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Developmental exposure to polychlorinated biphenyls (PCBs) has been associated with cognitive deficits in children. Rodent studies have revealed impairments in learning tasks involving the hippocampus. The present study sought to examine hippocampal synaptic plasticity in the dentate gyrus and spatial learning in animals exposed to PCBs early in development. Pregnant Long-Evans rats were administered either corn oil (control) or 6 mg/kg/day of a commercial PCB mixture, Aroclor 1254 (A1254) by gavage from gestational day (GD) 6 until pups were weaned on postnatal day (PND) 21. Spatial learning was assessed at 3 months of age in male and female offspring using the Morris water maze. Latency to find a hidden platform that remained in the same position over 20 days of testing did not differ between control and PCB-exposed groups. Neither were group differences evident in a repeated acquisition version of the task in which the platform remained in the same position over the 2 daily trials but was moved to a new spatial location each day. Male littermates of animals in the behavioral study were tested electrophysiologically at 5–7 months of age. Field potentials evoked by perforant path stimulation were recorded in the dentate gyrus under urethane anesthesia. Input/output (I/O) functions were assessed by averaging the response evoked in the dentate gyrus to stimulus pulses delivered to the perforant path in an ascending intensity series. Long-term potentiation (LTP) was induced by delivering a series of brief, high-frequency train bursts to the perforant path at increasing stimulus intensities, and I/O functions were reassessed 1 h later. No differences in baseline synaptic population spike (PS) and excitatory postsynaptic potential (EPSP) slope amplitudes were discerned between the groups prior to train delivery. Post-train I/O functions, however, revealed a decrement in the magnitude of evoked LTP in PCB-exposed animals, and an increase in the train intensity required to induce LTP. The observed dissociation between impaired hippocampal plasticity, in the absence of a detectable deficit in performance of a hippocampal-dependent task, may be due to task complexity, the maintenance of some degree of plasticity in the PCB-exposed animals, or the possibility that intact dentate gyrus LTP may not be requisite for water-maze learning. [ABSTRACT FROM PUBLISHER]

Abstract Background Pyrethroids are neurotoxic pesticides that interact with membrane bound ion channels in neurons and disrupt nerve function. The purpose of this study was to characterize and explore changes in gene expression that occur in the rat frontal cortex, an area of CNS affected by pyrethroids, following an acute low-dose exposure. Results Rats were acutely exposed to either deltamethrin (0.3 – 3 mg/kg) or permethrin (1 – 100 mg/kg) followed by collection of cortical tissue at 6 hours. The doses used range from those that cause minimal signs of intoxication at the behavioral level to doses well below apparent no effect levels in the whole animal. A statistical framework based on parallel linear (SAM) and isotonic regression (PIR) methods identified 95 and 53 probe sets as dose-responsive. The PIR analysis was most sensitive for detecting transcripts with changes in expression at the NOAEL dose. A sub-set of genes (Camk1g, Ddc, Gpd3, c-fos and Egr1) was then confirmed by qRT-PCR and examined in a time course study. Changes in mRNA levels were typically less than 3-fold in magnitude across all components of the study. The responses observed are consistent with pyrethroids producing increased neuronal excitation in the cortex following a low-dose in vivo exposure. In addition, Significance Analysis of Function and Expression (SAFE) identified significantly enriched gene categories common for both pyrethroids, including some relating to branching morphogenesis. Exposure of primary cortical cell cultures to both compounds resulted in an increase (~25%) in the number of neurite branch points, supporting the results of the SAFE analysis. Conclusion In the present study, pyrethroids induced changes in gene expression in the frontal cortex near the threshold for decreases in ambulatory motor activity in vivo. The penalized regression methods performed similarly in detecting dose-dependent changes in gene transcription. Finally, SAFE analysis of gene expression data identified branching morphogenesis as a biological process sensitive to pyrethroids and subsequent in vitro experiments confirmed this predicted effect. The novel findings regarding pyrethroid effects on branching morphogenesis indicate these compounds may act as developmental neurotoxicants that affect normal neuronal morphology.

We report the case of a patient with dextrocardia and situs inversus totalis associated with obstructive coronariopathy in the anterior and posterior descending arteries, right coronary artery, first diagonal branch and left marginal branch. The patient underwent coronary artery bypass grafting surgery. This surgery has been rarely reported in literature and we found only one similar case in the national medical literature. The myocardial revascularization was carried out with the right mammary artery for the anterior descending artery. The saphenous vein anastomosed the aorta to the right coronary artery, left marginal branch, fist diagonal branch and posterior descending artery. The surgery was performed with extracorporeal circulation. [ABSTRACT FROM AUTHOR]

