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Developmental exposure to glyphosate-based herbicide and depressive-like behavior in adult offspring: Implication of glutamate excitotoxicity and oxidative stress
Abstract
We have previously demonstrated that maternal exposure to glyphosate-based herbicide (GBH) leads to glutamate excitotoxicity in 15-day-old rat hippocampus. The present study was conducted in order to investigate the effects of subchronic exposure to GBH on some neurochemical and behavioral parameters in immature and adult offspring. Rats were exposed to 1% GBH in drinking water (corresponding to 0.36% of glyphosate) from gestational day 5 until postnatal day (PND)-15 or PND60. Results showed that GBH exposure during both prenatal and postnatal periods causes oxidative stress, affects cholinergic and glutamatergic neurotransmission in offspring hippocampus from immature and adult rats. The subchronic exposure to the pesticide decreased L-[(14)C]-glutamate uptake and increased (45)Ca(2+) influx in 60-day-old rat hippocampus, suggesting a persistent glutamate excitotoxicity from developmental period (PND15) to adulthood (PND60). Moreover, GBH exposure alters the serum levels of the astrocytic protein S100B. The effects of GBH exposure were associated with oxidative stress and depressive-like behavior in offspring on PND60, as demonstrated by the prolonged immobility time and decreased time of climbing observed in forced swimming test. The mechanisms underlying the GBH-induced neurotoxicity involve the NMDA receptor activation, impairment of cholinergic transmission, astrocyte dysfunction, ERK1/2 overactivation, decreased p65 NF-κB phosphorylation, which are associated with oxidative stress and glutamate excitotoxicity. These neurochemical events may contribute, at least in part, to the depressive-like behavior observed in adult offspring.
... Exposure to GBH has, however, been implicated in kidney disease (Jayasumana et al., 2014), birth defects in humans, endocrine disruption (Walsh et al., 2000;Ingaramo et al., 2020), cancer (Thongprakaisang et al., 2013;Guyton et al., 2015), and Parkinson's disease (Wang et al., 2011). Studies have also shown that GBH exposure plays a crucial role in neurological impairments (Ait- Bali et al., 2020;Cattani et al., 2021) and neurotoxicity (Roy et al., 2016;Cattani et al., 2017;Chávez-Reyes et al., 2024a,b). ...
... In this sense, the role of glyphosate on neurodevelopment has been poorly explored. Alteration in anxiety levels and memory in rats exposed orally to GBH during the developmental stage showed depressive-like behavior (Cattani et al., 2017). In addition, offsprings from Wistar rat exposed daily to GBH throughout the entire gestation period resulted in alterations in behavior and memory (de Oliveira et al., 2022). ...
... Frontiers in Neuroscience 10 frontiersin.org rat offspring produced an increment in glutamate release (Cattani et al., 2014(Cattani et al., , 2017; oxidative stress, since the perinatal exposure to GBH induced oxidative stress in the hippocampus and PFC from offspring Wistar rats (de Oliveira et al., 2022); or neuroinflammation, since mice offspring exposed to GBH during gestation showed an increase in TNF-α in the PFC (De Castro Vieira Carneiro et al., 2023). Exposition to GBH in early stages of the development may therefore drive alterations via modification in key signaling pathways, affecting neuronal growth and migration in the central and peripheral nervous systems (Costas-Ferreira et al., 2022). ...
Introduction
Glyphosate-based herbicides (GBHs) have been shown to have significant neurotoxic effects, affecting both the structure and function of the brain, and potentially contributing to the development of neurodegenerative disorders. Despite the known importance of glycosylation in disease progression, the glycome profile of systems exposed to GBH has not been thoroughly investigated.
Methods
In this study, we conducted a comprehensive glycomic profiling using LC-MS/MS, on the hippocampus and prefrontal cortex (PFC) of juvenile rats exposed to GBH orally, aiming to identify glyco-signature aberrations after herbicide exposure.
Results
We observed changes in the glycome profile, particularly in fucosylated, high mannose, and sialofucosylated N-glycans, which may be triggered by GBH exposure. Moreover, we found major significant differences in the N-glycan profiles between the GBH-exposed group and the control group when analyzing each gender independently, in contrast to the analysis that included both genders. Notably, gender differences in the behavioral test of object recognition showed a decreased performance in female animals exposed to GBH compared to controls (p < 0.05), while normal behavior was recorded in GBH-exposed male rats (p > 0.05).
Conclusion
These findings suggest that glycans may play a role in the neurotoxic effect caused by GBH. The result suggests that gender variation may influence the response to GBH exposure, with potential implications for disease progression and specifically the neurotoxic effects of GBHs. Understanding these gender-specific responses could enhance knowledge of the mechanisms underlying GBH-induced toxicity and its impact on brain health. Overall, our study represents the first detailed analysis of N-glycome profiles in the hippocampus and PFC of rats chronically exposed to GBH. The observed alterations in the expression of N-glycan structures suggest a potential neurotoxic effect associated with chronic GBH exposure, highlighting the importance of further research in this area.
... Studies have associated glyphosate with oxidative damage and changes in antioxidant status to in vitro human cells (Kašuba et al., 2017;Martínez et al., 2020), rats (Cattani et al., 2017) and other nontarget organisms (Tsui and Chu, 2003;Rodrigues et al., 2019), and a variety of toxic effects, including neurotoxicity, DNA damage, motor disorders and metabolic diseases, that are related to oxidative damage (Wang et al., 2022). In addition, adjuvants added to commercial formulations also increase toxicity (Tsui and Chu, 2003;Rodrigues et al., 2019;Wang et al., 2022). ...
... Glyphosate is reported to change important neuromarkers involved in regulating cellular proliferation and differentiation in rat hippocampus (Cattani et al., 2017). To investigate whether glyphosate and Roundup Original® could alter cell proliferation on the brain of zebrafish embryos, we performed a whole-mount immunohistochemistry (IHC) as previously described (Santos et al., 2018;Hammond-Weinberger and ZeRuth, 2020) with some modifications as described follow, using the mitotic specific marker phosphohistone H3. ...
... Taking together, our results demonstrated that exposure to glyphosate and Roundup Original® during developmental stages leads to oxidative stress in zebrafish embryos, responding in terms of defense system and oxidative damage as indicators of free radical formation, in accordance with previous studies performed in vitro with human cells (Kašuba et al., 2017;Martínez et al., 2020), as well as rats (Cattani et al., 2017) and adult zebrafish (Velasques et al., 2016). A recent review also pointed to the generation of oxidative stress induced by glyphosate and related products and the impacts on development and behavior (Lanzarin et al., 2023). ...
... Glyphosate exposure has previously been shown to modulate the expression of SOD1 by enhancing its expression in neural stem cells from the subventricular zone of postnatal mice [53]. Although the current study did not measure the activity of these antioxidant enzymes, others have demonstrated increased SOD activity in the hippocampus of young adult rats after subchronic exposure to GBH [15]. In addition, studies have reported increased GPx gene expression [54] and activity [55] in the brain of PND90 rats perinatally exposed to GBH. ...
... Changes in the expression and activity of this enzyme lead to a decline in glutathione levels [57]. We have previously shown that perinatal exposure to GBH decreases the levels of glutathione in the hippocampus of rat offspring at PND15 [15]. Interestingly, GCLC is induced by the major product of lipid peroxidation, 4-hydroxynonenal (4-HNE) [57,58], which was found to be increased in the GBH-treated animals. ...
... Melatonin has also been shown to have an important role in maintaining calcium homeostasis by preventing glutamate-induced increases in intracellular calcium levels [71,72]. In addition, molecular dynamic simulation has demonstrated that due to the structural similarity with glutamate, glyphosate may be able to bind to glutamate receptors resulting in an over-activation of these receptors [15]. Interestingly, the environmental toxin β-N-methylamino-L-alanine (BMAA), which also acts as a glutamate receptor agonist, was recently shown to target the pineal gland and decrease melatonin levels in adult rats following a short postnatal exposure as well as in primary pinealocytes through glutamatergic mechanisms [42]. ...
Concerns have been raised regarding the potential adverse health effects of the ubiquitous herbicide glyphosate. Here, we investigated long-term effects of developmental exposure to a glyphosate-based herbicide (GBH) by analyzing serum melatonin levels and cellular changes in the striatum of adult male rats (90 days old). Pregnant and lactating rats were exposed to 3% GBH (0.36% glyphosate) through drinking water from gestational day 5 to postnatal day 15. The offspring showed reduced serum melatonin levels (43%) at the adult age compared with the control group. The perinatal exposure to GBH also induced long-term oxidative stress-related changes in the striatum demonstrated by increased lipid peroxidation (45%) and DNA/RNA oxidation (39%) together with increased protein levels of the antioxidant enzymes, superoxide dismutase (SOD1, 24%), glutamate–cysteine ligase (GCLC, 58%), and glutathione peroxidase 1 (GPx1, 31%). Moreover, perinatal GBH exposure significantly increased the total number of neurons (20%) and tyrosine hydroxylase (TH)-positive neurons (38%) in the adult striatum. Mechanistic in vitro studies with primary rat pinealocytes exposed to 50 µM glyphosate demonstrated a decreased melatonin secretion partially through activation of metabotropic glutamate receptor 3 (mGluR3), while higher glyphosate levels (100 or 500 µM) also reduced the pinealocyte viability. Since decreased levels of the important antioxidant and neuroprotector melatonin have been associated with an increased risk of developing neurodegenerative disorders, this demonstrates the need to consider the melatonin hormone system as a central endocrine-related target of glyphosate and other environmental contaminants.
... Mice exposed to GBH also spent more time immobile in a forced swim test and this, like the anxiety effects previously discussed, also improved with quercetin therapy [204]. Rats exposed to 0.36% glyphosate in water from gestational day 5 until PND 60 demonstrated prolonged immobility time and decreased time climbing in a forced swim test, indicative of depressivelike behavior, though no effects on anhedonia-like behavior were seen [207]. ...
... Most commonly, GBH exposure causes increased anxiety [105][106][107][202][203][204] and changes in motor activity, whether animals exhibit decreased locomotion [107,201] or hyperactivity [118,194,206]. GBHs also cause depressive-like behavior [105,201,202,204,207], changes in aggressiveness [115,126], and ASD-like cognitive impairment [183,193,208]. Social behavior is also affected by GBH exposure, as demonstrated by deficits in early communication and olfactory discrimination [183], impairment of functions needed to carry out social activities [37,99,100,104], and decreased social interaction with other animals of the same species [106,126,183,193,208]. ...
... Several proteins associated with inflammation increase in concentration in the hippocampus and prefrontal cortex after exposure to GBHs, specifically GFAP and Iba-1, and of TNF-alpha in the hippocampus only [106]. Oxidative stress has also been proposed as a mechanism of glyphosate-induced toxicity with regard to avoidance behavior, [114], reproductive behaviors [114,183], and anxiety and depression [204,207]. ...
Use of glyphosate and glyphosate-based herbicides is ubiquitous in US agriculture and widespread around the world. Despite marketing efforts to the contrary, numerous studies demonstrate glyphosate toxicity to non-target organisms including animals, primarily focusing on mortality, carcinogenicity, renal toxicity, reproductive, and neurological toxicity, and the biochemical mechanisms underlying these physiological outcomes. Glyphosate toxicity also impacts animal behavior, both in model systems and in agricultural and environmentally relevant contexts. In this review, we examine the effects of glyphosate and glyphosate-based herbicides on animal behaviors, particularly activity, foraging and feeding, anti-predator behavior, reproductive behaviors, learning and memory, and social behaviors. Glyphosate can be detected both in food and in the environment, and avoided through activity and feeding strategies. However, exposure also reduces activity, depresses foraging and feeding, increases susceptibility to predation, interferes with courtship, mating, fertility and maternal behaviors, decreases learning and memory capabilities, and disrupts social behaviors. Changes in animal behavior as a result of glyphosate toxicity are important because of their sometimes severe effects on individual fitness, as well as ecosystem health. Implications for human behavior are also considered.
