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


OBJECTIVE
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.
Hill
Denise S
DS
Center for Environmental and Genetic Medicine, Institute of Biosciences and Technology, Texas A&M University System Health Science Center, Houston, 77030, USA.
Wlodarczyk
Bogdan J
BJ
Mitchell
Laura E
LE
Finnell
Richard H
RH
D000818:Animals; D001149:Arsenates / Q000633:toxicity*; D001786:Blood Glucose / Q000032:analysis*; D004195:Disease Models, Animal; D005260:Female; D018149:Glucose Intolerance / Q000097:blood / Q000139:chemically induced*; D005951:Glucose Tolerance Test; D007328:Insulin / Q000378:metabolism; D018811:Maternal Exposure / Q000009:adverse effects*; D051379:Mice; D008815:Mice, Inbred Strains; D009436:Neural Tube Defects / Q000139:chemically induced* / Q000196:embryology / Q000378:metabolism; D011247:Pregnancy; D011256:Pregnancy Outcome
D001149:Arsenates; D001786:Blood Glucose; D007328:Insulin; C009277:sodium arsenate