A key challenge in systematically incorporating mechanistic data into human health assessments is that, compared to studies of apical health endpoints, these data are both more abundant (mechanistic studies routinely outnumber other studies by several orders of magnitude) and more heterogeneous (e.g. different species, test system, tissue, cell type, exposure paradigm, or specific assays performed). A structured decision-making process for organizing, integrating, and weighing mechanistic DNT data for use in human health risk assessments will improve the consistency and efficiency of such evaluations. At the Developmental Neurotoxicology Society (DNTS) 2016 annual meeting, a symposium was held to address the application of existing organizing principles and frameworks for evaluation of mechanistic data relevant to interpreting neurotoxicology data. Speakers identified considerations with potential to advance the use of mechanistic DNT data in risk assessment, including considering the context of each exposure, since epigenetics, tissue type, sex, stress, nutrition and other factors can modify toxicity responses in organisms. It was also suggested that, because behavior is a manifestation of complex nervous system function, the presence and absence of behavioral change itself could be used to organize the interpretation of multiple complex simultaneous mechanistic changes. Several challenges were identified with frameworks and their implementation, and ongoing research to develop these approaches represents an early step toward full evaluation of mechanistic DNT data for assessments., Competing Interests: Declaration of competing interest None of the authors have any financial or other conflicts of interest to declare., (Published by Elsevier Inc.)

Mammals have a marked period of rapid brain growth and development (BGS), which is postnatal in mice and rats, spanning the first 3-4 weeks of life and reaching its peak around postnatal day 10. CaMKII, GAP-43 and BDNF play important roles during the BGS in mammals. One class of flame retardants, polybrominated diphenyl ethers (PBDEs), are present and increasing in the environment and in human milk, which is also true for the only congener still in use, decabrominated diphenyl ether (PBDE 209). In the present study, the brains from 1, 3, 7, 10, 14 and 28 days old mice, were analysed for CaMKII and GAP-43. The level of CaMKII increases continuously during the neonatal period, while GAP-43 has a bell-shaped ontogeny curve, which peaks around postnatal day 10, in mouse brain. Furthermore, the effects of PBDE 209 on the developmental expression of CaMKII, GAP-43 and BDNF were examined in mice. Neonatal NMRI-male mice were orally exposed on days 3-20.1mgPBDE 209/kg body weight. The animals were euthanized 7 days after exposure to PBDE 209 and levels of CaMKII, GAP-43 and BDNF were analysed in different brain regions. The protein analysis showed that CaMKII increased significantly in hippocampus, but not in cortex, in animals 7 days after exposure to PBDE 209. GAP-43 showed a significant increase in hippocampus and a significant decrease in cortex of animals 7 days after exposure to PBDE 209. BDNF decreased significantly in hippocampus, but not in cortex, in mice 7 days after exposure to PBDE 209. This shows that PBDE 209 affects important proteins involved in normal maturation of the brain and further strengthen our findings concerning PBDE 209 as a developmental neurotoxicological agent.

Cyclic AMP (cAMP)-responsive element-binding protein (CREB) is a transcription factor important in developing nervous system cells and is activated by a variety of signaling molecules. Aroclor 1254 (A1254), a polychlorinated biphenyl mixture, perturbs Ca(2+) homeostasis and increases CREB phosphorylation in rat neonatal cortical cell cultures in a time- and concentration-dependent manner. The present experiments determined that the cell type responding to A1254 with Ca(2+) increases and phosphorylated CREB (phospho-CREB) was predominantly of neuronal morphology and microtubule-associated protein (MAP2)-positive phenotype. Similarly, glutamate (100 microM) increased phospho-CREB immunoreactivity selectively in MAP2-immunopositive cells. Using Western blotting and immunocytochemical techniques, we identified key signal transduction pathways operative in phosphorylating CREB in cortical cell cultures and examined their participation in 3 ppm A1254-induced CREB activation. Cortical cultures treated with glutamate, forskolin or the phorbol ester phorbol 12-myristate 13-acetate exhibited robust increases in phospho-CREB. Tetrodotoxin (1 microM) completely inhibited CREB phosphorylation by A1254, suggesting that synaptic activity is involved in A1254-induced CREB activation. Buffering [Ca(2+)](i) with bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid tetrakis(acetoxymethyl) ester in the absence of extracellular Ca(2+) partially inhibited A1254-induced CREB phosphorylation. Inhibition of mitogen-activated protein kinase (10 microM U0126) or protein kinase C (PKC; bisindoylmaleimide, 5 microM) activation did not inhibit A1254-induced CREB phosphorylation. By contrast, inhibition of protein kinase A (PKA) with 100 microM PKA inhibitor peptide, PKI, blocked A1254-induced CREB phosphorylation. Thus, we examined whether A1254 activates PKA by increasing cAMP; 10 microM forskolin, but not A1254, elevated intracellular cAMP levels. These results indicate that in neocortical cells in culture, CREB phosphorylation occurs via Ca(2+)-, PKA-, and PKC-dependent pathways. Furthermore, A1254-induced CREB phosphorylation occurs predominantly in neurons, is dependent on synaptic activity and mediated by Ca(2+)- and PKA-dependent pathways.

