Maternal exposure to phenanthrene during gestation disturbs glucose homeostasis in adult mouse offspring.

Epidemiological studies have indicated that polycyclic aromatic hydrocarbons were related to diabetes and insulin resistance. However, studies in mammals on the development of diabetes caused by polycyclic aromatic hydrocarbons are lacking. Pregnant mice were orally exposed to phenanthrene (0, 60 and 600 µg kg-1 body weight) once every 3 days during gestation. In adult mouse offspring, in-utero phenanthrene exposure caused glucose intolerance and decreased insulin levels in females, while caused elevated fasting blood glucose and insulin levels in males. Serum resistin and interleukin-6 levels were elevated in offspring of both sexes. Serum adiponectin levels were decreased in females but increased in males. The insulin receptor signals were upregulated in the liver and downregulated in the skeletal muscle of F1 females, while they were inhibited in both tissues of F1 males. The visceral fat weight and body weight of the treated mice were not increased, suggesting that phenanthrene is not an obesogen, which is supported by the nonsignificant alteration in pparγ transcription in visceral adipose tissue. The transcription of retn in visceral adipose tissue was upregulated in both sexes, and that of adipoq was downregulated in females but upregulated in males, which were matched with the promoter methylation levels of these genes. The results indicated that phenanthrene exposure during gestation could disturb adipocytokine levels via epigenetic modification in adult offspring, and further influence glucose metabolism. These results might be helpful for understanding nonobesogenic pollutant-induced insulin resistance and preventing against diabetes without obesity.

In utero exposure to phenanthrene induced islet cell dysfunction in adult mice: Sex differences in the effects and potential causes.

Epidemiological studies show that the burden of polycyclic aromatic hydrocarbons in human body is associated with the occurrence of insulin resistance and diabetes. In the present study, pregnant mice were exposed to phenanthrene (Phe) at doses of 0, 60 and 600 µg/kg body weight of by gavage once every 3 days. The female F1 mice at 120 days of age showed no change in their fasting glucose levels (FGLs) but exhibited significantly decreased homeostasis model assessment (HOMA) ß-cell (49% and 43%) and significantly downregulated pancreatic proinsulin gene (ins2) transcription. The downregulation of transcription factors, such as PDX1, PAX4 and FGF21, indicated impaired development and function of ß-cells. The significantly reduced α-cell mass in 60 and 600 µg/kg groups, and the significantly downregulated expression of proglucagon gene gcg and ARX in the 600 µg/kg group suggested that the development and function of α-cells had been impacted. The males exhibited significantly increased FGLs (1.14- and 1.15-fold) in Phe exposed treatments and significantly elevated HOMA ß-cell (3.15-fold) in the 600 µg/kg group. Upregulated ins2 transcription and FGF21 protein in male mice prenatally exposed to 600 µg/kg Phe suggested that these animals appeared compensatory enhancement in ß-cell function. The reduced serum estradiol levels and downregulated pancreatic estrogen receptor α and ß were responsible for the dysfunction of ß-cells in the females. In the males, the significantly elevated androgen levels in the 600 µg/kg group might be related to the upregulated ins2 transcription, and the increased expression of pancreatic FGF21 further demonstrated the enhancement of ß-cell potential. The results will be helpful for assessing the risk of developing diabetes in adulthood after prenatal exposure to phenanthrene.

Exposure to Aroclor 1254 persistently suppresses the functions of pancreatic ß-cells and deteriorates glucose homeostasis in male mice.

Polychlorinated biphenyls (PCBs) are a class of persistent organic pollutants that have been shown to be related to the occurrence of type 2 diabetes mellitus (T2DM). Nevertheless, it is necessary to further explore the development of T2DM caused by PCBs and its underlying mechanisms. In the present study, 21-day-old C57BL/6 male mice were orally treated with Aroclor 1254 (0.5, 5, 50 or 500 µg kg-1) once every three days. After exposure for 66 d, the mice showed impaired glucose tolerance, 13% and 14% increased fasting serum insulin levels (FSIL), and 63% and 69% increases of the pancreatic ß-cell mass in the 50 and 500 µg kg-1 groups, respectively. After stopping exposure for 90 d, treated mice returned to normoglycemia and normal FSIL. After re-exposure of these recovered mice to Aroclor 1254 for 30 d, fasting plasma glucose showed 15%, 28% and 16% increase in the 5, 50 and 500 µg kg-1 treatments, FSIL exhibited 35%, 27%, 30% and 32% decrease in the 0.5, 5, 50 or 500 µg kg-1 groups respectively, and there was no change in pancreatic ß-cell mass. Transcription of the pancreatic insulin gene (Ins2) was significantly down-regulated in the 50 and 500 µg kg-1 groups, while DNA-methylation levels were simultaneously increased in the Ins2 promoter during the course of exposure, recovery and re-exposure. Reduced insulin levels were initially rescued by a compensative increase in ß-cell mass. However, ß-cell mass eventually failed to make sufficient levels of insulin, resulting in significant increases in fasting blood glucose, and indicating the development of T2DM.

Maternal Supplementation with ß-Carotene During Pregnancy Disturbs Lipid Metabolism and Glucose Homoeostasis in F1 Female Mice.

SCOPE: ß-Carotene (BC), a substitute for vitamin A, is widely used for its benefits. The present study investigates whether in-utero BC administration can alter lipid and glucose homoeostasis in offspring. METHODS AND RESULTS: Pregnant mice are supplemented with BC (1 mg kg-1 weight) by oral gavage once every 3 days, for a total of six doses. Increased visceral fat may be caused by up-regulated PPARγ (peroxisome proliferator-activated receptor gamma) and RXRα/ß (retinoid X receptors) in liver and adipose tissue, and glucose intolerance is observed in F1 adult females prenatally supplemented with BC, while F1 males do not exhibit these symptoms. In females, increased serum leptin, resistin, and IL-6 and reduced adiponectin, caused by visceral obesity, may result in downregulated insulin receptor signaling in muscle and further account for glucose intolerance. Increased pancreatic ß-cell mass might compensate for the downregulated insulin gene (ins2). Increased glucagon and α-cell mass, accompanied by upregulated glucagon gene (gcg), might also be risk factors for the development of diabetes. CONCLUSIONS: Maternal supplementation with BC disturbs lipid metabolism and induces glucose intolerance in F1 female mice, suggesting that BC supplementation during pregnancy should be used with caution.

Tributyltin in male mice disrupts glucose homeostasis as well as recovery after exposure: mechanism analysis.

Organotin compounds such as tributyltin (TBT) and triphenyltin can induce diabetes and insulin resistance. However, the development of diabetes caused by organotins and its underlying mechanisms remain unclear. In the present study, male KM mice were orally administered with TBT (0.5, 5, and 50 µg/kg) once every 3 days for 45 days. Their body weights increased and reached a significant difference compared to the control, and the fasting blood glucose levels were significantly elevated. The fasting levels of serum insulin and adiponectin increased, while glucagon levels decreased in the animals treated with TBT. The expression of the insulin receptor (IR) signaling cascade, including IR, IR substrate, phosphatidylinositol 3-kinase, Akt, and glucose transporter 4, was inhibited both in the skeletal muscle and the liver, which might be a main reason for the hyperglycemia and hyperinsulinemia. After removing the TBT stress for 60 days, the animals which had received exposure to TBT could recover normoglycemia, accompanied with a recovery of the suppressed IR signal pathway and fasting insulin levels. However, the fasting levels of serum adiponectin and glucagon were lower than that of the control mice, which would remain a potential risk inducing the disruption of glucose homeostasis.