Toxicogenomic Characterization of Molecular Mechanisms Contributing to Chlorpyrifos Neurotoxicity in Adult Male Rats
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ABSTRACT:
ORGANISM(S): Rattus norvegicus
PROVIDER: GSE74728 | GEO | 2016/12/30
SECONDARY ACCESSION(S): PRJNA301351
REPOSITORIES: GEO
Similar Datasets
Project description:Chlorpyrifos (CPF) is an organophosphorus pesticide (OP), and one of the most widely used pesticides in the world. Metabolites of CPF and other OPs continue to be identified in the majority of human samples, even in countries such as the United States where OP use is declining (Arcury et al., 2010). The effects of repeated occupational and environmental exposures to OPs are poorly understood, although human and animal studies consistently identify neurotoxicity as the primary endpoint of concern. Thus, occupational exposures to sublethal doses of CPF are consistently associated with problems in cognitive abilities, such as learning and memory but the biological mechanism(s) underlying this association remain speculative. To identify potential mechanisms of CPF neurotoxicity, we employed a rat model that simulated documented CPF exposures in Egyptian agricultural workers. We quantified mRNA expression profiles in the CA1 region of the hippocampus of adult male Long Evans (LE) rats administered CPF at 3 or 10 mg/kg/d (s.c.) for 21 days. Despite significant inhibition of cholinesterase activity by the end of the 21 d exposure period, the CPF-exposed rats displayed minimal signs of cholinergic toxicity. Distinct hippocampal mRNA and miRNA signatures were associated with CPF exposure. Toxicogenomics-based evidence identified increased expression of neuropeptide genes in the hippocampi of CPF-exposed rats, which have been shown to activate receptor-mediated signaling pathways involved in cell survival. The analysis of small non-coding RNA profiles suggested the possibility that miR132/212-mediated homeostatic regulatory pathways may also be activated by repeated exposures to CPF. These findings identify potential molecular effects that may contribute to neurobehavioral deficits.
2016-12-30 | GSE74676 | GEO
Project description:Chlorpyrifos (CPF) is an organophosphorus pesticide (OP), and one of the most widely used pesticides in the world. Metabolites of CPF and other OPs continue to be identified in the majority of human samples, even in countries such as the United States where OP use is declining (Arcury et al., 2010). The effects of repeated occupational and environmental exposures to OPs are poorly understood, although human and animal studies consistently identify neurotoxicity as the primary endpoint of concern. Thus, occupational exposures to sublethal doses of CPF are consistently associated with problems in cognitive abilities, such as learning and memory but the biological mechanism(s) underlying this association remain speculative. To identify potential mechanisms of CPF neurotoxicity, we employed a rat model that simulated documented CPF exposures in Egyptian agricultural workers. We quantified mRNA expression profiles in the CA1 region of the hippocampus of adult male Long Evans (LE) rats administered CPF at 3 or 10 mg/kg/d (s.c.) for 21 days. Despite significant inhibition of cholinesterase activity by the end of the 21 d exposure period, the CPF-exposed rats displayed minimal signs of cholinergic toxicity. Distinct hippocampal mRNA and miRNA signatures were associated with CPF exposure. Toxicogenomics-based evidence identified increased expression of neuropeptide genes in the hippocampi of CPF-exposed rats, which have been shown to activate receptor-mediated signaling pathways involved in cell survival. The analysis of small non-coding RNA profiles suggested the possibility that miR132/212-mediated homeostatic regulatory pathways may also be activated by repeated exposures to CPF. These findings identify potential molecular effects that may contribute to neurobehavioral deficits.
2016-12-30 | GSE74726 | GEO
Project description:Chlorpyrifos (CPF) is an organophosphorus pesticide (OP), and one of the most widely used pesticides in the world. Metabolites of CPF and other OPs continue to be identified in the majority of human samples, even in countries such as the United States where OP use is declining (Arcury et al., 2010). The effects of repeated occupational and environmental exposures to OPs are poorly understood, although human and animal studies consistently identify neurotoxicity as the primary endpoint of concern. Thus, occupational exposures to sublethal doses of CPF are consistently associated with problems in cognitive abilities, such as learning and memory but the biological mechanism(s) underlying this association remain speculative. To identify potential mechanisms of CPF neurotoxicity, we employed a rat model that simulated documented CPF exposures in Egyptian agricultural workers. We quantified mRNA expression profiles in the CA1 region of the hippocampus of adult male Long Evans (LE) rats administered CPF at 3 or 10 mg/kg/d (s.c.) for 21 days. Despite significant inhibition of cholinesterase activity by the end of the 21 d exposure period, the CPF-exposed rats displayed minimal signs of cholinergic toxicity. Distinct hippocampal mRNA and miRNA signatures were associated with CPF exposure. Toxicogenomics-based evidence identified increased expression of neuropeptide genes in the hippocampi of CPF-exposed rats, which have been shown to activate receptor-mediated signaling pathways involved in cell survival. The analysis of small non-coding RNA profiles suggested the possibility that miR132/212-mediated homeostatic regulatory pathways may also be activated by repeated exposures to CPF. These findings identify potential molecular effects that may contribute to neurobehavioral deficits.
