PMID- 29561882 OWN - NLM STAT- MEDLINE DCOM- 20180709 LR - 20181114 IS - 1932-6203 (Electronic) IS - 1932-6203 (Linking) VI - 13 IP - 3 DP - 2018 TI - Effect of developmental NMDAR antagonism with CGP 39551 on aspartame-induced hypothalamic and adrenal gene expression. PG - e0194416 LID - 10.1371/journal.pone.0194416 [doi] LID - e0194416 AB - RATIONALE: Aspartame (L-aspartyl phenylalanine methyl ester) is a non-nutritive sweetener (NNS) approved for use in more than 6000 dietary products and pharmaceuticals consumed by the general public including adults and children, pregnant and nursing mothers. However a recent prospective study reported a doubling of the risk of being overweight amongst 1-year old children whose mothers consumed NNS-sweetened beverages daily during pregnancy. We have previously shown that chronic aspartame (ASP) exposure commencing in utero may detrimentally affect adulthood adiposity status, glucose metabolism and aspects of behavior and spatial cognition, and that this can be modulated by developmental N-methyl-D-aspartate receptor (NMDAR) blockade with the competitive antagonist CGP 39551 (CGP). Since glucose homeostasis and certain aspects of behavior and locomotion are regulated in part by the NMDAR-rich hypothalamus, which is part of the hypothalamic-pituitary-adrenal- (HPA) axis, we have elected to examine changes in hypothalamic and adrenal gene expression in response to ASP exposure in the presence or absence of developmental NMDAR antagonism with CGP, using Affymetrix microarray analysis. RESULTS: Using 2-factor ANOVA we identified 189 ASP-responsive differentially expressed genes (DEGs) in the adult male hypothalamus and 2188 in the adrenals, and a further 23 hypothalamic and 232 adrenal genes significantly regulated by developmental treatment with CGP alone. ASP exposure robustly elevated the expression of a network of genes involved in hypothalamic neurosteroidogenesis, together with cell stress and inflammatory genes, consistent with previous reports of aspartame-induced CNS stress and oxidative damage. These genes were not differentially expressed in ASP mice with CGP antagonism. In the adrenal glands of ASP-exposed mice, GABA and Glutamate receptor subunit genes were amongst those most highly upregulated. Developmental NMDAR antagonism alone had less effect on adulthood gene expression and affected mainly hypothalamic neurogenesis and adrenal steroid metabolism. Combined ASP + CGP treatment mainly upregulated genes involved in adrenal drug and cholesterol metabolism. CONCLUSION: ASP exposure increased the expression of functional networks of genes involved in hypothalamic neurosteroidogenesis and adrenal catecholamine synthesis, patterns of expression which were not present in ASP-exposed mice with developmental NMDAR antagonism. FAU - Collison, Kate S AU - Collison KS AUID- ORCID: 0000-0002-0691-6859 AD - Department of Cell Biology, King Faisal Specialist Hospital & Research Centre, Riyadh, Saudi Arabia. FAU - Inglis, Angela AU - Inglis A AD - Department of Cell Biology, King Faisal Specialist Hospital & Research Centre, Riyadh, Saudi Arabia. FAU - Shibin, Sherin AU - Shibin S AD - Department of Cell Biology, King Faisal Specialist Hospital & Research Centre, Riyadh, Saudi Arabia. FAU - Saleh, Soad AU - Saleh S AD - Department of Cell Biology, King Faisal Specialist Hospital & Research Centre, Riyadh, Saudi Arabia. FAU - Andres, Bernard AU - Andres B AD - Department of Cell Biology, King Faisal Specialist Hospital & Research Centre, Riyadh, Saudi Arabia. FAU - Ubungen, Rosario AU - Ubungen R AD - Department of Cell Biology, King Faisal Specialist Hospital & Research Centre, Riyadh, Saudi Arabia. FAU - Thiam, Jennifer AU - Thiam J AD - Department of Cell Biology, King Faisal Specialist Hospital & Research Centre, Riyadh, Saudi Arabia. FAU - Mata, Princess AU - Mata P AD - Department of Cell Biology, King Faisal Specialist Hospital & Research Centre, Riyadh, Saudi Arabia. FAU - Al-Mohanna, Futwan A AU - Al-Mohanna FA AD - Department of Cell Biology, King Faisal Specialist Hospital & Research Centre, Riyadh, Saudi Arabia. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20180321 PL - United States TA - PLoS One JT - PloS one JID - 101285081 RN - 0 (Receptors, N-Methyl-D-Aspartate) RN - 127910-32-1 (CGP 39551) RN - 76726-92-6 (2-Amino-5-phosphonovalerate) RN - Z0H242BBR1 (Aspartame) SB - IM MH - 2-Amino-5-phosphonovalerate/*analogs & derivatives/chemistry/pharmacology MH - Animals MH - Aspartame/*adverse effects/pharmacology MH - Female MH - Gene Expression Regulation/*drug effects MH - Hypothalamo-Hypophyseal System/*metabolism MH - Male MH - Mice MH - Pituitary-Adrenal System/*metabolism MH - Receptors, N-Methyl-D-Aspartate/*antagonists & inhibitors PMC - PMC5862471 COIS- Competing Interests: The authors have declared that no competing interests exist. EDAT- 2018/03/22 06:00 MHDA- 2018/07/10 06:00 PMCR- 2018/03/21 CRDT- 2018/03/22 06:00 PHST- 2017/11/06 00:00 [received] PHST- 2018/03/04 00:00 [accepted] PHST- 2018/03/22 06:00 [entrez] PHST- 2018/03/22 06:00 [pubmed] PHST- 2018/07/10 06:00 [medline] PHST- 2018/03/21 00:00 [pmc-release] AID - PONE-D-17-39359 [pii] AID - 10.1371/journal.pone.0194416 [doi] PST - epublish SO - PLoS One. 2018 Mar 21;13(3):e0194416. doi: 10.1371/journal.pone.0194416. eCollection 2018.