The susceptibility of humans to neurodegenerative and neurodevelopmental toxicities caused by organophosphorus pesticides.

The toxicology field is concerned with the impact of organophosphorus (OP) compounds on human health. These compounds have been linked to an increased risk of neurological disorders, including neurodegenerative and neurodevelopmental diseases. This article aims to review studies on the role of OP compounds in developing these neurological disorders and explore how genetic variations can affect susceptibility to the neurotoxicity of these pesticides. Studies have shown that exposure to OP compounds can lead to the development of various neurological disorders, such as Alzheimer's disease (AD), Parkinson's disease (PD), attention deficit hyperactivity disorder (ADHD), autism, intellectual disability, and other developmental neurotoxicities. Apart from inhibiting the cholinesterase enzyme, OP compounds are believed to cause other pathological mechanisms at both the extracellular level (cholinergic, serotonergic, dopaminergic, glutamatergic, and GABAergic synapses) and the intracellular level (oxidative stress, mitochondrial dysfunction, inflammation, autophagy, and apoptosis) that contribute to these disorders. Specific genetic polymorphisms, including PON1, ABCB1, NOS, DRD4, GST, CYP, and APOE, have increased the risk of developing OP-related neurological disorders.

Pesticides and insulin resistance-related metabolic diseases: Evidences and mechanisms.

The use of pesticides in the past century has lot helped humankind in improving crops' field and general hygiene level. Nevertheless, there has been countless evidences on the toxic effects of pesticides on the living systems. The link of exposure to pesticides with different human chronic diseases in the context of carcinogenicity, neurotoxicity, developmental toxicity, etc., have been evaluated in various types of studies. There are also some evidences on the link of exposure to pesticides with higher incidence of metabolic diseases associated with insulin resistance like diabetes, obesity, metabolic syndrome, hypertension, polycystic ovary syndrome and chronic kidney diseases. Physiologically, weakening intracellular insulin signaling is considered as a compensatory mechanism for cells to cope with cellular stresses like xenobiotic effects, oxidative stress and inflammatory responses, but it can pathologically lead to a defective cycle with lowered sensitivity of the cells to insulin which happens in metabolic disorders. In this work, the data related to metabolic toxicity of pesticides categorized in the mentioned metabolic diseases with a focus on the effects of pesticides on insulin signaling pathway and the mechanisms of development of insulin resistance will be systematically reviewed and presented.

Neurotoxicity of pesticides in the context of CNS chronic diseases.

Following the introduction and application of pesticides in human life, they have always been along with health concerns both in acute poisoning and chronic toxicities. Neurotoxicity of pesticides in chronic exposures has been known as one of the most important human health problems, as most of these chemicals act through interacting with some elements of nervous system. Pesticide-induced neurotoxicity can be defined in different categories of neurological disorders including neurodegenerative (Alzheimer, Parkinson, amyotrophic lateral sclerosis, multiple sclerosis), neurodevelopmental (attention deficit hyperactivity disorder, autism spectrum disorders, developmental delay, and intellectual disability), neurobehavioral and neuropsychiatric (depression/suicide attempt, anxiety/insomnia, and cognitive impairment) disorders some of which are among the most debilitating human health problems. In this review, neurotoxicity of pesticides in the mentioned categories and sub-categories of neurological diseases have been systematically presented in relation to different route of exposures including general, occupational, environmental, prenatal, postnatal, and paternal.

Estrogens counteract tributyltin-induced toxicity in the rat islets of Langerhans.

BACKGROUND: Tributyltin (TBT) is known as an endocrine disruptor able to interfere with estrogen receptors (ERs) leading to toxic effects on the related endocrine pathways. TBT is an obesogen, reported to disrupt glucose homeostasis leading to diabetes. The aim of this study was to assess the influence of TBT and ß-estradiol on the pancreatic islets of Langerhans in simultaneous exposures. EXPERIMENTAL: Pancreatic islets of 15 male rat were isolated and exposed to TBT (10 µM), ß-estradiol, and TBT plus ß-estradiol for 24 h. Therewith, cellular viability, oxidative stress, apoptosis, and insulin secretion markers were investigated. RESULTS: TBT decreased the viability and increased the apoptosis, reactive oxygen species, and insulin secretion TBT led to increased amounts of apaptosis, reactive oxygen species (ROS), and insulin secretion in pancreatic islets; however, cellular viability was reduced. Co-exposure with ß-estradiol ameliorated the entire mentioned variables near to the control level. CONCLUSION: These results showed that ß-estradiol protect pancreatic islets of Langerhans against TBT-induced toxicity by counteracting oxidative stress and apoptosis as well as insulin secretion. In this way, it is postulated that pancreatic ER pathways particularly in ß-cells might be the determinant target of toxic effects of xenoestrogens like TBT. Hence, evaluation of xenoestrogens-induced ER dysfunction in the endocrine pancreas can be helpful in diabetic risk assessment of these contaminants. Pharmacological modifications of ER pathway in the ß-cells seems promising for better management of diabetes.

