AccScience Publishing / GPD / Online First / DOI: 10.36922/gpd.3113
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ORIGINAL RESEARCH ARTICLE

Association between dietary soy prevention of fetal alcohol spectrum disorder and normalization of placental insulin and insulin-like growth factor signaling networks and downstream effector molecule expression

Fusun Gundogan1,2 ,  Ming Tong1,3 ,  Suzanne M. de la Monte1,2,3,4*
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1 Department of Pathology and Laboratory Medicine, The Warren Alpert Medical School of Brown University, Providence, Rhode Island, United States of America
2 Department of Pathology and Laboratory Medicine, Women and Infants Hospital of Rhode Island, Providence, Rhode Island, United States of America
3 Liver Research Center, Department of Medicine, Rhode Island Hospital, Providence, Rhode Island, United States of America
4 Departments of Pathology and Laboratory Medicine, Neurology, and Neurosurgery, Rhode Island Hospital, Providence, Rhode Island, United States of America
GPD 2024, 3(2), 3113 https://doi.org/10.36922/gpd.3113
Submitted: 7 March 2024 | Accepted: 7 April 2024 | Published: 13 June 2024
© 2024 by the Author(s). This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution 4.0 International License ( https://creativecommons.org/licenses/by/4.0/ )
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Abstract

Chronic prenatal alcohol exposure causes fetal alcohol spectrum disorder (FASD), often associated with impaired placentation and intrauterine growth restriction. Ethanol’s inhibition of insulin and insulin-like growth factor Type 1 (IGF-1) signaling compromises trophoblastic cell motility and maternal vascular transformation at the implantation site. Previous studies have demonstrated that dietary soy effectively normalizes placentation and fetal growth in an experimental model of FASD. The studies were extended to better understand the mechanisms underlying soy’s beneficial effects. Pregnant Long Evans rats were pair-fed with isocaloric liquid diets containing either 0% or 36% caloric ethanol from gestation day (GD) 6. The protein source in the diets consisted of either casein (standard and control) or soy isolate. On GD19, placentas were harvested to measure mRNA levels corresponding to major components of the insulin/IGF-1 pathway, as well as aspartyl-asparaginyl-β-hydroxylase (ASPH), Notch, and HES, which play critical roles in placentation. Chronic gestational ethanol exposure in rats fed diets containing casein significantly reduced the expression of insulin, insulin receptor, Igf1, IGF-1 receptor (Igf1r), insulin receptor substrate Type 1 (Irs1), Irs2, Asph, and Hes1. In addition, ethanol significantly decreased ASPH protein expression. Dietary soy mitigated most of these effects and further enhanced signaling by upregulating Igf2, Igf2r, Irs1, Irs2, Irs4, Notch, and Hes1 in rats chronically exposed to ethanol relative to corresponding control samples. The protective effects of dietary soy in FASD act at the mRNA level and positively impact pathways imperative for normal placentation and fetal development. Gestational dietary soy may provide an effective means of preventing FASD in vulnerable populations.

Keywords
Aspartyl-asparaginyl-β-hydroxylase
Notch
mRNA
Polymerase chain reaction
Funding
This research was supported by grants R01-AA-11431 and R01-AA-28408 from the National Institute on Alcohol Abuse and Alcoholism at the National Institutes of Health.
Conflict of interest
The authors declare that they have no competing interests.
References
  1. Qi W, Gundogan F, Gilligan J, De la Monte S. Dietary soy prevents fetal demise, intrauterine growth restriction, craniofacial dysmorphic features, and impairments in placentation linked to gestational alcohol exposure: Pivotal role of insulin and insulin-like growth factor signaling networks. Alcohol. 2023;110:65-81. doi: 10.1016/j.alcohol.2023.01.006

 

  1. Carter JJ, Tong M, Silbermann E, et al. Ethanol impaired neuronal migration is associated with reduced aspartyl-asparaginyl-beta-hydroxylase expression. Acta Neuropathol. 2008;116(3):303-315. doi: 10.1007/s00401-008-0377-z

 

  1. Ince N, De la Monte SM, Wands JR. Overexpression of human aspartyl (asparaginyl) beta-hydroxylase is associated with malignant transformation. Cancer Res. 2000;60(5):1261-1266.

 

  1. Lawton M, Tong M, Gundogan F, Wands JR, De la Monte SM. Aspartyl-(asparaginyl) beta-hydroxylase, hypoxia-inducible factor-alpha and Notch cross-talk in regulating neuronal motility. Oxid Med Cell Longev. 2010;3(5):347-356. doi: 10.4161/oxim.3.5.13296

 

  1. Sepe PS, Lahousse SA, Gemelli B, et al. Role of the aspartyl-asparaginyl-beta-hydroxylase gene in neuroblastoma cell motility. Lab Invest. 2002;82(7):881-891. doi: 10.1097/01.lab.0000020406.91689.7f

 

  1. Gundogan F, Elwood G, Greco D, et al. Role of aspartyl- (asparaginyl) beta-hydroxylase in placental implantation: Relevance to early pregnancy loss. Hum Pathol. 2007;38(1):50-59. doi: 10.1016/j.humpath.2006.06.005

 

  1. Cantarini MC, De la Monte SM, Pang M, et al. Aspartyl-asparagyl beta hydroxylase over-expression in human hepatoma is linked to activation of insulin-like growth factor and notch signaling mechanisms. Hepatology. 2006;44(2):446-457. doi: 10.1002/hep.21272

 

  1. Tong M, Ziplow J, Chen WC, Nguyen QG, Kim C, De la Monte SM. Motor function deficits following chronic prenatal ethanol exposure are linked to impairments in insulin/IGF, notch and wnt signaling in the cerebellum. J Diabetes Metab. 2013;4(1):238.