... Pesticides and antibiotics (ANTs) are often indispensable for modern agricultural production (Dayan et al., 2019). However, these substances are often found in food and animal feed, prompting public concern (Klümper and Qaim, 2014;Cattani et al., 2017;Duke, 2018). Glyphosate (GLY), or N-phosphonomethyl glycine, is the most widely used herbicide in the world (Dayan et al., 2019;Maggi et al., 2020). ...
... Glyphosate (GLY), or N-phosphonomethyl glycine, is the most widely used herbicide in the world (Dayan et al., 2019;Maggi et al., 2020). As a competitive inhibitor of the shikimate pathway, it mediates the biosynthesis of aromatic amino acids in plants and microorganisms (Cattani et al., 2017;Duke, 2018). ...
Drugs and pesticide residues in broiler feed can compromise the therapeutic and production benefits of antibiotic (ANT) application and affect gene expression. In this study, we analyzed the expression of 13 key pancreatic genes and blood physiology parameters after administering one maximum residue limit of herbicide glyphosate (GLY), two ANTs, and one anticoccidial drug (AD). A total of 260 Ross 308 broilers aged 1-40 d were divided into the following four groups of 65 birds each: control group, which was fed the main diet (MD), and three experimental groups, which were fed MD supplemented with GLY, GLY+ANTs (enrofloxacin and colistin methanesulfonate), and GLY+AD (ammonium maduramicin), respectively. The results showed that the addition of GLY, GLY+ANTs, and GLY+AD caused significant changes in the expression of several genes of physiological and economic importance. In particular, genes related to inflammation and apoptosis (interleukin 6 (IL6), prostaglandin-endoperoxide synthase 2 (PTGS2), and caspase 6 (CASP6)) were downregulated by up to 99.1%, and those related to antioxidant protection (catalase (CAT), superoxide dismutase 1 (SOD1) and peroxiredoxin 6 (PRDX6)) by up to 98.6%, compared to controls. There was also a significant decline in the values of immunological characteristics in the blood serum observed in the experimental groups, and certain changes in gene expression were concordant with changes in the functioning of the pancreas and blood. The changes revealed in gene expression and blood indices in response to GLY, ANTs, and AD provide insights into the possible mechanisms of action of these agents at the molecular level. Specifically, these changes may be indicative of physiological mechanisms to overcome the negative effects of GLY, GLY+ANTs, and GLY+AD in broilers.
... Clinical evidence links the escalating use of GBH to conditions such as anxiety, depression, Parkinson, autism, and memory impairments [9,10]. Simultaneously, animal experiments have substantiated the neurotoxic effects associated with this pesticide [11][12][13]. ...
... Even though the precise mechanism leading to affective and cognitive disorders induced by GBH is not fully comprehended, there is solid evidence that mood and memory disturbances can arise due to microbial degradation in the intestines [14], neuroinflammation [15], and/or imbalances in neurotransmitter systems triggered by this pesticide [8,[11][12][13]. Certainly, oxidative stress (OS) appears to be a pivotal mechanism contributing to the neurotoxic effects of GBH. ...
Several studies have found that exposure to glyphosate-based herbicides (GBH) can lead to memory impairment and affective disorders. Oxidative stress (OS) is one of the mechanisms that can explain the neurotoxicity of GBH. Consequently, molecules with an antioxidant effect may have neuroprotective potential against GBH-related brain damage. In this work, we aim to evaluate the neuroprotective effect of melatonin (MEL) against affective and cognitive disorders caused by GBH. For this experiment, male Wistar rats received, during the peripubertal period, a daily administration of GBH (75 mg/kg) or GBH + MEL (4 mg/kg). At the end of the treatment, the open field, elevated plus maze, and forced swimming tests were used to explore anxiety levels and depression-like symptoms. While the Y-Maze and Morris Water Maze have been used to detect cognitive deficits, we also measured markers of OS, specifically catalase, nitric oxide, and lipid peroxidation, in the hippocampus and prefrontal cortex. Our results revealed that MEL reduces anxiety and depressive behavior, as well as the cognitive deficits caused by GBH. In addition, co-administration of MEL and GBH induced an improvement in the various markers of OS. The positive action of MEL against OS is therefore one of the mechanisms explaining its
neuroprotective power against GBH.
... Even though the exact mechanism underlying GBHinduced anxiety and depression behaviors remains poorly understood, it is well established that mood disturbances can occur as a result of intestinal microbial degradation (Rueda-Ruzafa et al., 2019), neuroinflammation (Winstone et al., 2022), and/or disbalance in neurotransmitter systems provoked by this pesticide (Ait-Bali et al., 2020;Baier et al., 2017;Cattani et al., 2017;Martínez et al., 2018). Indeed, oxidative stress (OS) could be a key mechanism behind the neurotoxicity induced by GBH. ...
... In agreement with our results, Baier et al. (2017) reported anxiogenic behavior at 50 mg/kg of the GBH in adult mice, administered intranasally for 4 weeks. In addition, subchronic exposure to 1% GBH in drinking water from gestational day 5 up to post-natal day 60 increased immobility time in the forced swimming test (Cattani et al., 2017). However, Gallegos et al. (2016) demonstrated that rats orally administered 100 or 200 mg/kg of GBH (Glifloglex®) in gestation and lactation had reduced anxiety scores in adulthood in comparison with control rats. ...
... The observed neurotoxic effects primarily consist of modifications in neurotransmitter and receptor levels, along with the disruption of their regulatory enzymes. Numerous studies conducted on experimental animals extensively document the impact of these effects on the nervous system [75][76][77]. Certain pesticides have the potential to influence the release, reuptake, metabolism, or receptors of neurotransmitters such as dopamine, glutamate, serotonin, or gamma-aminobutyric acid (GABA) [78]. ...
... Certain pesticides have the potential to influence the release, reuptake, metabolism, or receptors of neurotransmitters such as dopamine, glutamate, serotonin, or gamma-aminobutyric acid (GABA) [78]. In line with this, exposure to glyphosate-based herbicide during the prenatal and postnatal stages leads to neuronal damage through glutamate excitotoxicity and alteration of N-methyl-D-aspartate (NMDA) receptors in the hippocampus of immature and adult offspring [76,79]. Furthermore, another study revealed that exposure to various doses of glyphosate-based herbicide resulted in delayed innate reflexes, deficits in motor development, sociability, short and long-term learning, and memory. ...
Background and Objectives: Autism spectrum disorder (ASD) is a neurodevelopmental condition characterized by challenges in communication, social interactions, and repetitive behaviors. Although the factors that influence the development of this condition are unknown, certain chemical compounds such as pesticides have been proposed as possible contributors. Due to the lack of an established causal link between pesticide exposure and ASD, this study aimed to evaluate this potential association. Materials and Methods: A case-control study was carried out to ascertain the prevalence and risk associated with ASD in relation to pesticide exposure over a 21-year study period (2000–2021). Results: We included 2821 individuals diagnosed with ASD residing in areas of both high and low pesticide exposure in southern Spain. There was a rise in the ASD prevalence rate in regions with elevated pesticide use when compared to regions with low use [odds ratio (OR): 1.34, 95% confidence interval (CI), (1.24–1.44)]. Notably, men had the highest likelihood, with an OR: 1.42, 95% CI, (1.30–1.55). Furthermore, after performing multiple binary logistic regression adjusted for age, sex, and geographical area, males exhibited a higher likelihood compared to females [OR: 2.41, 95% CI, (2.21–2.62)]. Conclusions: Overall, this research suggests a connection between heightened environmental pesticide exposure due to increased agricultural use and autism.
... Perinatal exposure to glyphosate was associated with impacts on mitochondrial functions, cell proliferation, melatonin synthesis and protein expression in rat Cattani et al., 2014;Cattani et al., 2023). These biochemical and morphological events might be contributing to the depressive-like behavior observed in pesticide-exposed adult male rat offspring (Cattani et al., 2017), suggesting a potential impact on mental health later in life. A recent study demonstrated that exposure to glyphosate may be associated with depression and could be linked to neurological health outcomes in the adult population of the United States (Hsiao et al., 2023). ...
... It has been previously demonstrated that perinatal glyphosate exposure results in glutamatergic excitotoxicity, energy deficits, and oxidative stress in the offspring's hippocampus (Cattani et al., 2014). As adults, these offspring also exhibited depressive-like behavior (Cattani et al., 2017) and decreased melatonin levels (Cattani et al., 2023). It is noteworthy that, similar to the present study, the glyphosate exposure did not alter the serum/plasma acetylcholinesterase (AChE) activity, while decreased its activity in the offspring hippocampus, highlighting that peripheral AChE is not an ideal biomarker for glyphosate toxicity. ...
... Plaguicidas como los organofosforados están entre los más contaminantes del ambiente y son también los más utilizados en la agricultura. Estos se acumulan en el suelo y se han encontrado en los sedimentos residuos de plaguicidas prohibidos como son los organoclorados, dejando en evidencia el tiempo que pueden prevalecer en el suelo (Vryzas, 2018Cattani et al., 2017. Rosa Sinchire, Jhenny Cayambe, Marco Heredia-R La población más propensa a la contaminación por plaguicidas son los trabajadores agrícolas y, de manera indirecta, las personas que habitan cercan a los cultivos. ...
... Estudios realizados en mujeres que indirectamente han sido expuestas a plaguicidas revelan niveles significativos de contaminación. En Tailandia se descubrieron residuos de glifosato en el cordón umbilical de tres mujeres trabajadoras agrícolas gestantes (Jallow et al., 2017;Cattani et al., 2017;Dahiri et al., 2021). ...
Cada año se reporta un estimado de 3 millones de intoxicados por plaguicidas en todo el mundo, dando como resultado 250.000 muertos, la mayoría en países pobres. Los pequeños agricultores son los más expuestos a intoxicación por plaguicidas, esto se debe al conocimiento y prácticas deficientes sobre los métodos adecuados de aplicación, por lo que, tienden a minimizar el peligro de estos compuestos. Por esta razón, el objetivo del presente estudio fue determinar los factores que influyen en la toma de decisiones con respecto al uso, aplicación y almacenaje de plaguicidas, mediante el análisis de prácticas agrícolas realizadas por arroceros. Con base en los resultados, se elaboraron propuestas adecuadas de manipuleo de plaguicidas. El estudio se desarrolló en el cantón Macará provincia de Loja. Se utilizaron encuestas estructuradas dirigidas a productores de arroz que compran, almacenan y aplican plaguicidas. Para el análisis, los agricultores fueron agrupados según sus años de experiencia, estableciéndose dos grupos: menores a 30 años y mayores a 30 años. Se analizaron las características socioeconómicas, las prácticas de seguridad y el conocimiento: plaguicidas más utilizados y el riesgo para la salud, seguridad durante la aplicación de plaguicidas y el riesgo por el uso de plaguicidas. Los datos se evaluaron mediante frecuencias y porcentajes. Los resultados demostraron que los años de experiencia influyen en usos como: la reutilización de envases vacíos y la aplicación de plaguicidas altamente tóxicos, entre otras prácticas. Además, se evidenció que el empleo de equipo de protección personal en los dos grupos de estudio fue casi nulo, limitándose, principalmente, al uso de botas de caucho.
... As a result, products based on this compound (e.g., RoundUp ® ) have become leading pesticides worldwide [1,8]. Its mechanism of action consists of inhibiting the shikimate pathway for the synthesis of key aromatic amino acids in plants and microorganisms [9]. GLY is effective against more than 100 broadleaf weeds and cereals and more than 60 perennial weeds [7]. ...