Mechanistic assessment of cadmium toxicity in association with the functions of estrogen receptors in the Langerhans islets.

OBJECTIVES: Diabetes is a metabolic disease with an increasing prevalence for which finding new and efficient therapeutic approaches has always been a challenge. Preserving integrity and functionality of pancreatic ß-cells as the only source of insulin in the body is such a case. To achieve this goal different cellular targets have been proposed among which pancreatic estrogen receptors have gotten much attention. In this work, we evaluated the integrity and function of islets of Langerhans under the influence of factors known to intervene with estrogen receptors. Cadmium, a toxic heavy metal, has been recently shown to interact with estrogen receptors but its toxicity in the pancreatic islets regarding this mechanism remains unclear. MATERIALS AND METHODS: Isolated islets of Langerhans from the pancreas of rats were grouped and treated with cadmium chloride and also cadmium chloride plus ß-estradiol. After 24 hr incubation, parameters of cellular viability, oxidative stress, apoptosis, and insulin secretion were measured . RESULTS: The results indicated that cadmium reduced viability of the islets along with an increase in the formation of reactive oxygen species and apoptosis markers, and ß-estradiol, in turn, was able to alleviate these disturbances to some extent, implicating the protective role of ß-estradiol against pancreatic toxicity of cadmium. CONCLUSION: It can be concluded that modification of estrogen receptors in the endocrine pancreas and especially ß-cells may be a promising target to find a new therapeutic strategy for diabetes and even uncovering mechanisms of environmental toxicants that have been known as risk factors of diabetes.

The link of organophosphorus pesticides with neurodegenerative and neurodevelopmental diseases based on evidence and mechanisms.

Organophosphorus (OP) compounds have been known as the most widely used pesticides during the past half century and there have been a huge body of literature regarding their association with human chronic diseases. Neurodegenerative and neurodevelopmental disorders including Alzheimer, Parkinson, amyotrophic lateral sclerosis (ALS), attention deficit hyperactivity disorder (ADHD), and autism are among the afflicting neurological diseases which overshadow human life and their higher risk in relation to OP exposures have been uncovered by epidemiological studies. In addition, experimental studies exploring the underlying mechanisms have provided some evidence for involvement of cholinergic deficit, oxidative stress, neuro-inflammation, and epigenetic modifications as the processes which are common in the toxicity of the OP and pathophysiology of the mentioned diseases. In addition, genetic mutations and polymorphisms of different variants of some genes like paraoxonase have been shown to be implicated in both susceptibility to OPs toxicity and neurological diseases. In this article, we reviewed the epidemiological as well as experimental studies evidencing the association of exposure to OPs and incidence of neurodegenerative and neurodevelopmental diseases.

Pesticides: an update of human exposure and toxicity.

Pesticides are a family of compounds which have brought many benefits to mankind in the agricultural, industrial, and health areas, but their toxicities in both humans and animals have always been a concern. Regardless of acute poisonings which are common for some classes of pesticides like organophosphoruses, the association of chronic and sub-lethal exposure to pesticides with a prevalence of some persistent diseases is going to be a phenomenon to which global attention has been attracted. In this review, incidence of various malignant, neurodegenerative, respiratory, reproductive, developmental, and metabolic diseases in relation to different routes of human exposure to pesticides such as occupational, environmental, residential, parental, maternal, and paternal has been systematically criticized in different categories of pesticide toxicities like carcinogenicity, neurotoxicity, pulmonotoxicity, reproductive toxicity, developmental toxicity, and metabolic toxicity. A huge body of evidence exists on the possible role of pesticide exposures in the elevated incidence of human diseases such as cancers, Alzheimer, Parkinson, amyotrophic lateral sclerosis, asthma, bronchitis, infertility, birth defects, attention deficit hyperactivity disorder, autism, diabetes, and obesity. Most of the disorders are induced by insecticides and herbicides most notably organophosphorus, organochlorines, phenoxyacetic acids, and triazine compounds.