 

  1. Tong M, Gonzalez-Navarrete H, Kirchberg T, et al. Ethanol-induced white matter atrophy is associated with impaired expression of aspartyl-asparaginyl-β-hydroxylase (ASPH) and notch signaling in an experimental rat model. J Drug Alcohol Res. 2017;6:236033. doi: 10.4303/jdar/236033

 

  1. Dietrich B, Haider S, Meinhardt G, Pollheimer J, Knofler M. WNT and NOTCH signaling in human trophoblast development and differentiation. Cell Mol Life Sci. 2022;79(6):292. doi: 10.1007/s00018-022-04285-3

 

  1. Lange S, Probst C, Gmel G, Rehm J, Burd L, Popova S. Global prevalence of fetal alcohol spectrum disorder among children and youth: A systematic review and meta-analysis. JAMA Pediatr. 2017;171(10):948-956. doi: 10.1001/jamapediatrics.2017.1919

 

  1. De la Monte SM, Tong M, Lester-Coll N, Plater M Jr., Wands JR. Therapeutic rescue of neurodegeneration in experimental type 3 diabetes: Relevance to Alzheimer’s disease. J Alzheimers Dis. 2006;10(1):89-109. doi: 10.3233/jad-2006-10113

 

  1. De la Monte SM, Tong M, Schiano I, Didsbury J. Improved brain insulin/IGF signaling and reduced neuroinflammation with T3D-959 in an experimental model of sporadic Alzheimer’s disease. J Alzheimers Dis. 2017;55(2):849-864. doi: 10.3233/JAD-160656

 

  1. Pang M, De la Monte SM, Longato L, et al. PPARdelta agonist attenuates alcohol-induced hepatic insulin resistance and improves liver injury and repair. J Hepatol. 2009;50(6):1192-1201. doi: 10.1016/j.jhep.2009.01.021

 

  1. Tong M, Dominguez C, Didsbury J, De la Monte SM. Targeting Alzheimer’s disease neuro-metabolic dysfunction with a small molecule nuclear receptor agonist (T3D-959) reverses disease pathologies. J Alzheimers Dis Parkinsonism. 2016;6(3):238. doi: 10.4172/2161-0460.1000238

 

  1. Xu B, Xing A, Li S. The forgotten type 2 diabetes mellitus medicine: Rosiglitazone. Diabetol Int. 2022;13(1):49-65. doi: 10.1007/s13340-021-00519-0

 

  1. Zhang J, Liu X, Xie XB, Cheng XC, Wang RL. Multitargeted bioactive ligands for PPARs discovered in the last decade. Chem Biol Drug Des. 2016;88(5):635-663. doi: 10.1111/cbdd.12806

 

  1. Schoonjans K, Staels B, Auwerx J. The peroxisome proliferator activated receptors (PPARS) and their effects on lipid metabolism and adipocyte differentiation. Biochim Biophys Acta. 1996;1302(2):93-109.

 

  1. Schoonjans K, Staels B, Auwerx J. Role of the peroxisome proliferator-activated receptor (PPAR) in mediating the effects of fibrates and fatty acids on gene expression. J Lipid Res. 1996;37(5):907-925.

 

  1. Hassan SM. Soybean, nutrition and health. In: El-Shemy HA, editor. Soybean-Bio-Active Compounds. Ch. 20. London: IntechOpen; 2013.

 

  1. Tong M, Ziplow JL, Mark P, De la Monte SM. Dietary Soy Prevents Alcohol-Mediated neurocognitive dysfunction and associated impairments in brain insulin pathway signaling in an adolescent rat model. Biomolecules. 2022;12(5):676. doi: 10.3390/biom12050676

 

  1. De la Monte SM, Elgas E, Tong M, Delikkaya B, Yang Y. Differential rescue effects of choline chloride and soy isolate on metabolic dysfunction in immature central nervous system neurons: Relevance to fetal alcohol spectrum disorder. Diabetes Manag. 2023;13(1):107-118. doi: 10.37532/1758-1907.2023.13(S1).107-118

 

  1. De la Monte SM, Tong M, Delikkaya B. Differential early mechanistic frontal lobe responses to choline chloride and soy isoflavones in an experimental model of fetal alcohol spectrum disorder. Int J Mol Sci. 2023;24(8):7595. doi: 10.3390/ijms24087595

 

