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

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.

Keywords: Gene expression; Histone deacetylase; Insulin; Pancreas organogenesis; Rat; Valproic acid.

Fig. 1

Immunoreactivity on the islets of Langerhans of the pancreas of the offspring rat. (A) Represents the immunoreactivity to insulin levels from the islets of Langerhans of the pancreas of offspring rat. Representative images of these levels of immunoreactivity to insulin from the control group (T0), and islets of Langerhans in the treatment group on day 10, day 13, and day 16 of gestation (T1, T2, and T3) showed a low immunoreactivity to insulin (red arrow). (B) Represents the immunoreactivity to glucagon levels from the islets of Langerhans in the pancreas of an offspring rat. Representative images of these levels of immunoreactivity to glucagon from the control group (T0), and islets of Langerhans in the treatment group on day 10, day 13, and day 16 of gestation, (T2, and T3), showed a high immunoreactivity to glucagon (blue arrow) on day 16 of gestation (T3).