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

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 (I.P.) 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-α-phenylnitrone (PBN)) were investigated for their potential to mitigate arsenate’s effects. Results Arsenate caused significant glucose elevation during an I.P. 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.

Metabolism disrupting chemicals and metabolic disorders

“…Cadmium exposure has been shown to promote glucose intolerance with a specific reduction in adipose expression of Glut4 [518] and TCDD has been shown to also reduce glucose uptake in adipose and brain [519, 520]. In addition, the fungicide tolylfluanid promotes glucose intolerance with concomitant global and adipose-specific insulin resistance, with the latter resulting from a specific down-regulation of insulin receptor substrate-1 (IRS-1) [521]. …”

Evaluation of the Association between Arsenic and Diabetes: A National Toxicology Program Workshop Review

“…Other, less common forms of administration were gavage, oral capsules, or subcutaneous injection. Most of the studies treated animals with AsIII or arsenic trioxide, but other arsenicals have also been studied (Aguilar et al 1997; Arnold et al 2003; Hill et al 2009; Paul et al 2008). The studies also vary in experimental design and model systems used to assess end points relevant to diabetes as a health effect, ranging from urinary glucose in fasted animals (Pal and Chatterjee 2005), to blood glucose in nonfasted animals (Mitchell et al 2000), to glucose tolerance test (Cobo and Castineira 1997; Ghafghazi et al 1980; Hill et al 2009; Paul et al 2007b, 2008, 2011; Wang et al 2009).…”

“…Most of the studies treated animals with AsIII or arsenic trioxide, but other arsenicals have also been studied (Aguilar et al 1997; Arnold et al 2003; Hill et al 2009; Paul et al 2008). The studies also vary in experimental design and model systems used to assess end points relevant to diabetes as a health effect, ranging from urinary glucose in fasted animals (Pal and Chatterjee 2005), to blood glucose in nonfasted animals (Mitchell et al 2000), to glucose tolerance test (Cobo and Castineira 1997; Ghafghazi et al 1980; Hill et al 2009; Paul et al 2007b, 2008, 2011; Wang et al 2009). Glucose was a commonly reported end point but findings were inconsistent across studies, which may stem from differences in the biological compartment assessed (urine, serum, plasma, whole blood) and fasting status of the animal (fasted, nonfasted, fasting status not reported) in addition to the differences in experimental design noted above related to arsenical tested, species, route of administration, and dose levels (Aguilar et al 1997; Arnold et al 2003; Biswas et al 2000; Boquist et al 1988; Ghafghazi et al 1980; Hill et al 2009; Izquierdo-Vega et al 2006; Judd 1979; Mitchell et al 2000; Pal and Chatterjee 2004a, 2004b, 2005; Paul et al 2007b, 2008, 2011; Wang et al 2009).…”

Environmental Endocrine Disruption of Energy Metabolism and Cardiovascular Risk

“…A number of compounds have been shown to promote glucose intolerance and frank hyperglycemia in animal models. This includes organic toxins, including the plasticizer diethylhexylphthalate (DEHP) [58], PCBs [59], and triphenyltin [60] as well as the inorganic contaminant arsenic [61]. In addition to overt disruption of glucose handling, several EDCs have been shown to promote hyperinsulinism and insulin resistance.…”