Studies have shown the presence of residual amounts of the herbicide glyphosate in poultry feed, which leads to its bioaccumulation in the body. Recently, it has been established that exposure to low levels of glyphosate over a long period may have serious negative effects on poultry health. Moreover, combined exposure to several toxicants can potentially lead to additive and/or synergistic effects. The purpose of this study was to analyze changes in meat productivity and the expression dynamics of key genes (IGF1, IGF2, MYOG, MYOZ2, SLC2A1, SLC2A2, MSTN, MUC2, OCLN, CLDN1, TLR2, TLR4, CAT, SOD1, PRDX6, and HMOX1) in the cecum of broilers as affected by glyphosate, antibiotics and a coccidiostat (anticoccidial drug). Day-old Ross 308 broiler chickens (n = 260) were divided into four groups, including a control group (CONT) fed the basic diet (BD), and three experimental groups: GLY (BD + glyphosate), GLY+ANT (BD + glyphosate and antibiotics enrofloxacin and colistin methanesulfonate), and GLY+CS (BD + glyphosate and the coccidiostat ammonium maduramycin). Samples were collected at control 7, 14, and 40 days of rearing, 50 mg each from three birds from each group. The mean body weight in each group was determined after the individual weighing of the entire flock. At 7 days of age, an upregulating effect on the expression of the immune-related TLR2 gene was detected in Groups GLY+ANT and GLY+CS compared to Group CONT (p = 0.044 and p = 0.042, respectively) and Group GLY (p = 0.049 and p = 0.044, respectively). At 40 days of age, this gene expression, conversely, decreased in Groups GLY+ANT and GLY+CS compared to Group CONT (p = 0.041 and p = 0.038, respectively). Glyphosate (Group GLY) upregulated the mRNA level of genes associated with productivity (IGF1, IGF2, and MSTN) at 7 days of age by 3.7 times (p = 0.041, p = 0.036 and p = 0.039, respectively) and, conversely, decreased it at a later age (14 and 40 days) compared to Group CONT (p = 0.024, p = 0.049 and p = 0.047, respectively, at 14 days, and p = 0.037 and p = 0.036 and p = 0.035, respectively, at 40 days of age). Thus, we identified detrimental changes in the expression of key broiler genes as influenced by glyphosate, as well as its combinations with antibiotics and a coccidiostat, which may have negative consequences for the poultry industry.
... In this context, the PFC, a brain structure strongly associated with cognitive function, seems to be especially susceptible. Specifically, among others, neuroinflammation, loss of neurotransmitters, and oxidative stress, as well as neuronal hyperactivity, were observed in the PFC of rodents exposed to this herbicide [12][13][14]. However, it is still unknown whether exposure to GBH affects higher brain functions (e.g. ...
... In addition, early-life exposure of rodents to permethrin was shown to impair glutamatergic signalling in vitro and in vivo (Carloni et al. 2012;Shafer et al. 2008), and another study linked overactivation of glutamatergic receptors to a depressive-like behaviour (i.e. reduced mobility) in rats (Cattani et al. 2017). Altogether, this indicates that upregulation of genes related to glutamatergic synaptic activity may support the behavioural effects observed in animals (Blanc et al. 2021). ...
cyhalothrin, a synthetic type II pyrethroid, has become increasingly popular for control of aphids, butterfly larvae, and beetles, replacing other agricultural chemicals. As a result of which, residues of this synthetic pesticide are being reported across the globe in natural water, which poses a serious threat to aquatic life. Therefore, the present study was designed to understand the toxicity effects of λ-cyhalothrin on behaviour, oxidative stress and neurotoxicity in a vertebrate aquatic model, zebrafish (Danio rerio). The fish were exposed to 0.129, 0.194 and 0.388 µg/L corresponding to 5%, 10% and 20% of 96hLC50 (1.94 µg/L) for 28 days. Upon exposure to the highest concentration (0.388 µg/L), the test animal exhibited significant alterations in behavioural patterns like number of entries to the top zone (n), decrease in average speed (m/s) and decrease in time spent in top zone (s). Moreover, the shoaling test demonstrated a significant decrease (p < 0.05) in the relative time spent by the tested fish (%) near the stimulus fish. The change in behavioural alterations might be linked to a significant decrease (p < 0.05) in the brain acetylcholine esterase activity. Furthermore, the present study also illustrates oxidative stress exerted by λ-cyhalothrin through an increase in the production of reactive oxygen species, which is again clearly depicted by a significant increase (p < 0.05) in Superoxide dismutase, Catalase and Glutathione peroxidase activities. Overall, the present study systematically demonstrates the chronic effects of λ-cyhalothrin on adult fish behaviour and physiology, which will contribute to assessing the risks of λ-cyhalothrin to organismal health.
... GLY metabolism can explain current findings in earthworms; during this process, higher levels of free radicals induce oxidative stress that can collapse the activity of antioxidant defenses (Cattani et al. 2017). In addition, the inhibition of AChE induced by GLY in E. fetida can be attributed to cysteine residues near the enzyme's active site (Frasco et al. 2007), compromising, in this way, the catalytic activity or denaturation of the enzyme. ...
Under laboratory conditions, the toxicological effects of pesticides tend to be less variable and realistic than under field conditions, limiting their usefulness in environmental risk assessment. In the current study, the earthworm Eisenia fetida was selected as a bioindicator for assessing glyphosate toxic effects in two different trials to solve this dilemma. In Trial 1, the worms were exposed for 7 and 14 days to concentrations of a commercial glyphosate formulation (1 to 500 mg a.i. kg⁻¹) currently used in the field. In Trial 2, the worms were kept in nine soils collected from different plots with crops for 14 days of exposure. In both experiments, glutathione S-transferase (GST), superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), and acetylcholinesterase (AChE) activities and contents of lipid peroxidation (LPO) were evaluated. In T1, the glyphosate formulation produced a 40% inhibition of AChE activity and a significant increase in GST, SOD, CAT, and GPx activities and LPO contents in E. fetida on day 7. In T2, higher concentrations of glyphosate were detected in the soils of soybean, papaya, and corn (0.92, 0.87, and 0.85 mg kg⁻¹), which induced a positive correlation between the levels of glyphosate residues with GST, SOD, CAT, GPx, and LPO and a negative correlation with AChE. These findings indicate that crop soils polluted with glyphosate elicited higher oxidative stress than under laboratory conditions, confirmed by IBRv2, PCA, and AHC analyses.
... In another study by Cattani et al., rats chronically exposed to low-dose glyphosate both prenatally and postnatally exhibited evidence of glutamate-related neurotoxicity at 60 days of age [80]. The exposed rats exhibited oxidative stress markers associated with depressive-like behavior. ...
... It can be concluded that GBH causes a decrease in AchE. This effect is consistent with previous research showing that maternal exposure to GBH reduces cholinesterase activity in the maturing hippocampus (Cattani et al. 2017). Similarly, another study confirmed that exposure to GBH reduces AChE activity in the brains of adult rats (Gallegos et al. 2018). ...
Glyphosate-based Herbicide (GBH) is a widely used pesticide that functions as a broad-spectrum, non-selective herbicide. Despite advanced research to describe the neurotoxic potential of GBH, the harmful effects on maternal behavior and neurodevelopment of offspring remain unclear. This study was conducted to highlight the effects of GBH on the antioxidant system, anxiety traits, social interaction, and cognitive and sensorimotor functions in pups exposed to 25 or 50 mg/l daily via their mother’s milk. Concerning the biochemical biomarkers, GBH administered during the early stages of development negatively affected the status of antioxidant enzymes and lipid peroxidation in the brain structures of the pups. Furthermore, our results showed a significant decrease in acetylcholinesterase (AChE) specific activity within the brains of treated pups. The results of the behavioral tests indicated that the treated offspring developed anxiety, memory, and sociability disorders, as evidenced by the Open Field, Y-maze, object recognition task, and social interaction tests. Through neurodevelopmental testing, we also showed sensorimotor impairment (righting reflex and negative geotaxis) and abnormal maternal behavior. Altogether, our study clearly demonstrates that the developing brain is sensitive to GBH.
... The involvement of excitotoxicity is also speculated from the structure of glyphosate. Since glyphosate has structural similarities to both glutamate and glycine, both of which are important for regulating NMDA receptors, it is possible that glyphosate behaves like an NMDA receptor agonist (Cattani et al., 2017;Madani and Carpenter, 2022). Alternatively, glyphosate may promote the release or accumulation of glutamate in the brain (Costas-Ferreira et al., 2022). ...
Glyphosate-based herbicides are widely used around the world, making it likely that most humans have significant exposure. Because of habitual exposure, there are concerns about toxicity including neurotoxicity that could result in neurological, psychiatric, or cognitive impairment. We recently found that a single injection of glyphosate inhibits long-term potentiation, a cellular model of learning and memory, in rat hippocampal slices dissected 1 day after injection, indicating that glyphosate-based herbicides can alter cognitive function. Glyphosate-based herbicides could adversely affect cognitive function either indirectly and/or directly. Indirectly, glyphosate could affect gut microbiota, and if dysbiosis results in endotoxemia (leaky gut), infiltrated bacterial by-products such as lipopolysaccharides could activate pro-inflammatory cascades. Glyphosate can also directly trigger pro-inflammatory cascades. Indeed, we observed that acute glyphosate exposure inhibits long-term potentiation in rat hippocampal slices. Interestingly, direct inhibition of long-term potentiation by glyphosate appears to be similar to that of lipopolysaccharides. There are several possible measures to control dysbiosis and neuroinflammation caused by glyphosate. Dietary intake of polyphenols, such as quercetin, which overcome the inhibitory effect of glyphosate on long-term potentiation, could be one effective strategy. The aim of this narrative review is to discuss possible mechanisms underlying neurotoxicity following glyphosate exposure as a means to identify potential treatments.
... Conversely, synthetic herbicides have demonstrated remarkable activity and have been used extensively worldwide to meet the growing demand for crop production [6,7]. However, the excessive use of synthetic chemical herbicides has been associated with adverse effects on both human health and the environment [8,9]. Recent statistics highlight a significant increase in the production and consumption of pesticides on a global scale. ...
Weeds present a significant hazard to crop production, necessitating the development of effective and sustainable strategies for weed management. Although synthetic herbicides are effective, concerns about their environmental and health impact have been raised. This study investigates the allelopathic potential, antimicrobial activity, and phytochemical profile of Artemisia monosperma. Extracts from A. monosperma proficiently impede the growth of Chenopodium murale and Amaranthus viridis, while exhibiting varying effects on crops Solanum lycopersicum and Cucumis sativus. Leaf and seed extracts demonstrate the most significant inhibition of weed growth. Interestingly, the leaf extract at a concentration of 50% inhibited weed growth in pot experiments without affecting crop growth. Moreover, extracts from A. monosperma exhibit noteworthy antifungal and antibacterial activity, with the root extract demonstrating the strongest inhibition. The root extract inhibited the mycelial growth of Colletotrichum musae by 63% as compared to control. The leaf extract exhibited the highest levels of phenolic acids, in particular gallic acid, amounting to 116.30 ppm. This study emphasizes the multifaceted potential of A. monosperma as a sustainable solution for weed management and proposes its use in crop protection. Further investigation of its practical applications and optimization of extraction methods can aid in its integration into contemporary agricultural systems, promoting both crop yield and environmental sustainability.
... Additionally, acute exposure of rats to glyphosate decreases monoamine levels in brain 9,10 supporting a possible link to Parkinson's disease (PD) 11 . Oral exposure of glyphosate to mice (250 or 500 mg/kg/day 12 or 1% GBH in drinking water of pregnant rats 13 ) is reported to cause depression-like behaviors. Moreover, glyphosate exposure (250 or 500 mg/kg/day of GBH as oral gavages 14 ) may diminish memory formation in mice. ...
