» Articles » PMID: 29686779

Valproic Acid Exposure of Pregnant Rats During Organogenesis Disturbs Pancreas Development in Insulin Synthesis and Secretion of the Offspring

Overview
Journal Toxicol Res
Specialty Toxicology
Date 2018 Apr 25
PMID 29686779
Citations 2
Authors
Affiliations
Soon will be listed here.
Abstract

Valproic acid (VPA) plays a role in histone modifications that eventually inhibit the activity of histone deacetylase (HDAC), and will affect the expressions of genes Pdx1, Nkx6.1, and Ngn3 during pancreatic organogenesis. This experiment was designed to study the effect of VPA exposure in pregnant rats on the activity of HDAC that controls the expression of genes regulating the development of beta cells in the pancreas to synthesize and secrete insulin. This study used 30 pregnant Sprague-Dawley rats, divided into 4 groups, as follows: (1) a control group of pregnant rats without VPA administration, (2) pregnant rats administered with 250 mg VPA on day 10 of pregnancy, (3) pregnant rats administered with 250 mg VPA on day 13 of pregnancy, and (4) pregnant rats administered with 250 mg VPA on day 16 of pregnancy. Eighty-four newborn rats born to control rats and rats administered with VPA on days 10, 13, and 16 of pregnancy were used to measure serum glucose, insulin, DNA, RNA, and ratio of RNA/DNA concentrations in the pancreas and to observe the microscopical condition of the pancreas at the ages of 4 to 32 weeks postpartum with 4-week intervals. The results showed that at the age of 32 weeks, the offspring of pregnant rats administered with 250 mg VPA on days 10, 13, and 16 of pregnancy had higher serum glucose concentrations and lower serum insulin concentrations, followed by decreased concentrations of RNA, and the ratio of RNA/DNA in the pancreas. Microscopical observations showed that the pancreas of the rats born to pregnant rats administered with VPA during pregnancy had low immunoreaction to insulin. The exposure of pregnant rats to VPA during pregnancy disturbs organogenesis of the pancreas of the embryos that eventually disturb the insulin production in the beta cells indicated by the decreased insulin secretion during postnatal life.

Citing Articles

The Protective Role of Prenatal Alpha Lipoic Acid Supplementation against Pancreatic Oxidative Damage in Offspring of Valproic Acid-Treated Rats: Histological and Molecular Study.

Ghoneim F, Alrefai H, Elsamanoudy A, El-Khair S, Khalaf H Biology (Basel). 2020; 9(9).

PMID: 32825436 PMC: 7564314. DOI: 10.3390/biology9090239.


Epigenetic Programming and Fetal Metabolic Programming.

Zhu Z, Cao F, Li X Front Endocrinol (Lausanne). 2019; 10:764.

PMID: 31849831 PMC: 6901800. DOI: 10.3389/fendo.2019.00764.

References
1.
Otsuka T, Tsukahara T, Takeda H . Development of the pancreas in medaka, Oryzias latipes, from embryo to adult. Dev Growth Differ. 2015; 57(8):557-69. DOI: 10.1111/dgd.12237. View

2.
Guerrini R . Valproate as a mainstay of therapy for pediatric epilepsy. Paediatr Drugs. 2006; 8(2):113-29. DOI: 10.2165/00148581-200608020-00004. View

3.
Arystarkhova E, Liu Y, Salazar C, Stanojevic V, Clifford R, Kaplan J . Hyperplasia of pancreatic beta cells and improved glucose tolerance in mice deficient in the FXYD2 subunit of Na,K-ATPase. J Biol Chem. 2013; 288(10):7077-85. PMC: 3591617. DOI: 10.1074/jbc.M112.401190. View

4.
Schulpen S, Pennings J, Piersma A . Gene Expression Regulation and Pathway Analysis After Valproic Acid and Carbamazepine Exposure in a Human Embryonic Stem Cell-Based Neurodevelopmental Toxicity Assay. Toxicol Sci. 2015; 146(2):311-20. DOI: 10.1093/toxsci/kfv094. View

5.
Rajendran P, Kidane A, Yu T, Dashwood W, Bisson W, Lohr C . HDAC turnover, CtIP acetylation and dysregulated DNA damage signaling in colon cancer cells treated with sulforaphane and related dietary isothiocyanates. Epigenetics. 2013; 8(6):612-23. PMC: 3857341. DOI: 10.4161/epi.24710. View