Review of endocrine disorders associated with environmental toxicants and possible involved mechanisms.

Endocrine disrupting chemicals (EDC) are released into environment from different sources. They are mainly used in packaging industries, pesticides and food constituents. Clinical evidence, experimental models, and epidemiological studies suggest that EDC have major risks for human by targeting different organs and systems in the body. Multiple mechanisms are involved in targeting the normal system, through estrogen receptors, nuclear receptors and steroidal receptors activation. In this review, different methods by which xenobiotics stimulate signaling pathways and genetic mutation or DNA methylation have been discussed. These methods help to understand the results of xenobiotic action on the endocrine system. Endocrine disturbances in the human body result in breast cancer, ovarian problems, thyroid eruptions, testicular carcinoma, Alzheimer disease, schizophrenia, nerve damage and obesity. EDC characterize a wide class of compounds such as organochlorinated pesticides, industrial wastes, plastics and plasticizers, fuels and numerous other elements that exist in the environment or are in high use during daily life. The interactions and mechanism of toxicity in relation to human general health problems, especially endocrine disturbances with particular reference to reproductive problems, diabetes, and breast, testicular and ovarian cancers should be deeply investigated. There should also be a focus on public awareness of these EDC risks and their use in routine life. Therefore, the aim of this review is to summarize all evidence regarding different physiological disruptions in the body and possible involved mechanisms, to prove the association between endocrine disruptions and human diseases.

Persistent Organic Pollutants and Concern Over the Link with Insulin Resistance Related Metabolic Diseases.

Persistent organic pollutants (POPs) are mostly halogenated compounds tending to persist in the environment, enter into the food chain, and accumulate in fat mass of mammals due to their high lipophilicity. They include some organochlorine pesticides, polychlorinated biphenyls, brominated flame retardants and polycyclic aromatic hydrocarbons. Some of these chemicals were widely used in the past so that their residues can be detected in the human body, though their usage has been banned for years. POPs have been shown to perturb the health of biological systems in different ways evidenced by carcinogenicity and disrupting effects on endocrine, immune, and reproductive systems. There are many epidemiologic and experimental studies on the association of exposure to POPs with insulin resistance and related metabolic disorders like obesity, diabetes, and metabolic syndrome. Inflammation as a known mechanism accompanying insulin resistance has also been shown to arise in insulin target tissues exposed to POPs. This review addresses the breast milk concentration of POPs in different regions of the world, synthesizes the current information on the association of POPs with insulin resistance related metabolic disorders, and discusses the inflammation as an involved mechanism. Considering high prevalence of insulin resistance related metabolic diseases and their relation with POPs, much need is felt regarding international and regional programs to not only limit their production and usage but eliminate these persistent pollutants from the environment.

The molecular mechanisms of liver and islets of Langerhans toxicity by benzene and its metabolite hydroquinone in vivo and in vitro.

Benzene (C6H6) is one of the most commonly used industrial chemicals causing environmental pollution. This study aimed to examine the effect of benzene and its metabolite hydroquinone on glucose regulating organs, liver and pancreas, and to reveal the involved toxic mechanisms, in rats. In the in vivo part, benzene was dissolved in corn oil and administered through intragastric route at doses of 200, 400 and 800 mg/kg/day, for 4 weeks. And, in the in vitro part, toxic mechanisms responsible for weakening the antioxidant system in islets of Langerhans by hydroquinone at different concentrations (0.25, 0.5 and 1 mM), were revealed. Benzene exposure raised the activity of phosphoenolpyruvate carboxykinase (PEPCK), glucose 6-phosphatase (G6Pase) enzymes and increased fasting blood sugar (FBS) in comparison to control animals. Also, the activity of hepatic glucokinase (GK) was decreased significantly. Along with, a significant increase was observed in hepatic tumor necrosis factor (TNF-α) and plasma insulin in benzene treated rats. Moreover, benzene caused a significant rise in hepatic lipid peroxidation, DNA damage and oxidation of proteins. In islets of Langerhans, hydroquinone was found to decrease the capability of antioxidant system to fight free radicals. Also, the level of death proteases (caspase 3 and caspase 9) was found higher in hydroquinone exposed islets. The current study demonstrated that benzene and hydroquinone causes toxic effects on liver and pancreatic islets by causing oxidative impairment.