Glyphosate, a herbicide marketed as Roundup, is widely used but there are concerns this exposure could impair cognitive function. In the CA1 region of rat hippocampal slices, we investigated whether glyphosate alters synaptic transmission and long-term potentiation (LTP), a cellular model of learning and memory. Our hypothesis is that glyphosate alters neuronal function and impairs LTP induction via activation of pro-inflammatory processes. Roundup depressed excitatory synaptic potentials(EPSPs) in a dose-dependent manner with complete suppression at 2000 mg/L. At concentrations ≤ 20 mg/L Roundup did not affect basal transmission, but 4 mg/L Roundup administered for 30 min inhibited LTP induction. Acute administration of 10–100 μM glyphosate also inhibited LTP induction. Minocycline, an inhibitor of microglial activation, and TAK-242, an inhibitor of toll-like receptor 4 (TLR4), both overcame the inhibitory effects of 100 µM glyphosate. Similarly, lipopolysaccharide from Rhodobacter sphaeroides (LPS-RS), a different TLR4 antagonist, overcame the inhibitory effects. In addition, ISRIB (integrated stress response inhibitor) and quercetin, an inhibitor of endoplasmic reticulum stress, overcame the inhibitory effects. We also observed that in vivo glyphosate injection (16.9 mg/kg i.p.) impaired one-trial inhibitory avoidance learning. This learning deficit was overcome by TAK-242. These observations indicate that glyphosate can impair cognitive function through pro-inflammatory signaling in microglia.
... compared to non-applicators; (2) both pesticides were applied by more than half of our study population (Fuhrimann et al. 2022); and (3) Mancozeb's metabolite ETU was associated with a disruption of thyroid functioning which could result in a disrupted circadian rhythm (Costa et al. 2008;Leemans et al. 2019;Richardson et al. 2019). Glyphosate exposure was suggested to cause neurotoxic effects, including depressive behavior (Ait Bali et al. 2017;Cattani et al. 2017). Important to note is also that we assess two active ingredients which are fundamentally different in terms of their application and physical-chemical properties (e.g., half-life in soil) or metabolism in the human bodies (excretion rates and biomarkers). ...
Objective
We aim to showcase the impact of applying eight different self-reported and urinary biomarker-based exposure measures for glyphosate and mancozeb on the association with sleep problems in a study among 253 smallholder farmers in Uganda.
Methods
The questionnaire-based exposure measures included: (1) the number of application days of any pesticide in the last 7 days (never, 1-2; >2 days) and six glyphosate and mancozeb-specific measures: (2) application status over the last 12 months (yes/no), (3) recent application status (never, last 7 days and last 12 months), (4) the number of application days last 12 months, (5) average exposure-intensity scores (EIS) and (6) EIS-weighted number of application days in last 12 months. Based on 384 repeated urinary biomarker concentrations of ethylene thiourea (ETU) and glyphosate from 84 farmers, we also estimated (7) average biomarker concentrations for all 253 farmers. Also in the 84 farmers the measured pre-work and post-work biomarker concentrations were used (8). Multivariable logistic regression models were used to assess the association between the exposure measures and selected Medical Outcomes Study Sleep Scale (MOS-SS) indices (6-item, sleep inadequacy and snoring).
Results
We observed positive associations between (1) any pesticide application in the last 7 days with all three MOS-SS indices. Glyphosate application in the last 7 days (3) and mancozeb application in the last 12 months (3) were associated with the 6-item sleep problem index. The estimated average urinary glyphosate concentrations showed an exposure-response association with the 6-item sleep problem index and sleep inadequacy in the same direction as based on self-reported glyphosate application in the last 7 days. In the analysis with the subset of 84 farmers, both measured and modelled post-work urinary glyphosate concentration showed an association with snoring.
Conclusions
Self-reported, estimated average biomarker concentrations and measured urinary biomarker exposure measures of glyphosate and mancozeb showed similar exposure-response associations with sleep outcomes.
... Overall, the number of epidemiological studies describing glyphosate exposure as a potential risk factor for neurodevelopmental disorders is still limited. Using experimental approaches with animal models, direct chronic and subchronic oral exposure to GHBs induced depression-like symptoms in adult rats (Ait Bali et al., 2017;Aitbali et al., 2018), while a developmental GBH exposure led to an increased immobility and decreased locomotor activity in young offspring (Cattani et al., 2017). However, it is noteworthy that GBHs contain many additional constituents like surfactants, which themselves have been shown to potentially induce adverse health outcomes. ...
Emerging evidence indicates potential adverse effects on infant neurodevelopment from exposure to glyphosate during prenatal and postnatal periods. This systematic review examines the scientific literature to explore links between prenatal/postnatal glyphosate exposure and neurodevelopmental abnormalities in humans and non-humans. Twenty-five original articles were reviewed, focusing on the following descriptors: glyphosate-based herbicides, pre and postnatal exposure, and neurodevelopmental outcomes. Risk of bias assessment was conducted to quality of studies. Experimental studies commonly used tests such as open field and novel object recognition, while epidemiological studies relied on medical records for diagnoses of conditions like depression and autism-like behavior. Surprisingly, only one experimental study directly measured glyphosate levels, and one of the epidemiological studies included a biomarker measure. In rodents, GLY exposure was associated to impaired cognition, motor function, memory, as well as ASD and anxiety-like behavior. In fish models, impairment of swimming activity was predominant. Overall, findings suggest possible associations between glyphosate exposure and neurodevelopmental deficits, emphasizing the need for further research to comprehend the extent of glyphosate's impact on developmental functioning.
Objective
The global incidence and burden of Major Depressive Disorder (MDD) are increasing annually, with current antidepressant treatments proving ineffective for 30-40% of patients. Biomolecular mechanisms within the microbiota-gut-brain axis (MGBA) may significantly contribute to MDD, potentially paving the way for novel treatment approaches. However, integrating the MGBA with the psychological and environmental aspects of MDD remains challenging. This manuscript aims to: 1) investigate the underlying biomolecular mechanisms of MDD using a modeling approach, and 2) integrate this knowledge into a comprehensive ‘spiraling risk factor model’ to develop a biopsychosocial translational research framework for the prevention and treatment of MDD.
Methods
For the first aim, a systematic review (PROSPERO registration) was conducted using PubMed, Embase, and Scopus to query literature published between 2016–2020, with select additional sources. A narrative review was performed for the second aim.
Results
In addition to genetics and neurobiology, research consistently indicates that hyperactivation of the HPA axis and a pro-inflammatory state are interrelated components of the MGBA and likely underlying mechanisms of MDD. Dysregulation of the MGBA, along with imbalances in mental and physical conditions, lifestyle factors, and pre-existing treatments, can trigger a downward spiral of stress and anxiety, potentially leading to MDD.
Conclusions
MDD is not solely a brain disorder but a heterogeneous condition involving biomolecular, psychological, and environmental risk factors. Future interdisciplinary research can utilize the integrated biopsychosocial insights from this manuscript to develop more effective lifestyle-focused multimodal treatment interventions, enhance diagnosis, and stimulate early-stage prevention of MDD.
Systematic Review Registration
https://www.crd.york.ac.uk/PROSPERO/, identifier CRD42020215412.
The age‐standardized prevalence of Parkinson's disease (PD) has increased substantially over the years and is expected to increase further. This emphasizes the need to identify modifiable risk factors of PD, which could form a logical entry point for the prevention of PD. The World Health Organization (WHO) has recommended reducing exposure to specific environmental factors that have been reported to be associated with PD, in particular pesticides, trichloroethylene (TCE), and air pollution. In this review we critically evaluate the epidemiological and biological evidence on the associations of these factors with PD and review evidence on whether these putative associations are causal. We conclude that when considered in isolation, it is difficult to determine whether these associations are causal, in large part because of the decades‐long lag between relevant exposures and the incidence of manifest PD. However, when considered in tandem with evidence from complementary research lines (such as animal models), it is increasingly likely that these associations reflect harmful causal effects. Fundamentally, whilst we highlight some evidence gaps that require further attention, we believe the current evidence base is sufficiently strong enough to support our call for stronger policy action. © 2024 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
The massive use of herbicides, particularly glyphosate‐based herbicides (GBHs), raises several worries, notably their neurotoxic effects. Several studies have explored the consequences of developmental exposure. Our work aims to determine the impact of maternal exposure to GBH on behavioral disorders and memory deficits, as well as the involvement of oxidative stress in the hippocampus and prefrontal cortex. In addition, our study explores the neuroprotective properties of melatonin in male and female offspring. Pregnant Wistar rats were injected with GBH 75 mg/kg during gestation and lactation. After weaning, the offspring were treated with melatonin (4 mg/kg) from postnatal days 30–58. Our results show that GBH increases anxiety‐like behavior levels in offspring, as well as depression‐like behavior. GBH also impairs working memory in progeny. While markers of oxidative stress show a disturbance in lipid peroxidation and catalase activity, with a more pronounced effect in females, on the other hand, melatonin considerably attenuated the neurotoxic impact observed in the offspring, with higher efficacy in females. The oxidative stress results confirm the antioxidant power of melatonin to counteract the damaging effects of exposure to environmental contaminants such as glyphosate‐based pesticides. It will then be interesting to further our work to fully understand the sex‐dependent effect of melatonin.
Chronic exposure to glyphosate-based herbicide (Gly) has been associated with neurological disorders. Tannic acid (TA) is an antioxidant with attenuating action against neuroinflammation-associated conditions. This study evaluated the effect of Gly on pain perception alongside antinociceptive and anti-inflammatory actions of TA in Gly-exposed mice. Male Swiss mice were randomly divided into six groups (n=8): control (distilled water 0.2 ml/kg), Gly (Gly 500 mg/kg), Pre-TA + Gly (TA 50 mg/kg pre-treatment, afterwards Gly-administered), TA + Gly (TA 50 mg/kg and Gly co-administered), Pre-AA + Gly (ascorbic acid (AA) 10 mg/kg pre-treatment, afterwards Gly-administered), and AA + Gly (AA 10 mg/kg and Gly co-administered). Mechanical, thermal, and chemical pain were evaluated six weeks post vehicle/drugs administrations orally, followed by brain biochemical measurements. TA treatment alleviated Gly-induced hyperalgesia in similar version to the values of control and AA groups by increasing significantly (p < 0.05) nociceptive thresholds. Moreover, TA-treatment significantly decreased malondialdehyde (MDA) and pro-inflammatory cytokines (TNF-α, IL-1β, and IL-6) levels, significantly increased anti-inflammatory cytokines (IL-10, IL-4, and TGF-1β) levels, and antioxidant enzymes, catalase (CAT), glutathione peroxidase (GPx), and superoxide dismutase (SOD) activities compared to Gly-treated mice (p < 0.05). Conclusively, TA treatment exerted antinociceptive and anti-inflammatory actions, possibly through its antioxidant and anti-inflammatory actions in Gly-exposed mice. Notably, TA pre-treatment showed a better response than TA and Gly co-administration. We propose the potential neuroprotective and ameliorative functions of TA in Gly-induced hyperalgesia. This merits further clinical research into protective roles of TA against pesticide-related conditions.
Glyphosate (GLY) is a pesticide that severely alters nigrostriatal dopaminergic neurotransmission, inducing great increases in dopamine release from rat dorsal striatum. This GLY‐induced striatal dopamine overflow occurs through mechanisms not yet fully understood, hence the interest in evaluating the role of other neurotransmitter systems in such effects. So, the main objective of this mechanistic study was to evaluate the possible mediation of the glutamatergic, cholinergic, and nitrergic systems in the GLY‐induced in vivo dopamine release from rat dorsal striatum. The extracellular dopamine levels were measured by cerebral microdialysis and HPLC with electrochemical detection. Intrastriatal administration of GLY (5 mmol/L) significantly increased the dopamine release (1102%). Pretreatment with MK‐801 (50 or 400 μmol/L), a non‐competitive antagonist of NMDA receptors, significantly decreased the effect of GLY (by 70% and 74%, respectively), whereas AP‐5 (400 μmol/L), a competitive antagonist of NMDA receptors, or CNQX (500 μmol/L), an AMPA/kainate receptor antagonist, had no significant effect. Administration of the nitric oxide synthase inhibitors, L‐nitroarginine (L‐NAME, 100 μmol/L) or 7‐nitroindazole (7‐NI, 100 μmol/L), also did not alter the effect of GLY on dopamine release. Finally, pretreatment of the animals with mecamylamine, an antagonist of nicotinic receptors, decreased the effect of GLY on dopamine release by 49%, whereas atropine, a muscarinic antagonist, had no significant effect. These results indicate that GLY‐induced dopamine release largely depends on the activation of NMDA and nicotinic receptors in rat dorsal striatum. Future research is needed to determine the effects of this pesticide at environmentally relevant concentrations.
