No abstract

3,3',4,4',5-pentachlorobiphenyl (PCB126), a dioxin-like PCB, elicits toxicity through a wide array of noncarcinogenic effects, including metabolic syndrome, wasting, and nonalcoholic fatty-liver disease. Previously, we reported decreases in the transcription of several enzymes involved in gluconeogenesis, before the early onset of lipid accumulation. Hence, this study was aimed at understanding the impact of resultant decreases gluconeogenic enzymes on growth, weight, and metabolism in the liver, upon extended exposure. Male Sprague Dawley rats (75-100 g), fed a defined AIN-93G diet, were injected (ip) with single dose of soy oil (5 ml/kg body weight; n = 14) or PCB126 (5 µmol/kg; n = 15), 28 days, prior euthanasia. A subset of rats from each group were fasted for 12 h (vehicle [n = 6] and PCB126 [n = 4]). Rats only showed significant weight loss between days 14 and 28 (p < .05) and some mortality (p = .0413). As in our previous studies, the expression levels of enzymes involved in gluconeogenesis (Pepck-c, G6Pase, Sds, Pc, and Ldh-A) and glycogenolysis (Pygl) were strongly downregulated. The decreased expression of these enzymes in PCB126-treated rats after a 12 h fast decreased hepatic glucose production from glycogen and gluconeogenic substrates, exacerbating the hypoglycemia. Additionally, PCB126 caused hepatic steatosis and decreased the expression of the transcription factor Pparα and its targets, necessary for fatty-acid oxidation. The observed metabolic disruption across multiple branches of fasting metabolism resulted from inhibition in the activation of enzyme AMPK and transcription factor CREB signaling, necessary for "sensing" energy-deprivation and the induction of enzymes that respond to the PCB126 triggered fuel crisis in liver.

Prenatal exposure to cypermethrin is a risk factor for adverse neurodevelopmental outcomes in children. In addition, maternal psychological stress during pregnancy has significant effects on fetal neurodevelopment and may influence end-stage toxicity to offspring by altering maternal xenobiotic metabolism. As such, this study examined effects of maternal exposure to alpha-cypermethrin and stress, alone and in combination, on offspring development, with a focus on fetal neurotoxicity. CD1 mouse dams were administered 10 mg/kg alpha-cypermethrin or corn oil vehicle via oral gavage from embryonic day 11 (E11) to E14. In addition, dams from each treatment were subjected to a standard model of restraint stress from E12 to E14. Cypermethrin treatment impaired fetal growth, reduced fetal forebrain volume, and increased ventral forebrain proliferative zone volume, the latter effects driven by combined exposure with stress. Cypermethrin also impaired migration of GABAergic progenitors, with different transcriptional changes alone and in combination with stress. Stress and cypermethrin also interacted in effects on embryonic microglia morphology. In addition, levels of cypermethrin were elevated in the serum of stressed dams, which was accompanied by interacting effects of cypermethrin and stress on hepatic expression of cytochrome P450 enzymes. Levels of cypermethrin in amniotic fluid were below the limit of quantification, suggesting minimal transfer to fetal circulation. Despite this, cypermethrin increased placental malondialdehyde levels and increased placental expression of genes responsive to oxidative stress, effects significantly modified by stress exposure. These findings suggest a role for interaction between maternal exposures to cypermethrin and stress on offspring neurodevelopment, involving indirect mechanisms in the placenta and maternal liver.

No abstract

No abstract