Assessment of benzene induced oxidative impairment in rat isolated pancreatic islets and effect on insulin secretion.

Benzene (C6H6) is an organic compound used in petrochemicals and numerous other industries. It is abundantly released to our environment as a chemical pollutant causing widespread human exposure. This study mainly focused on benzene induced toxicity on rat pancreatic islets with respect to oxidative damage, insulin secretion and glucokinase (GK) activity. Benzene was dissolved in corn oil and administered orally at doses 200, 400 and 800mg/kg/day, for 4 weeks. In rats, benzene significantly raised the concentration of plasma insulin. Also the effect of benzene on the release of glucose-induced insulin was pronounced in isolated islets. Benzene caused oxidative DNA damage and lipid peroxidation, and also reduced the cell viability and total thiols groups, in the islets of exposed rats. In conclusion, the current study revealed that pancreatic glucose metabolism is susceptible to benzene toxicity and the resultant oxidative stress could lead to functional abnormalities in the pancreas.

Growing burden of diabetes in Pakistan and the possible role of arsenic and pesticides.

This review is undertaken to address the possible role of arsenic and pesticides in the prevalence of diabetes in Pakistan and to highlight a resourceful targeted research in this area. A bibliographic search of scientific databases was conducted with key words of "epidemics of diabetes in Pakistan", "diabetes in Asia", "diabetes mellitus and environmental pollutants", "diabetes mellitus and heavy metals", "diabetes mellitus and pesticides", "prevalence of pesticides in Pakistan", and "heavy metals contamination of drinking water, "vegetables and fruits in Pakistan". More than 200 articles were examined. Studies reporting the prevalence of diabetes mellitus (DM), pesticides and heavy metal contamination of drinking water, fruits and vegetables were included in the study. According to WHO 2011 report, about 12.9 million people are suffering from DM and the number is constantly increasing. Water pollution is a major public health threat in Pakistan. Most of the people in Pakistan are exposed to arsenic and pesticides either in drinking water or through vegetables, fruits, and other edible items with various concentrations above the WHO/FAO permissible limits. Being an agricultural country, a 1169% increase has been recorded with the use of different types of pesticides since last two decades, and almost similar rise in the burden of diabetes. There is a growing global concern of arsenic and pesticides exposure with the incidence of DM. Besides other factors, the environmental attributors in the incidence of DM in Pakistan have not been conclusively elucidated yet which in turn deserve a resourceful targeted research.

Current understandings and perspectives on non-cancer health effects of benzene: a global concern.

OBJECTIVE: Benzene, as a volatile organic compound, is known as one of the main air pollutants in the environment. The aim of this review is to summarize all available evidences on non-cancerous health effects of benzene providing an overview of possible association of exposure to benzene with human chronic diseases, specially, in those regions of the world where benzene concentration is being poorly monitored. METHODOLOGY: A bibliographic search of scientific databases including PubMed, Google Scholar, and Scirus was conducted with key words of "benzene toxic health effects", "environmental volatile organic compounds", "diabetes mellitus and environmental pollutants", "breast cancer and environmental pollution", "prevalence of lung cancer", and "diabetes prevalence". More than 300 peer reviewed papers were examined. Experimental and epidemiologic studies reporting health effects of benzene and volatile organic compounds were included in the study. RESULTS: Epidemiologic and experimental studies suggest that benzene exposure can lead to numerous non-cancerous health effects associated with functional aberration of vital systems in the body like reproductive, immune, nervous, endocrine, cardiovascular, and respiratory. CONCLUSION: Chronic diseases have become a health burden of global dimension with special emphasis in regions with poor monitoring over contents of benzene in petrochemicals. Benzene is a well known carcinogen of blood and its components, but the concern of benzene exposure is more than carcinogenicity of blood components and should be evaluated in both epidemiologic and experimental studies. Aspect of interactions and mechanism of toxicity in relation to human general health problems especially endocrine disturbances with particular reference to diabetes, breast and lung cancers should be followed up.

Pesticides and human chronic diseases: evidences, mechanisms, and perspectives.