Autism is a neurodevelopmental disorder, the prevalence of which has increased dramatically in the United States over the past two decades. It is characterized by stereotyped behaviors and impairments in social interaction and communication. In this paper, we present evidence that autism can be viewed as a PIN1 deficiency syndrome. Peptidyl‐prolyl cis/trans isomerase, NIMA‐Interacting 1 (PIN1) is a peptidyl‐prolyl cis/trans isomerase, and it has widespread influences in biological organisms. Broadly speaking, PIN1 deficiency is linked to many neurodegenerative diseases, whereas PIN1 over‐expression is linked to cancer. Death‐associated protein kinase 1 (DAPK1) strongly inhibits PIN1, and the hormone melatonin inhibits DAPK1. Melatonin deficiency is strongly linked to autism. It has recently been shown that glyphosate exposure to rats inhibits melatonin synthesis as a result of increased glutamate release from glial cells and increased expression of metabotropic glutamate receptors. Glyphosate's inhibition of melatonin leads to a reduction in PIN1 availability in neurons. In this paper, we show that PIN1 deficiency can explain many of the unique morphological features of autism, including increased dendritic spine density, missing or thin corpus callosum, and reduced bone density. We show how PIN1 deficiency disrupts the functioning of powerful high‐level signaling molecules, such as nuclear factor erythroid 2‐related factor 2 (NRF2) and p53. Dysregulation of both of these proteins has been linked to autism. Severe depletion of glutathione in the brain resulting from chronic exposure to oxidative stressors and extracellular glutamate leads to oxidation of the cysteine residue in PIN1, inactivating the protein and further contributing to PIN1 deficiency. Impaired autophagy leads to increased sensitivity of neurons to ferroptosis. It is imperative that further research be conducted to experimentally validate whether the mechanisms described here take place in response to chronic glyphosate exposure and whether this ultimately leads to autism. image
The roles of perinatal development, intracellular calcium [Ca2+]i, and synaptogenesis disruption are not novel in the autism/ASD literature. The focus on six mechanisms controlling synaptogenesis, each regulated by [Ca2+]i, and each aberrant in ASDs is novel. The model presented here predicts that autism epidemic causation involves central roles of both electromagnetic fields (EMFs) and chemicals. EMFs act via voltage-gated calcium channel (VGCC) activation and [Ca2+]i elevation. A total of 15 autism-implicated chemical classes each act to produce [Ca2+]i elevation, 12 acting via NMDA receptor activation, and three acting via other mechanisms. The chronic nature of ASDs is explained via NO/ONOO(-) vicious cycle elevation and MeCP2 epigenetic dysfunction. Genetic causation often also involves [Ca2+]i elevation or other impacts on synaptogenesis. The literature examining each of these steps is systematically examined and found to be consistent with predictions. Approaches that may be sed for ASD prevention or treatment are discussed in connection with this special issue: The current situation and prospects for children with ASDs. Such approaches include EMF, chemical avoidance, and using nutrients and other agents to raise the levels of Nrf2. An enriched environment, vitamin D, magnesium, and omega-3s in fish oil may also be helpful.
Introdução. A necessidade de maximizar a produtividade visando maior lucratividade houve a pungente necessidade de uso de mecanismos para maximizar a produção agrícola, neste contexto, os agroquímicos galgaram patamares e hoje são usados de maneira desenfreada. A exposição à mesma está correlacionada às diversas injúrias, seja no reino animal ou vegetal. O glifosato, um potente herbicida responsável por extirpar erva daninha em meio às plantas, está sendo amplamente correlacionado a diversas patologias, e mais recentemente observou se que o mesmo tem a capacidade de perpassar a barreira hematopoiética e assim, causas alterações as estruturas do sistema nervoso. Objetivo. Revisar a bibliografia existente que delineia as injúrias causadas ao tecido neurológico pela exposição ao glifosato. Método. Uma busca sistemática foi realizada nas bases de dados PubMed, Science Direct e Medline, aplicando os descritores ‘’Brain’’ OR ‘’Central Nervous System’’ AND ‘’ Glyphosate’’ AND “Agrochemical”. Foram incluídos estudos originais primários, publicados entre 2018 a 2023. Foram excluídos artigos que não traziam em seu escopo do texto a temática proposta para o estudo. Resultados. O assunto ainda necessita de maiores estudos, contudo, diante das evidências científicas disponíveis, é possível inferir que existe uma correlação direta e indireta de injúria a diversas estruturas do sistema nervoso. Conclusão. As manifestações neurológicas apresentaram ocorrência frequente no curso da exposição ao glifosato. A adoção de novas fórmulas menos agressiva torna se cada vez mais necessária diante de tamanhas evidências cientificas mostrando o quão nocivo esses produtos e subprodutos são para todos os seres vivos.
It has been reported that glyphosate, one of the most common herbicides used in agriculture, impairs locomotion and cognition. Glyphosate has a variable half-life in soil up to biotic and/or abiotic factors transform the molecule in metabolites such as the aminomethylphosphonic acid (AMPA) that has a longer half-life. In this study, female Sprague Dawley rats were acutely exposed to different doses of glyphosate or AMPA (i.e. 10, 56 or 100 mg/kg) and, subsequently, the acetylcholinesterase (AChE) activity was measured in the hippocampus, prefrontal cortex (PFC) and the gastrocnemius muscle. Both glyphosate and AMPA produced a similar decrease in the AChE activity in all the tissues tested. These results suggest that interference with normal cholinergic neurotransmission may be one of the mechanisms involved in glyphosate-induced motor alterations in rats. Moreover, our results highlight the biological importance of AMPA as a molecule with anticholinesterase action in brain and skeletal muscle. To our knowledge, this is the first report showing in vivo that AMPA, the major metabolite of glyphosate, behaves as an organophosphate.
The increasing global burden of Parkinson’s disease (PD), termed the PD pandemic, is exceeding expectations related purely to population aging and is likely driven in part by lifestyle changes and environmental factors. Pesticides are well recognized risk factors for PD, supported by both epidemiological and experimental evidence, with multiple detrimental effects beyond dopaminergic neuron damage alone. The microbiome-gut-brain axis has gained much attention in recent years and is considered to be a significant contributor and driver of PD pathogenesis. In this narrative review, we first focus on how both pesticides and the microbiome may influence PD initiation and progression independently, describing pesticide-related central and peripheral neurotoxicity and microbiome-related local and systemic effects due to dysbiosis and microbial metabolites. We then depict the bidirectional interplay between pesticides and the microbiome in the context of PD, synthesizing current knowledge about pesticide-induced dysbiosis, microbiome-mediated alterations in pesticide availability, metabolism and toxicity, and complex systemic pesticide-microbiome-host interactions related to inflammatory and metabolic pathways, insulin resistance and other mechanisms. An overview of the unknowns follows, and the role of pesticide-microbiome interactions in the proposed body-/brain-first phenotypes of PD, the complexity of environmental exposures and gene-environment interactions is discussed. The final part deals with possible further steps for translation, consisting of recommendations on future pesticide use and research as well as an outline of promising preventive/therapeutic approaches targeted on strengthening or restoring a healthy gut microbiome, closing with a summary of current gaps and future perspectives in the field.
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.
Major depressive disorder is a severe and complex mental disorder. Impaired neurotransmission and disrupted signalling pathways may influence neuroplasticity, which is involved in the brain dysfunction in depression. Traditional neurobiological theories of depression, such as monoamine hypothesis, cannot fully explain the whole picture of depressive disorders. In this review, we discussed new treatment directions of depression, including modulation of glutamatergic system and noninvasive brain stimulation. Dysfunction of glutamatergic neurotransmission plays an important role in the pathophysiology of depression. Ketamine, an N-methyl-D-aspartate (NMDA) receptor antagonist, has rapid and lasting antidepressive effects in previous studies. In addition to ketamine, other glutamatergic modulators, such as sarcosine, also show potential antidepressant effect in animal models or clinical trials. Noninvasive brain stimulation is another new treatment strategy beyond pharmacotherapy. Growing evidence has demonstrated that superficial brain stimulations, such as transcranial magnetic stimulation, transcranial direct current stimulation, cranial electrotherapy stimulation, and magnetic seizure therapy, can improve depressive symptoms. The antidepressive effect of these brain stimulations may be through modulating neuroplasticity. In conclusion, drugs that modulate neurotransmission via NMDA receptor and noninvasive brain stimulation may provide new directions of treatment for depression. Furthermore, exploring the underlying mechanisms will help in developing novel therapies for depression in the future.
The broadband herbicide glyphosate (N-[phosphonomethyl]-glycine) and its main metabolite aminomethylphosphonic acid (AMPA) were analyzed by GC-MS-MS in 24 h-urine samples cryo-archived by the German Environmental Specimen Bank (ESB). Samples collected in 2001, 2003, 2005, 2007, 2009, 2011, 2012, 2013, 2014, and 2015 were chosen for this retrospective analysis. All urine samples had been provided by 20 to 29 years old individuals living in Greifswald, a city in north-eastern Germany. Out of the 399 analyzed urine samples, 127 (=31.8 %) contained glyphosate concentrations at or above the limit of quantification (LOQ) of 0.1μg/L. For AMPA this was the case for 160 (=40.1 %) samples. The fraction of glyphosate levels at or above LOQ peaked in 2012 (57.5 %) and 2013 (56.4 %) after having discontinuously increased from 10.0% in 2001. Quantification rates were lower again in 2014 and 2015 with 32.5 % and 40.0 %, respectively. The overall trend for quantifiable AMPA levels was similar. Glyphosate and AMPA concentrations in urine were statistically significantly correlated (spearman rank correlations coefficient=0.506, p≤0.001). Urinary glyphosate and AMPA levels tended to be higher in males. The possible reduction in exposure since 2013 indicated by ESB data may be due to changes in glyphosate application in agricultural practice. The ESB will continue monitoring internal exposures to glyphosate and AMPA for following up the time trend, elucidating inter-individual differences, and contributing to the ongoing debate on the further regulation of glyphosate-based pesticides
Numerous studies have found agricultural workers, including farmers, at elevated risk of suicide, and socio-economic conditions have been suggested as one of the important determinants of this mortality cause. The real agricultural income per worker in Europe increased steadily from 2005 to 2007 and then fell by 1.8% in 2008 and by 11.6% in 2009. This drop was particularly pronounced in France. Repeated cross-sectional studies were conducted to investigate suicide mortality rates among French farmers in 2007-2009. The study population included all French farmers enrolled yearly in the compulsory Agricultural Social Security and Health Insurance (CCMSA). Most of the mean of 500,164 subjects per year were men (68%). National cause-specific mortality rates were used to calculate standardized mortality ratios (SMRs) and associated 95%-confidence interval [95%CI] for both genders and for each of the 3 years. During the 3-year study period, 2769 men and 997 women died. Suicide accounted for 417 of the men's deaths (15%) and 68 of the women's (6.8%). Hanging was the most frequent method of suicide for both. Compared with the general population, the increased rate of suicide deaths among male farmers was 28% in 2008 and 22% in 2009. This increased rate was particularly high among those aged 45-54 years (31%) and 55-64 years (47%) in 2008 (and in the 55-64 year-old group in 2009 (64%). Two specific types of farming activity were associated with increased suicide mortality rates in both 2008 and 2009: dairy cattle farming (SMR=1.56 [1.09-2.15] and SMR=1.47 [1.01-2.04]) and beef cattle farming (SMR=2.27 [1.59-3.10] and SMR=1.57 [1.01-2.27]). These results may be useful for a better understanding of the situation from an epidemiological standpoint and for improving suicide prevention policies in this particular population.
