emphasis on Animal Studies

“…This led to some clinical trials with minimal success [16]. VPA-induced autistic-like behavior in mice was prevented by concomitant administration of S-adenosyl methionine [17,18].…”