The present study assessed intracellular Ca(2+) signaling pathways sensitive to polychlorinated biphenyls (PCBs), xenobiotics that perturb neural development and plasticity. Mobilization of intracellular Ca(2+) stores after acute exposure to a PCB mixture, Aroclor 1254 (A1254), as well as selected PCB congeners, was studied in P0 rat cortical neuronal culture using fluorescence microscopy. Ca(2+) responses to A1254 progressed from a transient intracellular Ca(2+) increase (lasting 3--5 min) at 1 to 2 microM (0.3-0.6 ppm) to a Ca(2+) transient with store-operated Ca(2+) influx and later disturbances of basal Ca(2+) concentration; this latter pattern occurred more often with 10 to 20 microM (3--6 ppm) A1254. Thapsigargin, xestospongin C, and carbachol/Ca(2+)-free buffer blocked significantly the PCB-induced Ca(2+) transient, whereas both ryanodine (to deplete ryanodine-sensitive stores) and the L-type Ca(2+) channel blocker nifedipine were without effect on the A1254 initial Ca(2+) transient. Both thapsigargin and xestospongin also blocked latent elevations (at 0.5 h) in Ca(2+), disturbances that depend upon extracellular Ca(2+) entry via ion channels. Two possible consequences were explored. Phosphorylation of cAMP responsive element binding protein, a Ca(2+)-activated nuclear transcription factor (CREB), occurred in an A1254 concentration-dependent manner and persisted at least 1 h. Cell viability following a 24-h exposure to A1254 (2-20 microM) was decreased at 20 microM, but only in cells cultured >6 days. This cell death did not occur via an apoptotic mechanism. These results indicate that Ca(2+) disturbances following PCB exposure are associated with 1) discrete alterations in IP(3) receptor-mediated signals and 2) activation of downstream events that impact developing cortical cells.

Polychlorinated biphenyls (PCBs) are environmental contaminants, which accumulate in the food chain and are transferred to the offspring during prenatal development through the placenta and postnatally via breast milk. It is reported that PCBs exert effects on thyroid hormone levels and brain neurotransmitter levels. Both actions may alter neuronal development. The aim of the present study was to investigate, if PCB-induced effects on concentrations of catecholamines and serotonin can be attributed to PCB-induced reductions in thyroid hormone concentrations. In addition, binding to dopamine D(1) and D(2) receptors was examined. Time-mated Wistar rats were treated prenatally with 1 mg 3,4,3',4'-tetrachlorobiphenyl (PCB 77)/kg bodyweight or the vehicle. A third group serving as the positive control received perinatally 5 mg propylthiouracil (PTU)/l drinking water. There were no overt toxic signs in dams or offspring. Thyroid hormone measurements demonstrated effects in dams and offspring up to postnatal day 40. In particular, total T(4) in serum and in the thyroid were decreased in PCB- and PTU-treated dams and offspring. Only PTU exposed rats exhibited significantly increased concentrations of TSH in the serum and pituitary. Measurement of neurotransmitters revealed changes in the PCB-exposed offspring at PND 40, while PTU-treatment was without effect. Dopamine and DOPAC were increased in the medial prefrontal cortex. In adulthood, there were no PCB-related effects on thyroid hormones and neurotransmitters. Binding studies of dopamine D1 and D2 receptors demonstrated that PCB and PTU had no influence on receptor concentration and affinity. Comparison of PCB 77 exposed offspring to PTU exposed offspring demonstrated differential effects on TSH and neurotransmitter levels, the latter result indicating that not all PCB-induced effects on the nervous system can be ascribed to decreases in thyroid hormone concentrations.

It is widely recognized that prolonged increases in reactive oxygen species (ROS) and intracellular free calcium ([Ca2+]i) are part of a signaling pathway leading to cell death. ROS production resulting in oxidative stress and disruption of calcium homeostasis leading to increases in [Ca2+]i have been described as early events following exposure to a number of neurotoxicants. In order to determine the intrinsic sensitivity of developing neurons to toxicant-induced oxidative stress and disruption of calcium homeostasis, we exposed immature neurons to iron (Fe2+) or methylmercury (MeHg). Primary cultures of cortical cells (prepared from 1 day old rats) or cerebellar granule cells (prepared from 7 day old rats) were exposed to the toxicants on day in vitro (DIV) 1 (immature response to receptor agonists) or DIV 7 (mature response to receptor agonists). ROS was measured using the fluorescent probe 2',7'-dichlorodihydrofluorescin. In both cerebellar granule cells and cortical cells, Fe2+ or MeHg exposure (0.1-30 microM) produced time- and concentration-dependent increases in ROS. In general, the increase in ROS induced by both metals was greater in immature cells compared to mature cells, except for cerebellar granule cells in which the effects of Fe2+ were similar at DIV1 and 7. Changes in intracellular cation concentrations (including Ca2+) were measured using the fluorescent probe fluo-3. MeHg exposure produced a time- and concentration-dependent increase in fluo-3 fluorescence in both cerebellar granule cells and cortical cells. In cortical cultures, the fluorescence increase after MeHg exposure was greater in immature cells. In contrast, mature and immature cells were equally sensitive to the effects of MeHg in cerebellar granule cell cultures. These results suggest that there may be inherent differences in the sensitivity of neurons to toxicant-induced increases in ROS and [Ca2+] depending upon age and cell type.