The rate of autoxidation of epinephrine and the sensitivity of this autoxidation to inhibition by superoxide dismutase were both augmented, as the pH was raised from 7.8 → 10.2. O2⁻, generated by the xanthine oxidase reaction, caused the oxidation of epinephrine to adrenochrome and the yield of adrenochrome produced per O2⁻ introduced, increased with increasing pH in the range 7.8 → 10.2 and also increased with increasing concentration of epinephrine. These results, in conjunction with complexities in the kinetics of adrenochrome accumulation, lead to the proposal that the autoxidation of epinephrine proceeds by at least two distinct pathways, only one of which is a free radical chain reaction involving O2⁻ and hence inhibitable by superoxide dismutase. This chain reaction accounted for a progressively greater fraction of the total oxidation as the pH was raised. The ability of superoxide dismutase to inhibit the autoxidation of epinephrine at pH 10.2 has been used as the basis of a convenient and sensitive assay for this enzyme.
The broad-spectrum herbicide glyphosate (common trade name "Roundup") was first sold to farmers in 1974. Since the late 1970s, the volume of glyphosate-based herbicides (GBHs) applied has increased approximately 100-fold. Further increases in the volume applied are likely due to more and higher rates of application in response to the widespread emergence of glyphosate-resistant weeds and new, pre-harvest, dessicant use patterns. GBHs were developed to replace or reduce reliance on herbicides causing well-documented problems associated with drift and crop damage, slipping efficacy, and human health risks. Initial industry toxicity testing suggested that GBHs posed relatively low risks to non-target species, including mammals, leading regulatory authorities worldwide to set high acceptable exposure limits. To accommodate changes in GBH use patterns associated with genetically engineered, herbicide-tolerant crops, regulators have dramatically increased tolerance levels in maize, oilseed (soybeans and canola), and alfalfa crops and related livestock feeds. Animal and epidemiology studies published in the last decade, however, point to the need for a fresh look at glyphosate toxicity. Furthermore, the World Health Organization's International Agency for Research on Cancer recently concluded that glyphosate is "probably carcinogenic to humans." In response to changing GBH use patterns and advances in scientific understanding of their potential hazards, we have produced a Statement of Concern drawing on emerging science relevant to the safety of GBHs. Our Statement of Concern considers current published literature describing GBH uses, mechanisms of action, toxicity in laboratory animals, and epidemiological studies. It also examines the derivation of current human safety standards. We conclude that: (1) GBHs are the most heavily applied herbicide in the world and usage continues to rise; (2) Worldwide, GBHs often contaminate drinking water sources, precipitation, and air, especially in agricultural regions; (3) The half-life of glyphosate in water and soil is longer than previously recognized; (4) Glyphosate and its metabolites are widely present in the global soybean supply; (5) Human exposures to GBHs are rising; (6) Glyphosate is now authoritatively classified as a probable human carcinogen; (7) Regulatory estimates of tolerable daily intakes for glyphosate in the United States and European Union are based on outdated science. We offer a series of recommendations related to the need for new investments in epidemiological studies, biomonitoring, and toxicology studies that draw on the principles of endocrinology to determine whether the effects of GBHs are due to endocrine disrupting activities. We suggest that common commercial formulations of GBHs should be prioritized for inclusion in government-led toxicology testing programs such as the U.S. National Toxicology Program, as well as for biomonitoring as conducted by the U.S. Centers for Disease Control and Prevention.
The NF-κB (nuclear factor κ-light-chain-enhancer of activated B cells) transcription factor family is a pleiotropic regulator of many cellular signaling pathways, providing a mechanism for the cells in response to a wide variety of stimuli linking to inflammation. The stimulated cells will be regulated by not only the canonical but also non-canonical NF-κB pathways. To initiate both of these pathways, IκB-degradation triggers NF-κB release and the nuclear translocated-heterodimer (or homodimer) can associate with the κB sites of promoter to regulate the gene transcriptions. NF-κB ubiquitously expresses in neurons and the constitutive NF-κB activation is associated with processing of neuronal information. NF-κB can regulate the transcription of genes such as chemokines, cytokines, proinflammatory enzymes, adhesion molecules, proinflammatory transcription factors, and other factors to modulate the neuronal survival. In neuronal insult, NF-κB constitutively active in neuron cell bodies can protect neurons against different injuries and regulate the neuronal inflammatory reactions. Besides neurons, NF-κB transcription factors are abundant in glial cells and cerebral blood vessels and the diverse functions of NF-κB also regulate the inflammatory reaction around the neuronal environment. NF-κB transcription factors are abundant in the brain and exhibit diverse functions. Several central nerve system (CNS) diseases are linked to NF-κB activated by inflammatory mediators. The RelA and c-Rel expression produce opposite effects on neuronal survival. Importantly, c-Rel expression in CNS plays a critical role in anti-apoptosis and reduces the age-related behaviors. Moreover, the different subunits of NF-κB dimer formation can modulate the neuroninflammation, neuronal protection, or neurotoxicity. The diverse functions of NF-κB depend on the subunits of the NF-κB dimer-formation which enable us to develop a therapeutic approach to neuroinflammation based on a new concept of inflammation as a strategic tool in neuronal cells. However, the detail role of NF-κB in neuroinflammation, remains to be clarified. In the present article, we provide an updated review of the current state of our knowledge about relationship between NF-κB and neuroinflammation.
Background
Alcohol abuse during pregnancy leads to intellectual disability and morphological defects in the offspring. The aim of this study was to determine the effect of chronic maternal ethanol (EtOH) consumption during pregnancy and lactation on glutamatergic transmission regulation, energy deficit, and oxidative stress in the hippocampus of the offspring.
Methods
EtOH was administered to dams in drinking water at increasing doses (2 to 20%) from the gestation day 5 to lactation day 21. EtOH and tap water intake by treated and control groups, respectively, were measured daily.
Results
Results showed that EtOH exposure does not affect fluid intake over the course of pregnancy and lactation. The toxicity of maternal exposure to EtOH was demonstrated by decreased offspring body weight at experimental age, on postnatal day 21. Moreover, maternal EtOH exposure decreased ⁴⁵Ca²⁺ influx in the offspring's hippocampus. Corroborating this finding, EtOH increased both Na⁺‐dependent and Na⁺‐independent glial [¹⁴C]‐glutamate uptake in hippocampus of immature rats. Also, maternal EtOH exposure decreased glutamine synthetase activity and induced aspartate aminotransferase enzymatic activity, suggesting that in EtOH‐exposed offspring hippocampus, glutamate is preferentially used as a fuel in tricarboxylic acid cycle instead of being converted into glutamine. In addition, EtOH exposure decreased [U‐14C]‐2‐deoxy‐D‐glucose uptake in offspring hippocampus.
Conclusions
The decline in glucose transport coincided with increased lactate dehydrogenase activity, suggesting an adaptative response in EtOH‐exposed offspring hippocampus, using lactate as an alternative fuel. These events were associated with oxidative damage, as demonstrated by changes in the enzymatic antioxidant defense system and lipid peroxidation. Taken together, the results demonstrate that maternal exposure to EtOH during pregnancy and lactation impairs glutamatergic transmission, as well as inducing oxidative stress and energy deficit in immature rat hippocampus.
N-methyl-D-aspartate (NMDA) receptors, a family of L-glutamate receptors, play an important role in learning and memory, and are critical for spatial memory. These receptors are tetrameric ion channels composed of a family of related subunits. One of the hallmarks of the aging human population is a decline in cognitive function; studies in the past couple of years have demonstrated deterioration in NMDA receptor subunit expression and function with advancing age. However, a direct relationship between impaired memory function and a decline in NMDA receptors is still ambiguous. Recent studies indicate a link between an age-associated NMDA receptor hypofunction and memory impairment and provide evidence that age-associated enhanced oxidative stress might be contributing to the alterations associated with senescence. However, clear evidence is still deficient in demonstrating the underlying mechanisms and a relationship between age-associated impaired cognitive faculties and NMDA receptor hypofunction. The current review intends to present an overview of the research findings regarding changes in expression of various NMDA receptor subunits and deficits in NMDA receptor function during senescence and its implication in age-associated impaired hippocampal-dependent memory function.
Hard cover, 492 pages Publisher: InTech This book is divided into two sections namely: synthesis and properties of herbicides and herbicidal control of weeds. Chapters 1 to 11 deal with the study of different synthetic pathways of certain herbicides and the physical and chemical properties of other synthesized herbicides. The other 14 chapters (12-25) discussed the different methods by which each herbicide controls specific weed population. The overall purpose of the book, is to show properties and characterization of herbicides, the physical and chemical properties of selected types of herbicides, and the influence of certain herbicides on soil physical and chemical properties on microflora. In addition, an evaluation of the degree of contamination of either soils and/or crops by herbicides is discussed alongside an investigation into the performance and photochemistry of herbicides and the fate of excess herbicides in soils and field crops.
As the major excitatory neurotransmitter in the mammalian central nervous system, glutamate plays a key role in many central pathologies, including gliomas, psychiatric, neurodevelopmental, and neurodegenerative disorders. Post-mortem and serological studies have implicated glutamatergic dysregulation in these pathologies, and pharmacological modulation of glutamate receptors and transporters has provided further validation for the involvement of glutamate. Furthermore, efforts from genetic, in vitro, and animal studies are actively elucidating the specific glutamatergic mechanisms that contribute to the aetiology of central pathologies. However, details regarding specific mechanisms remain sparse and progress in effectively modulating glutamate to alleviate symptoms or inhibit disease states has been relatively slow. In this report, we review what is currently known about glutamate signalling in central pathologies. We also discuss glutamate’s mediating role in comorbidities, specifically cancer-induced bone pain and depression.
Publisher Summary Glutathione reductase is a flavoprotein catalyzing the NADPH-dependent reduction of glutathione disulfide (GSSG) to glutathione (GSH). The reaction is essential for the maintenance of glutathione levels. Glutathione has a major role as a reductant in oxidation–reduction processes, and serves in detoxication and several other cellular functions of great importance. A purification method of this enzyme from calf liver and rat liver is described in this chapter. Similar methods are used for the purification of the enzyme from yeast, porcine, and human erythrocytes. All the steps are carried out at about 5 ° . The purification method from calf liver consists of various steps including preparation of cytosol fraction, chromatography on DEAE-sephadex, precipitation with ammonium sulfate, and chromatography on hydroxyapatite. The purification of glutathione reductase from rat liver is usually combined with the preparation of glutathione transferases, thioltransferase, and glyoxalase I.
Suicide rates have risen considerably in recent years. National workplace suicide trends have not been well documented. The aim of this study is to describe suicides occurring in U.S. workplaces and compare them to suicides occurring outside of the workplace between 2003 and 2010.
Suicide data originated from the Census of Fatal Occupational Injury database and the Web-Based Injury Statistics Query and Reporting System. Suicide rates were calculated using denominators from the 2013 Current Population Survey and 2000 U.S. population census. Suicide rates were compared among demographic groups with rate ratios and 95% CIs. Suicide rates were calculated and compared among occupations. Linear regression, adjusting for serial correlation, was used to analyze temporal trends. Analyses were conducted in 2013-2014.
Between 2003 and 2010, a total of 1,719 people died by suicide in the workplace. Workplace suicide rates generally decreased until 2007 and then sharply increased (p=0.035). This is in contrast with non-workplace suicides, which increased over the study period (p=0.025). Workplace suicide rates were highest for men (2.7 per 1,000,000); workers aged 65-74 years (2.4 per 1,000,000); those in protective service occupations (5.3 per 1,000,000); and those in farming, fishing, and forestry (5.1 per 1,000,000).
The upward trend of suicides in the workplace underscores the need for additional research to understand occupation-specific risk factors and develop evidence-based programs that can be implemented in the workplace.
Published by Elsevier Inc.
Depression is a serious psychiatric illness that affects millions of people worldwide. Weeks of antidepressant therapy are required to relieve depressive symptoms, and new drugs are still being extensively researched. The latest studies have shown that in depression, there is an imbalance between the main excitatory (glutamatergic) and inhibitory (GABAergic) systems. Administration of antagonists of the glutamatergic system, including zinc, has shown an antidepressant effect in preclinical as well as clinical studies. Zinc inhibits the NMDA receptor via its binding site located on one of its subunits. This is thought to be the main mechanism explaining the antidepressant properties of zinc. In the present review, a link between zinc and the glutamatergic system is discussed in the context of depressive disorder.
Neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), Amyotrophic lateral sclerosis (ALS) and retinal degeneration have been studied extensively and varying molecular mechanisms have been proposed for onset of such diseases. Although genetic analysis of these diseases has also been described, yet the mechanisms governing the extent of vulnerability to such diseases remains unresolved. Recent studies have, therefore, focused on the role of environmental exposure in progression of such diseases especially in the context of prenatal and postnatal life, explaining how molecular mechanisms mediate epigenetic changes leading to degenerative diseases. This review summarizes both the animal and human studies describing various environmental stimuli to which an individual or an animal is exposed during in-utero and postnatal period and mechanisms that promote neurodegeneration. The SNPs mediating gene environment interaction are also described. Further, preventive and therapeutic strategies are suggested for effective intervention.
Glyphosate (GLP), the active ingredient of many weed killing formulations, is a broad spectrum herbicide compound. Wistar rats were exposed during 30 or 90 days to the highest level (0.7mg/L) of GLP allowed in water for human consumption (US EPA, 2011) and a 10-fold higher concentration (7mg/L). The low levels of exposure to the herbicide did not produce histomorphological changes. The production of TBARS was similar or tended to be lower compared to control animals not exposed to the herbicide. In rats exposed to GLP, increased levels of reduced glutathione (GSH) and enhanced glutathione peroxidase (GPx) activity may act as a protective mechanism against possible detrimental effects of the herbicide. Overall, this work showed certain biochemical modifications, even at 3-20-fold lower doses of GLP than the oral reference dose of 2mg/kg/day (US EPA, 1993). The toxicological significance of these findings remains to be clarified.
The incidence and/or prevalence of health problems associated with endocrine-disruption have increased. Many chemicals have endocrine-disrupting properties, including bisphenol A, some organochlorines, polybrominated flame retardants, perfluorinated substances, alkylphenols, phthalates, pesticides, polycyclic aromatic hydrocarbons, alkylphenols, solvents, and some household products including some cleaning products, air fresheners, hair dyes, cosmetics, and sunscreens. Even some metals were shown to have endocrine-disrupting properties. Many observations suggesting that endocrine disruptors do contribute to cancer, diabetes, obesity, the metabolic syndrome, and infertility are listed in this paper. An overview is presented of mechanisms contributing to endocrine disruption. Endocrine disruptors can act through classical nuclear receptors, but also through estrogen-related receptors, membrane-bound estrogen-receptors, and interaction with targets in the cytosol resulting in activation of the Src/Ras/Erk pathway or modulation of nitric oxide. In addition, changes in metabolism of endogenous hormones, cross-talk between genomic and nongenomic pathways, cross talk with estrogen receptors after binding on other receptors, interference with feedback regulation and neuroendocrine cells, changes in DNA methylation or histone modifications, and genomic instability by interference with the spindle figure can play a role. Also it was found that effects of receptor activation can differ in function of the ligand.
Objectives:
This longitudinal study measured the glyphosate and paraquat concentrations found in maternal and umbilical cord serum in 82 pregnant women who gave birth in three provinces of Thailand.
Methods:
Through questionnaires and biological samples collected at childbirth, factors such as personal characteristics, occupation, agricultural activities, and herbicide use in agricultural work were evaluated as predictors of glyphosate and paraquat levels in the pregnant women. Statistical analysis used univariate and binary multiple logistic regression, where the outcome was the probability of exposure to paraquat or glyphosate above the limit of detection associated with occupation and household factors.
Results:
The glyphosate concentrations in the pregnant women's serum at childbirth (median 17.5, range 0.2-189.1 ng/ml) were significantly higher (p<0.007) than those in the umbilical cord serum (median 0.2, range 0.2-94.9 ng/ml). However, the paraquat concentrations in the serum of the pregnant women at childbirth (83% ≤ limit of detection [LOD] with maximum of 58.3 ng/ml) were similar to those in the umbilical cord serum (80% < LOD with maximum of 47.6 ng/ml). Women with glyphosate levels > LOD in serum at childbirth were 11.9 times more likely to report work as an agriculturist (p<0.001), 3.7 times more likely to live near agricultural areas (p=0.006), and 5.9 times more likely to have a family member who worked in agriculture (p<0.001). The only factors affecting paraquat exposures in pregnant women at childbirth were reporting the agricultural activity of digging in farm soil and working in the agricultural fields in the third trimester of pregnancy.
Conclusions:
These results show that pregnant women who work in agriculture or live in families that work in agriculture have higher exposures to the herbicides glyphosate and paraquat. The potential for long term health impacts of these prenatal exposures to children should be evaluated, and greater regulation of the sale and use of herbicides should be considered in Thailand.
In this study, it has been investigated that the effects of glyphosate, which is a herbicide within organophosphate and unselective widely used in agriculture on enzyme activity of carbonic anhydrase, production of reactive oxygen species, cell apoptosis and body morphology during the embryonic development of zebrafish. To this end, it has been treated embryo with 1, 5, 10 and 100 mg/L gyphosate at 96 h. The embryos treated with glyphosate from 4 hpf were evaluated by considering the survival rates, hatching rates, body malformations under the stereo microscope in 24, 48, 72 and 96th hours. In order to clarify the mechanism of the abnormalities ROS, enzyme activity of carbonic anhydrase and cellular death were detected end of the 96th hour. The data obtained in the present study have shown that glyphosate treatment inhibited CA activity, caused production of ROS especially branchial regions, triggered cellular apoptosis and caused several types of malformations including pericardial edema, yolk sac edema, spinal curvature and body malformation in a dose-dependent manner. As a conclusion, in light of present and previous studies, we can deduce that (1) the probable reason of ROS production was CA inhibition via decreasing of CO2 extraction and developing respiratory acidosis (however, one needs to clarify), (2) abundance of ROS triggered cellular apoptosis and (3) as a result of cellular apoptosis malformations increased. These data will enable us to further understand potential toxic mechanism of glyphosate on embryonic development stage of zebrafish and may be useful for assessment in the toxicology studies.
Chronic organ ophosphorus pesticides (OP) exposure is associated with an increased risk of depression, and there is an urgent need to find an effective treatment for the depressive-like symptoms caused by OP. The main purpose of this study was to investigate whether combined lithium chloride (LiCl) and astaxanthin (AST) treatment would manifest synergetic antidepressant effects on mice with chronic OP exposure, and to determine the role of the Akt/GSK3?/CREB signaling pathway. Our results showed that chronic omethoate exposure significantly increased immobility time in behavioral tests and induced neuron damage in HE staining. The expression of p-GSK3?, p-CREB, p-PI3K and p-Akt in hippocampus after OP exposure were significantly down-regulated, while the influences were reversed by LiCl and AST treatment. Moreover, the combined application of AST and LiCl had synergistic therapeutic effects compared to LiCl and AST treatment alone, the expression of p-GSK3?, p-CREB, p-PI3K and p-Akt after combined LiCl-AST treatment were significantly higher than that with single drug application. These results showed that the combination of LiCl and AST could efficiently ameliorate depressive-like behavior induced by omethoate, and Akt/GSK3?/CREB signaling pathway might be responsible for the neuroprotective effect.
Background:
Central nervous system (CNS) complications such as seizures and reduced consciousness are important in glufosinate and may occur in severe glyphosate poisoning. The aim of this study was to assess the possible role of serum S100B protein as a biochemical marker of CNS complications associated with glyphosate or glufosinate poisoning.
Methods:
The study enrolled 40 patients (23 glyphosate poisoning and 17 glufosinate poisoning). Altered consciousness and seizure were observed during hospitalization. S100B level was measured with fully automated modular analytic E170 system using electrochemoluminometric immunoassay.
Results:
Among 40 patients, neurologic features were observed in 12 patients with a median time to onset of 21.5 (IQR 8.25-24.75) h. Serum S100B concentrations measured on admission were higher in the group with neurologic features than in the group without neurologic features [0.148 μg/L (IQR 0.128-0.248) vs. 0.072 μg/L (IQR 0.047-0.084), p < .001]. Univariate analysis of measured patient raw parameters using a ROC curve showed that S100B was a significant predictor of neurologic features in glyphosate and glufosinate poisoning. The area under the ROC curve was 0.894 (95% confidential interval 0.791-0.998). When S100B was set at 0.0965, its sensitivity and specificity for predicting neurologic features in glyphosate and glufosinate poisoning were 92% and 82%, respectively.
Conclusions:
In our pilot study, S100B was a significant predictor of neurologic complications in patients with glyphosate and glufosinate poisoning. Large prospective cohorts are needed to confirm this finding.
Glyphosate based herbicides (GBH) like Roundup® are used extensively in agriculture as well as in urban and rural settings as a broad spectrum herbicide. Its mechanism of action was thought to be specific only to plants and thus considered safe and non-toxic. However, mounting evidence suggests that GBHs may not be as safe as once thought as initial studies in frogs suggest that GBHs may be teratogenic. Here we utilize the zebrafish vertebrate model system to study early effects of glyphosate exposure using technical grade glyphosate and the Roundup® Classic formulation. We find morphological abnormalities including cephalic and eye reductions and a loss of delineated brain ventricles. Concomitant with structural changes in the developing brain, using in situ hybridization analysis, we detect decreases in genes expressed in the eye, fore and midbrain regions of the brain including pax2, pax6, otx2 and ephA4. However, we do not detect changes in hindbrain expression domains of ephA4 nor exclusive hindbrain markers krox-20 and hoxb1a. Additionally, using a Retinoic Acid (RA) mediated reporter transgenic, we detect no alterations in the RA expression domains in the hindbrain and spinal cord, but do detect a loss of expression in the retina. We conclude that glyphosate and the Roundup® formulation is developmentally toxic to the forebrain and midbrain but does not affect the hindbrain after 24h exposure.
The growth and morphological differentiation of neurons are critical events in the establishment of proper neuronal connectivity and functioning. The developing nervous system is highly susceptible to damage caused by exposure to environmental contaminants. Glyphosate-containing herbicides are the most used agrochemicals in the world, particularly on genetically modified plants. Previous studies have demonstrated that glyphosate induces neurotoxicity in mammals. Therefore, its action mechanism on the nervous system needs to be determined. In this study, we report about impaired neuronal development caused by glyphosate exposure. Particularly, we observed that the initial axonal differentiation and growth of cultured neurons is affected by glyphosate since most treated cells remained undifferentiated after 1day in culture. Although they polarized at 2 days in vitro, they elicited shorter and unbranched axons and they also developed less complex dendritic arbors compared to controls. To go further, we attempted to identify the cellular mechanism by which glyphosate affected neuronal morphology. Biochemical approaches revealed that glyphosate led to a decrease in Wnt5a level, a key factor for the initial neurite development and maturation, as well as inducing a down-regulation of CaMKII activity. This data suggests that the morphological defects would likely be a consequence of the decrease in both Wnt5a expression and CaMKII activity induced by glyphosate. Additionally, these changes might be reflected in a subsequent neuronal dysfunction. Therefore, our findings highlight the importance of establishing rigorous control on the use of glyphosate-based herbicides in order to protect mammals' health.
The LIGPLOT program automatically generates schematic 2-D representations of protein-ligand complexes from standard Protein Data Bank file input. The output is a colour, or black-and-white, PostScript file giving a simple and informative representation of the intermolecular interactions and their strengths, including hydrogen bonds, hydrophobic interactions and atom accessibilities. The program is completely general for any ligand and can also be used to show other types of interaction in proteins and nucleic acids. It was designed to facilitate the rapid inspection of many enzyme complexes, but has found many other applications.