2016-12-30 | GSE74727 | GEO
Project description:Toxicogenomic Characterization of Molecular Mechanisms Contributing to Chlorpyrifos Neurotoxicity in Adult Male Rats
| PRJNA301351 | ENA
Project description:Authorization of pesticides for market release requires toxicity testing on animals, typically performed by test laboratories on contract with the pesticide producer. The latter provides the results and summary to the regulatory authorities. For the commonly used pesticide chlorpyrifos, an industry-funded toxicity study concludes that no selective effects on neurodevelopment occur even at high exposures. In contrast, the evidence from independent studies points to adverse effects of current exposures on cognitive development in children. We reviewed the industry-funded developmental neurotoxicity test data on chlorpyrifos and the related substance chlorpyrifos-methyl. We noted treatment-related changes in a brain dimension measure for chlorpyrifos at all dose levels tested, although not been reported in the original test summary. We further found issues which inappropriately decrease the ability of the studies to reveal true effects, including a dosage regimen that resulted in too low exposure of the nursing pups for chlorpyrifos and possibly for chlorpyrifos-methyl, and a failure to detect any neurobehavioral effects of lead nitrate used as positive control in the chlorpyrifos study. Our observations thus suggest that conclusions in test reports submitted by the producer may be misleading. This discrepancy affects the ability of regulatory authorities to perform a valid and safe evaluation of these pesticides. The difference between raw data and conclusions in the test reports indicates a potential existence of bias that would require regulatory attention and possible resolution.
| S-EPMC6238321 | biostudies-literature
Project description:Occupational and environmental exposures to organophosphorus pesticides (OPs) are associated with increased incidence of asthma and other pulmonary diseases. Although the canonical mechanism of OP neurotoxicity is inhibition of acetylcholinesterase (AChE), it was previously reported that the OP chlorpyrifos (CPF) causes airway hyperreactivity (AHR) in guinea pigs at levels that do not inhibit lung or brain AChE. The guinea pig is considered to have inherently hyperresponsive airways, thus, cross-species validation is needed to confirm relevance to humans. Additionally, sex differences in asthma incidence have been demonstrated in the human population, but whether OP-induced AHR is sex-dependent has not been systematically studied in a preclinical model. In this study, 8-week old male and female Sprague Dawley rats were administered CPF at doses causing comparable AChE inhibition in whole lung homogenate (30?mg/kg in males, 7?mg/kg in females, sc) prior to assessing pulmonary mechanics in response to electrical stimulation of the vagus nerves at 24?h, 48?h, 72?h, 7 d or 14 d post-exposure in males, and 24?h or 7 d post-exposure in females. CPF significantly potentiated vagally induced airway resistance and tissue elastance at 7 d post-exposure in males, and at 24?h and 7 d post-exposure in females. These effects occurred independent of significant AChE inhibition in cerebellum, blood, trachealis, or isolated airway, suggesting that AChE independent OP-induced airway hyperreactivity is a cross-species phenomenon. These findings have significant implications for assessing the risk posed by CPF, and potentially other OPs, to human health and safety.
| S-EPMC6135637 | biostudies-literature
Project description:Chlorpyrifos (CPF) is a common organophosphorus insecticide. It is associated with negative consequences such as neurotoxicity and reproductive injury. This study aimed to observe the ability of olive leaf extract to attenuate chlorpyrifos toxicity, which induced neuro- and reproductive toxicity in male albino rats. Olive leaf extract (OLE) exhibits potent antioxidant and antiapoptotic properties. Twenty-two mature male rats were divided into four groups: control (saline), CPF (9 mg/kg), OLE (150 mg/kg), and CPF + OLE. Treatment was administered orally for 80 days. The CPF significantly reduced serum sex hormones, sperm counts and motility, high oxidants (MDA), and depleted antioxidants (GSH, SOD, TAC) in the brain and testes homogenate; additionally, it decreased serum AChE and brain neurotransmitters, increased Bax, decreased Bcl-2, and boosted caspase-3 immune expression in neural and testicular cells. Immunological expression of Ki 67 in the cerebrum, cerebellum, choroid plexus, and hippocampus was reduced, and α-SMA in testicular tissue also decreased. Histopathological findings were consistent with the above impacts. OLE co-administration significantly normalized all these abnormalities. OLE showed significant protection against neural and reproductive damage caused by CPF.