  1. Gundogan F, Elwood G, Longato L, et al. Impaired placentation in fetal alcohol syndrome. Placenta. 2008;29(2):148-157. doi: 10.1016/j.placenta.2007.10.002

 

  1. Gundogan F, Gilligan J, Qi W, Chen E, Naram R, De la Monte SM. Dose effect of gestational ethanol exposure on placentation and fetal growth. Placenta. 2015;36(5):523-530. doi: 10.1016/j.placenta.2015.02.010

 

  1. Cohen AC, Tong M, Wands JR, De la Monte SM. Insulin and insulin-like growth factor resistance with neurodegeneration in an adult chronic ethanol exposure model. Alcohol Clin Exp Res. 2007;31(9):1558-1573. doi: 10.1111/j.1530-0277.2007.00450.x

 

  1. Lester-Coll N, Rivera EJ, Soscia SJ, Doiron K, Wands JR, De la Monte SM. Intracerebral streptozotocin model of type 3 diabetes: Relevance to sporadic Alzheimer’s disease. J Alzheimers Dis. 2006;9:13-33. doi: 10.3233/jad-2006-9102

 

  1. De la Monte SM, Tong M, Carlson RI, et al. Ethanol inhibition of aspartyl-asparaginyl-beta-hydroxylase in fetal alcohol spectrum disorder: Potential link to the impairments in central nervous system neuronal migration. Alcohol. 2009;43(3):225-240. doi: 10.1016/j.alcohol.2008.09.009

 

  1. Lewitt MS, Boyd GW. The role of insulin-like growth factors and insulin-like growth factor-binding proteins in the nervous system. Biochem Insights. 2019;12:1 178626419842176. doi: 10.1177/1178626419842176

 

  1. Kan J, Wu F, Wang F, et al. Phytonutrients: Sources, bioavailability, interaction with gut microbiota, and their impacts on human health. Front Nutr. 2022;9:960309. doi: 10.3389/fnut.2022.960309

 

  1. Tong M, Yu R, Deochand C, De la Monte SM. Differential contributions of alcohol and the nicotine-derived nitrosamine ketone (NNK) to insulin and insulin-like growth factor resistance in the adolescent rat brain. Alcohol Alcohol. 2015;50(6):670-679. doi: 10.1093/alcalc/agv101

 

  1. Blyth AJ, Kirk NS, Forbes BE. Understanding IGF-II action through insights into receptor binding and activation. Cells. 2020;9(10):2276. doi: 10.3390/cells9102276

 

  1. Suzawa M, Bland ML. Insulin signaling in development. Development. 2023;150(20):dev201599. doi: 10.1242/dev.201599

 

  1. De la Monte SM, Tamaki S, Cantarini MC, et al. Aspartyl- (asparaginyl)-beta-hydroxylase regulates hepatocellular carcinoma invasiveness. J Hepatol. 2006;44(5):971-983. doi: 10.1016/j.jhep.2006.01.038

 

  1. Tong M, Gao JS, Borgas D, De la Monte SM. Phosphorylation modulates Aspartyl-(Asparaginyl)-β hydroxylase protein expression, catalytic activity and migration in human immature neuronal cerebellar cells. Cell Biol (Henderson, NV). 2013;6(2):133. doi: 10.4172/2324-9293.1000133

 

  1. Aihara A, Huang CK, Olsen MJ, et al. A cell-surface β-hydroxylase is a biomarker and therapeutic target for hepatocellular carcinoma. Hepatology. 2014;60(4):1302-1313. doi: 10.1002/hep.27275

 

  1. Gundogan F, Bedoya A, Gilligan J, et al. siRNA inhibition of aspartyl-asparaginyl β-hydroxylase expression impairs cell motility, Notch signaling, and fetal growth. Pathol Res Pract. 2011;207(9):545-553. doi: 10.1016/j.prp.2011.06.001

 

  1. Lavaissiere L, Jia S, Nishiyama M, et al. Overexpression of human aspartyl (asparaginyl) beta-hydroxylase in hepatocellular carcinoma and cholangiocarcinoma. J Clin Invest. 1996;98(6):1313-1323. doi: 10.1172/JCI118918

 

  1. Stenflo J, Lundwall A, Dahlback B. Beta-hydroxyasparagine in domains homologous to the epidermal growth factor precursor in vitamin K-dependent protein S. Proc Natl Acad Sci U S A. 1987;84(2):368-372. doi: 10.1073/pnas.84.2.368

 

  1. Wagner JD, Zhang L, Shadoan MK, et al. Effects of soy protein and isoflavones on insulin resistance and adiponectin in male monkeys. Metabolism. 2008; 57(7 Suppl 1):S24-S31. doi: 10.1016/j.metabol.2008.04.001

 

  1. De la Monte SM. Malignant brain aging: The formidable link between dysregulated signaling through mechanistic target of rapamycin pathways and Alzheimer’s disease (type 3 diabetes). J Alzheimers Dis. 2023;95(4):1301-1337. doi: 10.3233/JAD-230555
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Gene & Protein in Disease, Electronic ISSN: 2811-003X Published by AccScience Publishing
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