Along with the wide use of pesticides in the world, the concerns over their health impacts are rapidly growing. There is a huge body of evidence on the relation between exposure to pesticides and elevated rate of chronic diseases such as different types of cancers, diabetes, neurodegenerative disorders like Parkinson, Alzheimer, and amyotrophic lateral sclerosis (ALS), birth defects, and reproductive disorders. There is also circumstantial evidence on the association of exposure to pesticides with some other chronic diseases like respiratory problems, particularly asthma and chronic obstructive pulmonary disease (COPD), cardiovascular disease such as atherosclerosis and coronary artery disease, chronic nephropathies, autoimmune diseases like systemic lupus erythematous and rheumatoid arthritis, chronic fatigue syndrome, and aging. The common feature of chronic disorders is a disturbance in cellular homeostasis, which can be induced via pesticides' primary action like perturbation of ion channels, enzymes, receptors, etc., or can as well be mediated via pathways other than the main mechanism. In this review, we present the highlighted evidence on the association of pesticide's exposure with the incidence of chronic diseases and introduce genetic damages, epigenetic modifications, endocrine disruption, mitochondrial dysfunction, oxidative stress, endoplasmic reticulum stress and unfolded protein response (UPR), impairment of ubiquitin proteasome system, and defective autophagy as the effective mechanisms of action.

Environmental and population studies concerning exposure to pesticides in iran: a comprehensive review.

Pesticides are widely used in Iranian agriculture and this has made a major toxicological concern among health professionals. The objective of this study is to explore national data about pesticides toxicity. All relevant databases such as Google Scholar, PubMed, and Scopus in a time period of 1960 to 2012 were searched for the keywords "Pesticides, Iran, Environment, and Population studies". A total of 57 studies were found relevant and then included into study. Almost all non-experimental studies carried out in Iran were classified into two main categories of residue assessment in different samples and toxic effects on human. Depending on the dose and duration of exposure, toxic effects of pesticides have been studied in two classifications including acute toxicity or acute poisoning and chronic toxicity. High extent of pesticides have been used during the past decade in Iran while no enough proper studies were done to explore their possible toxic effects in the environment and the people.

Biochemical evidence on the potential role of organophosphates in hepatic glucose metabolism toward insulin resistance through inflammatory signaling and free radical pathways.

Several studies show that organophosphate pesticides exert several effects on glucose homeostasis. The current study investigates the influence of subchronic exposure to malathion (MT) on hepatic gluconeogenesis in relation to acetyl cholinesterase (AChE) inhibition, oxidative stress and inflammatory response in the rat. MT was administered by gavage at doses of 25, 50 and 100 mg/kg for 32 days. Fasting hyperglycemia was seen in line with an increased activity of hepatic phosphoenolpyruvate carboxykinase, glucose 6-phosphatase and tumor necrosis factor α. In addition to the impaired glucose tolerance and inhibition of AChE in a dose-dependent manner, there were significant increases in hepatic lipid peroxidation, carbonyl groups and 8-deoxyguanosine as the biomarkers of reactive oxygen species-mediated damage to lipid, protein and DNA, respectively. Altered quality of the liver in glucose production especially gluconeogenesis could be a compensatory mechanism against MT toxicity or even result in tissue damage. MT-induced insulin resistance in the liver occurs through oxidative and inflammatory signaling pathways.

Ineffectiveness of allopurinol in reduction of oxidative stress in diabetic patients; a randomized, double-blind placebo-controlled clinical trial.

The objective of this randomized, double-blind placebo-controlled clinical trial was to evaluate the value of allopurinol treatment on reduction of oxidative stress in patients with diabetes type II patients. Forty-one diabetic type II subjects were randomly assigned to two groups. One group (n = 20) received 100 mg allopurinol three times a day for 14 days and the other group (n = 21) received a placebo. Blood and saliva samples were collected before and after intervention for analysis of lipid peroxidation level and total antioxidant power as indices of oxidative stress. At the beginning of the study, the groups were similar based upon age, duration of diabetes, fasting glucose, and HbA1c. Both allopurinol and placebo were effective in reduction of lipid peroxidation and total antioxidant power whether in saliva or plasma in a similar extent. HbA1c and FBS levels did not change through the study neither in case or placebo group. It is concluded that allopurinol therapy is not more effective than placebo in reduction of oxidative stress in diabetic patients. The same trend of changes in blood and saliva shown for oxidative stress indices was interesting and suggests a chance for saliva to be valuable in diagnosis of oxidative stress. However, to elaborate the exact role of allopurinol in diabetes, further large randomized clinical trials are needed.