| S-EPMC9605092 | biostudies-literature
Project description:BackgroundOxidative stress and excitotoxicity underlie the developmental neurotoxicity of numerous chemicals.ObjectivesWe compared the effects of organophosphates (chlorpyrifos and diazinon), an organo-chlorine (dieldrin), and a metal [divalent nickel (Ni2+)] to determine how these mechanisms contribute to similar or dissimilar neurotoxic outcomes.MethodsWe used PC12 cells as a model of developing neurons and evaluated transcriptional profiles for genes for oxidative stress responses and glutamate receptors.ResultsChlorpyrifos had a greater effect on oxidative-stress-related genes in differentiating cells compared with the undifferentiated state. Chlorpyrifos and diazinon showed significant concordance in their effects on glutathione-related genes, but they were negatively correlated for effects on catalase and superoxide dismutase isoforms and had no concordance for effects on ionotropic glutamate receptors. Surprisingly, the correlations were stronger between diazinon and dieldrin than between the two organophosphates. The effects of Ni2+ were the least similar for genes related to oxidative stress but had significant concordance with dieldrin for effects on glutamate receptors.ConclusionsOur results point to underlying mechanisms by which different organophosphates produce disparate neurotoxic outcomes despite their shared property as cholinesterase inhibitors. Further, apparently unrelated neurotoxicants may produce similar outcomes because of convergence on oxidative stress and excitotoxicity. The combined use of cell cultures and microarrays points to specific end points that can distinguish similarities and disparities in the effects of diverse developmental neurotoxicants.
| S-EPMC2679603 | biostudies-literature
Project description:Mesenchymal stem/stromal cells (MSCs) are a reservoir for tissue homeostasis and repair that age during organismal aging. Beside the fundamental in vivo role of MSCs, they have also emerged in the last years as extremely promising therapeutic agents for a wide variety of clinical conditions. MSC use frequently requires in vitro expansion, thus exposing cells to replicative senescence. Aging of MSCs (both in vivo and in vitro) can affect not only their replicative potential, but also their properties, like immunomodulation and secretory profile, thus possibly compromising their therapeutic effect. It is therefore of critical importance to unveil the underlying mechanisms of MSC senescence and to define shared methods to assess MSC aging status. The present review will focus on current scientific knowledge about MSC aging mechanisms, control and effects, including possible anti-aging treatments.
| S-EPMC7072652 | biostudies-literature
Project description:Physical activity has been known as an essential element to promote human health for centuries. Thus, exercise intervention is encouraged to battle against sedentary lifestyle. Recent rapid advances in molecular biotechnology have demonstrated that both endurance and resistance exercise training, two traditional types of exercise, trigger a series of physiological responses, unraveling the mechanisms of exercise regulating on the human body. Therefore, exercise has been expected as a candidate approach of alleviating a wide range of diseases, such as metabolic diseases, neurodegenerative disorders, tumors, and cardiovascular diseases. In particular, the capacity of exercise to promote tissue regeneration has attracted the attention of many researchers in recent decades. Since most adult human organs have a weak regenerative capacity, it is currently a key challenge in regenerative medicine to improve the efficiency of tissue regeneration. As research progresses, exercise-induced tissue regeneration seems to provide a novel approach for fighting against injury or senescence, establishing strong theoretical basis for more and more "exercise mimetics." These drugs are acting as the pharmaceutical alternatives of those individuals who cannot experience the benefits of exercise. Here, we comprehensively provide a description of the benefits of exercise on tissue regeneration in diverse organs, mainly focusing on musculoskeletal system, cardiovascular system, and nervous system. We also discuss the underlying molecular mechanisms associated with the regenerative effects of exercise and emerging therapeutic exercise mimetics for regeneration, as well as the associated opportunities and challenges. We aim to describe an integrated perspective on the current advances of distinct physiological mechanisms associated with exercise-induced tissue regeneration on various organs and facilitate the development of drugs that mimics the benefits of exercise.
| S-EPMC9709153 | biostudies-literature