Correlation of telomere length in brain tissue with peripheral tissues in living human subjects.

Telomeres are important to chromosomal stability, and changes in their length correlate with disease, potentially relevant to brain disorders. Assessing telomere length in human brain is invasive, but whether peripheral tissue telomere length correlates with that in brain is not known. Saliva, buccal, blood, and brain samples were collected at time points before, during, and after subjects undergoing neurosurgery (n = 35) for intractable epilepsy. DNA was isolated from samples and average telomere length assessed by qPCR. Correlations of telomere length between tissue samples were calculated across subjects. When data were stratified by sex, saliva telomere length correlated with brain telomere length in males only. Buccal telomere length correlated with brain telomere length when males and females were combined. These findings indicate that in living subjects, telomere length in peripheral tissues variably correlates with that in brain and may be dependent on sex. Peripheral tissue telomere length may provide insight into brain telomere length, relevant to assessment of brain disorder pathophysiology.

A narrative review of converging evidence addressing developmental toxicity of pyrethroid insecticides.

Pyrethroid insecticides are broadly used in agriculture and household products throughout the world. Exposure to this class of insecticides is widespread, and while generally believed to be safe for use, there is increasing concern regarding their effects on neurodevelopment. Due to the critical roles that molecular targets of pyrethroids play in the regulation of neurodevelopment, particular focus has been placed on evaluating the effects of in utero and childhood pyrethroid exposure on child cognition and behavior. As such, this narrative review synthesizes an assessment of converging study types; we review reports of neonatal pyrethroid levels together with current epidemiological literature that convergently address the risk for developmental toxicity linked to exposure to pyrethroid insecticides. We first address studies that assess the degree of direct fetal exposure to pyrethroids in utero through measurements in cord blood, meconium, and amniotic fluid. We then focus on the links between prenatal exposure to these insecticides and child neurodevelopment, fetal growth, and other adverse birth outcomes. Furthermore, we assess the effects of postnatal exposure on child neurodevelopment through a review of the data on pediatric exposures and child cognitive and behavioral outcomes. Study quality was evaluated individually, and the weight of evidence was assessed broadly to characterize these effects. Overall, while definitive conclusions cannot be reached from the currently available literature, the available data suggest that the potential links between pyrethroid exposure and child neurodevelopmental effects deserve further investigation.

Maternal and fetal tissue distribution of α-cypermethrin and permethrin in pregnant CD-1 mice.

Pyrethroid insecticides are widely used throughout agriculture and household products. Recent studies suggest that prenatal exposure to these insecticides may adversely affect fetal development; however, little is known about the distribution of these chemicals in pregnant animals. The present study aimed to address this gap in knowledge by investigating the distribution of two commonly used pyrethroid insecticides, permethrin and α-cypermethrin, in maternal and fetal tissues of pregnant CD-1 mice. Dams were dosed from gestational days 6 to 16 via oral gavage with permethrin (1.5, 15, and 50 mg/kg), α-cypermethrin (0.3, 3, and 10 mg/kg), or corn oil vehicle. Pyrethroid levels were determined in gestational day 16 tissues collected 90 min after the final dose was administered. Across maternal tissues, levels of both pyrethroids were the highest in maternal ovaries, followed by liver and brain, respectively. In addition, levels of both pyrethroids in maternal tissues and placenta were significantly higher than those in the fetal body and amniotic fluid, suggesting that these compounds may exhibit low transfer across the mouse placenta. While additional toxicokinetic studies are needed to verify the time course of pyrethroids in the fetal compartment, these findings support investigation into indirect modes of action relevant to the effects of pyrethroids on mammalian fetal development.

Combined Maternal Exposure to Cypermethrin and Stress Affect Embryonic Brain and Placental Outcomes in Mice.

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.

Cellular stress mechanisms of prenatal maternal stress: Heat shock factors and oxidative stress.

Development of the brain prenatally is affected by maternal experience and exposure. Prenatal maternal psychological stress changes brain development and results in increased risk for neuropsychiatric disorders. In this review, multiple levels of prenatal stress mechanisms (offspring brain, placenta, and maternal physiology) are discussed and their intersection with cellular stress mechanisms explicated. Heat shock factors and oxidative stress are closely related to each other and converge with the inflammation, hormones, and cellular development that have been more deeply explored as the basis of prenatal stress risk. Increasing evidence implicates cellular stress mechanisms in neuropsychiatric disorders associated with prenatal stress including affective disorders, schizophrenia, and child-onset psychiatric disorders. Heat shock factors and oxidative stress also have links with the mechanisms involved in other kinds of prenatal stress including external exposures such as environmental toxicants and internal disruptions such as preeclampsia. Integrative understanding of developmental neurobiology with these cellular and physiological mechanisms is necessary to reduce risks and promote healthy brain development.

PCB126 Inhibits the Activation of AMPK-CREB Signal Transduction Required for Energy Sensing in Liver.

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.