Arsenate-induced maternal glucose intolerance and neural tube defects in a mouse model

Toxicol Appl Pharmacol. 2009 Aug 15;239(1):29-36. doi: 10.1016/j.taap.2009.05.009. Epub 2009 May 14.

Abstract

Background: Epidemiological studies have linked environmental arsenic (As) exposure to increased type 2 diabetes risk. Periconceptional hyperglycemia is a significant risk factor for neural tube defects (NTDs), the second most common structural birth defect. A suspected teratogen, arsenic (As) induces NTDs in laboratory animals.

Objectives: We investigated whether maternal glucose homeostasis disruption was responsible for arsenate-induced NTDs in a well-established dosing regimen used in studies of arsenic's teratogenicity in early neurodevelopment.

Methods: We evaluated maternal intraperitoneal (IP) exposure to As 9.6 mg/kg (as sodium arsenate) in LM/Bc/Fnn mice for teratogenicity and disruption of maternal plasma glucose and insulin levels. Selected compounds (insulin pellet, sodium selenate (SS), N-acetyl cysteine (NAC), l-methionine (L-Met), N-tert-Butyl-alpha-phenylnitrone (PBN)) were investigated for their potential to mitigate arsenate's effects.

Results: Arsenate caused significant glucose elevation during an IP glucose tolerance test (IPGTT). Insulin levels were not different between arsenate and control dams before (arsenate, 0.55 ng/dl; control, 0.48 ng/dl) or after glucose challenge (arsenate, 1.09 ng/dl; control, 0.81 ng/dl). HOMA-IR index was higher for arsenate (3.9) vs control (2.5) dams (p=0.0260). Arsenate caused NTDs (100%, p<0.0001). Insulin pellet and NAC were the most successful rescue agents, reducing NTD rates to 45% and 35%.

Conclusions: IPGTT, insulin assay, and HOMA-IR results suggest a modest failure of glucose stimulated insulin secretion and insulin resistance characteristic of glucose intolerance. Insulin's success in preventing arsenate-induced NTDs provides evidence that these arsenate-induced NTDs are secondary to elevated maternal glucose. The NAC rescue, which did not restore maternal glucose or insulin levels, suggests oxidative disruption plays a role.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Arsenates / toxicity*
  • Blood Glucose / analysis*
  • Disease Models, Animal
  • Female
  • Glucose Intolerance / blood
  • Glucose Intolerance / chemically induced*
  • Glucose Tolerance Test
  • Insulin / metabolism
  • Maternal Exposure / adverse effects*
  • Mice
  • Mice, Inbred Strains
  • Neural Tube Defects / chemically induced*
  • Neural Tube Defects / embryology
  • Neural Tube Defects / metabolism
  • Pregnancy
  • Pregnancy Outcome

Substances

  • Arsenates
  • Blood Glucose
  • Insulin
  • sodium arsenate