Inhibition Kinetics of 16 Organophosphorus Pesticides or Their Active Metabolites on Erythrocyte Acetylcholinesterase From Humans and Rats.

Inhibition kinetics assays were conducted with 16 commercial organophosphate (OP) pesticides or their metabolites on acetylcholinesterase (AChE) in erythrocyte "ghost" preparations from 18 individual humans (both sexes; adults, juveniles, and cord blood samples; mixed races/ethnicities) and pooled samples from adult rats (both sexes). A well-established spectrophotometric assay using acetylthiocholine as substrate and a chromogen was employed. The kinetic parameters bimolecular rate constant (ki), dissociation constant (KI), and phosphorylation constant (kp) were calculated for each compound. As expected, a wide range of potencies were displayed among the tested compounds. Statistical analysis of the resultant data indicated no differences in sex, age, or race/ethnicity among the human samples that are unexpected based on chance (4.2% statistically significant out of 48 parameters calculated) and no differences between the sexes in rats. The bimolecular rate constants for 10 of the compounds were not statistically different between rats and humans. The data indicate that, consistent with the high level of conservation of AChE among species and the fact that AChE at different locations within a species arises from the same gene, the inhibition kinetic parameters calculated from rat erythrocyte ghost preparations should be useful in estimating potencies of OP compounds on target AChE in humans. Additionally, the data indicate that differences in sensitivities among individual humans were not apparent.

Exposure to p,p'-dichlorodiphenyldichloroethylene (DDE) induces fasting hyperglycemia without insulin resistance in male C57BL/6H mice.

Approximately 8.3% of the United States (U.S.) population have either diagnosed or undiagnosed diabetes mellitus. Out of all the cases of diabetes mellitus, approximately 90-95% of these cases are type 2 diabetes mellitus (T2D). Although the exact cause of T2D remains elusive, predisposing factors include age, weight, poor diet, and a sedentary lifestyle. Until recently the association between exposure to environmental contaminants and the occurrence of diabetes had been unexplored. However, recent epidemiological studies have revealed that elevated serum concentrations of certain persistent organic pollutants (POPs), especially organochlorine pesticides, are positively associated with increased prevalence of T2D and insulin resistance. The current study seeks to investigate if this association is causative or coincidental. Male C57BL/6H mice were exposed to DDE (2.0mg/kg or 0.4mg/kg) or vehicle (corn oil; 1mL/kg) for 5 days via oral gavage; fasting blood glucose, glucose tolerance, and insulin challenge tests were performed following a 7 day resting period. Exposure to DDE caused significant hyperglycemia compared to vehicle and this hyperglycemic effect persisted for up to 21 days following cessation of DDE administration. Intraperitoneal glucose tolerance tests and phosphorylation of Akt in the liver, skeletal muscle, and adipose tissue following insulin challenge were comparable between vehicle and DDE treated animals. To determine the direct effect of exposure to DDE on glucose uptake, in vitro glucose uptake assays following DDE exposure were performed in L6 myotubules and 3T3-L1 adipocytes. In summary, subacute exposure to DDE does produce fasting hyperglycemia, but this fasting hyperglycemia does not appear to be mediated by insulin resistance. Thus, the current study reveals that subacute exposure to DDE does alter systemic glucose homeostasis and may be a contributing factor to the development of hyperglycemia associated with diabetes.