Molecular Mechanics – Poisson Boltzmann Surface Area (MM-PBSA), a method to estimate interaction free energies, has been increasingly used in the study of bio-molecular interactions. Recently, this method has also been applied as a scoring function in computational drug design. Here a new tool g_mmpbsa, which implements the MM-PBSA approach using subroutines written in-house or sourced from the GROMACS and APBS packages is described. g_mmpbsa was developed as part of the Open Source Drug Discovery (OSDD) consortium. Its aim is to integrate high-throughput MD simulations with binding energy calculations. The tool provides options to select alternative atomic radii and different non-polar solvation models including models based on the solvent accessible surface area (SASA), solvent accessible volume (SAV) and a model which contains both repulsive (SASA-SAV) and attractive components (described using a Weeks-Chandler-Andersen like integral method). We showcase the effectiveness of the tool by comparing the calculated interaction energy of 37 structurally diverse HIV-1 protease inhibitor complexes with their experimental binding free energies. The effect of varying several combinations of input parameters such as atomic radii, dielectric constant, grid resolution, solute-solvent dielectric boundary definition and non-polar models was investigated. g_mmpbsa can also be used to estimate the energy contribution per residue to the binding energy. It has been used to identify those residues in HIV-1 protease that are most critical for binding a range of inhibitors.
Glyphosate use in the United States increased from less than 5,000 to more than 80,000 metric tons/yr between 1987 and 2007. Glyphosate is popular due to its ease of use on soybean, cotton, and corn crops that are genetically modified to tolerate it, utility in no-till farming practices, utility in urban areas, and the perception that it has low toxicity and little mobility in the environment. This compilation is the largest and most comprehensive assessment of the environmental occurrence of glyphosate and aminomethylphosphonic acid (AMPA) in the United States conducted to date, summarizing the results of 3,732 water and sediment and 1,018 quality assurance samples collected between 2001 and 2010 from 38 states. Results indicate that glyphosate and AMPA are usually detected together, mobile, and occur widely in the environment. Glyphosate was detected without AMPA in only 2.3% of samples, whereas AMPA was detected without glyphosate in 17.9% of samples. Glyphosate and AMPA were detected frequently in soils and sediment, ditches and drains, precipitation, rivers, and streams; and less frequently in lakes, ponds, and wetlands; soil water; and groundwater. Concentrations of glyphosate were below the levels of concern for humans or wildlife; however, pesticides are often detected in mixtures. Ecosystem effects of chronic low-level exposures to pesticide mixtures are uncertain. The environmental health risk of low-level detections of glyphosate, AMPA, and associated adjuvants and mixtures remain to be determined.
Previous studies demonstrate that glyphosate exposure is associated with oxidative damage and neurotoxicity. Therefore, the mechanism of glyphosate-induced neurotoxic effects needs to be determined. The aim of this study was to investigate whether Roundup(®) (a glyphosate-based herbicide) leads to neurotoxicity in hippocampus of immature rats following acute (30min) and chronic (pregnancy and lactation) pesticide exposure. Maternal exposure to pesticide was undertaken by treating dams orally with 1% Roundup(®) (0.38% glyphosate) during pregnancy and lactation (till 15-day-old). Hippocampal slices from 15 day old rats were acutely exposed to Roundup(®) (0.00005 to 0.1%) during 30min and experiments were carried out to determine whether glyphosate affects (45)Ca(2+) influx and cell viability. Moreover, we investigated the pesticide effects on oxidative stress parameters, (14)C-α-methyl-amino-isobutyric acid ((14)C-MeAIB) accumulation, as well as glutamate uptake, release and metabolism. Results showed that acute exposure to Roundup(®) (30min) increases (45)Ca(2+) influx by activating NMDA receptors and voltage-dependent Ca(2+) channels, leading to oxidative stress and neural cell death. The mechanisms underlying Roundup(®)-induced neurotoxicity also involve the activation of CaMKII and ERK. Moreover, acute exposure to Roundup(®) increased (3)H-glutamate released into the synaptic cleft, decreased GSH content and increased the lipoperoxidation, characterizing excitotoxicity and oxidative damage. We also observed that both acute and chronic exposure to Roundup(®) decreased (3)H-glutamate uptake and metabolism, while induced (45)Ca(2+) uptake and (14)C-MeAIB accumulation in immature rat hippocampus. Taken together, these results demonstrated that Roundup(®) might lead to excessive extracellular glutamate levels and consequently to glutamate excitotoxicity and oxidative stress in rat hippocampus.
AutoDock Vina, a new program for molecular docking and virtual screening, is presented. AutoDock Vina achieves an approximately two orders of magnitude speed-up compared with the molecular docking software previously developed in our lab (AutoDock 4), while also significantly improving the accuracy of the binding mode predictions, judging by our tests on the training set used in AutoDock 4 development. Further speed-up is achieved from parallelism, by using multithreading on multicore machines. AutoDock Vina automatically calculates the grid maps and clusters the results in a way transparent to the user.
Avermectins (AVMs) are the active components of some insecticidal and nematicidal products used in agriculture and veterinary medicine for the prevention of parasitic diseases. Residues of AVM drugs or their metabolites in livestock feces have toxic effects on non-target aquatic and terrestrial organisms. In this study, oxidative stress responses and pathological changes on pigeon brain tissues and serum after subchronic exposure to AVM for 30, 60 and 90 days were investigated. The decrease in antioxidant enzyme (superoxide dismutase, SOD and glutathione peroxidase, GSH-Px) activities and increase in methane dicarboxylic aldehyde content in a dose-time-dependent manner in the brain and serum of pigeon were observed. The protein carbonyl content, an indicator of protein oxidation, and DNA-protein crosslink coefficient were significantly augmented with dose-time-dependent properties. The microscopic structures of the cerebrum, cerebellum and optic lobe altered obviously, the severity of which increased with the concentration of AVM and exposure time. The results imply that AVM could induce oxidative damage to the brain tissue and serum of pigeon. The information presented in this study is helpful to understand the mechanism of AVM-induced oxidative stress in birds.
Argentinian agricultural production is fundamentally based on a technological package that combines no-till and glyphosate in the cultivation of transgenic crops. Transgenic crops (soybean, maize and cotton) occupy 23million hectares. This means that glyphosate is the most employed herbicide in the country, where 180-200million liters are applied every year. The aim of this work is to study the environmental fate of glyphosate and its major degradation product, aminomethylphosphonic acid (AMPA), in surface water and soil of agricultural basins. Sixteen agricultural sites and forty-four streams in the agricultural basins were sampled three times during 2012. The samples were analyzed by UPLC-MS/MS ESI(+/-). In cultivated soils, glyphosate was detected in concentrations between 35 and 1502μgkg(-1), while AMPA concentration ranged from 299 to 2256μgkg(-1). In the surface water studied, the presence of glyphosate and AMPA was detected in about 15% and 12% of the samples analyzed, respectively. In suspended particulate matter, glyphosate was found in 67% while AMPA was present in 20% of the samples. In streams sediment glyphosate and AMPA were also detected in 66% and 88.5% of the samples respectively. This study is, to our knowledge, the first dealing with glyphosate fate in agricultural soils in Argentina. In the present study, it was demonstrated that glyphosate and AMPA are present in soils under agricultural activity. It was also found that in stream samples the presence of glyphosate and AMPA is relatively more frequent in suspended particulate matter and sediment than in water.
Oxidative stress is now recognized as accountable for redox regulation involving reactive oxygen species (ROS) and reactive nitrogen species (RNS). Its role is pivotal for the modulation of critical cellular functions, notably for neurons astrocytes and microglia, such as apoptosis program activation, and ion transport, calcium mobilization, involved in excitotoxicity. Excitotoxicity and apoptosis are the two main causes of neuronal death. The role of mitochondria in apoptosis is crucial. Multiple apoptotic pathways emanate from the mitochondria. The respiratory chain of mitochondria that by oxidative phosphorylation, is the fount of cellular energy, i.e. ATP synthesis, is responsible for most of ROS and notably the first produced, superoxide anion (O2 ̇−). Mitochondrial dysfunction, i.e. cell energy impairment, apoptosis and overproduction of ROS, is a final common pathogenic mechanism in aging and in neurodegenerative disease such as Alzheimer’s disease (AD), Parkinson’s disease (PD) and amyotrophic lateral sclerosis (ALS). Nitric oxide (NO ̇), an RNS, which can be produced by three isoforms of NO-synthase in brain, plays a prominent role. The research on the genetics of inherited forms notably ALS, AD, PD, has improved our understanding of the pathobiology of the sporadic forms of neurodegenerative diseases or of aging of the brain. ROS and RNS, i.e. oxidative stress, are not the origin of neuronal death. The cascade of events that leads to neurons, death is complex. In addition to mitochondrial dysfunction (apoptosis), excitotoxicity, oxidative stress (inflammation), the mechanisms from gene to disease involve also protein misfolding leading to aggregates and proteasome dysfunction on ubiquinited material.
Glyphosate is the primary active constituent of the commercial pesticide Roundup®. The present results show that acute Roundup® exposure at low doses (36ppm, 0.036g/L) for 30min induces oxidative stress and activates multiple stress-response pathways leading to Sertoli cell death in prepubertal rat testis. The pesticide increased intracellular Ca(2+) concentration by opening L-type voltage-dependent Ca(2+) channels (L-VDCC) as well as endoplasmic reticulum IP3 and ryanodine receptors, leading to Ca(2+) overload within the cells, which set off oxidative stress and necrotic cell death. Similarly, 30min incubation of testis with glyphosate alone (36ppm) also increased (45)Ca(2+) uptake. These events have been prevented by the antioxidants Trolox® and ascorbic acid. Activated protein kinase C (PKC), phosphatidylinositol-3-kinase (PI3K) and the mitogen-activated protein kinases (MAPKs), such as ERK1/2 and p38MAPK have played a role in eliciting Ca(2+) influx and cell death. Roundup® decreased the levels of reduced glutathione (GSH) and increased the amounts of thiobarbituric reactive species (TBARS) and protein carbonyls. Also, exposure to the glyphosate-Roundup® has stimulated the activity of glutathione peroxidase, glutathione reductase, glutathione-S-transferase, gamma-glutamyl transferase (γGT), catalase, superoxide dismutase and glucose-6-phosphate dehydrogenase, supporting downregulated GSH levels. Glyphosate has been described as an endocrine disruptor affecting the male reproductive system; however, the molecular basis of its toxicity remains to be clarified. We could propose that Roundup® toxicity, implicating in Ca(2+) overload, cell signaling misregulation, stress response of the endoplasmic reticulum and/or depleted antioxidant defenses could contribute to Sertoli cell disruption of spermatogenesis that could impact male fertility.
Congenital hypothyroidism is associated with delay in cell migration and proliferation in brain tissue, impairment of synapse formation, misregulation of neurotransmitters, hypomyelination and mental retardation. However, the mechanisms underlying the neuropsychological deficits observed in congenital hypothyroidism are not completely understood. In the present study we proposed a mechanism by which hypothyroidism leads to hippocampal neurotoxicity. Congenital hypothyroidism induces c-Jun-N-terminal kinase (JNK) pathway activation leading to hyperphosphorylation of the glial fibrillary acidic protein (GFAP), vimentin and neurofilament subunits from hippocampal astrocytes and neurons, respectively. Moreover, hyperphosphorylation of the cytoskeletal proteins was not reversed by T3 and poorly reversed by T4. In addition, congenital hypothyroidism is associated with downregulation of astrocyte glutamate transporters (GLAST and GLT-1) leading to decreased glutamate uptake and subsequent influx of Ca(2)(+)through N-methyl-D-aspartate (NMDA) receptors. The Na(+)-coupled (14)C-α-methyl-amino-isobutyric acid ((14)C-MeAIB) accumulation into hippocampal cells also might cause an increase in the intracellular Ca(2+) concentration by opening voltage-dependent calcium channels (VDCC). The excessive influx of Ca(2)(+)through NMDA receptors and VDCCs might lead to an overload of Ca(2)(+)within the cells, which set off glutamate excitotoxicity and oxidative stress. The inhibited acetylcholinesterase (AChE) activity might also induce Ca(2)(+) influx. The inhibited glucose-6-phosphate dehydrogenase (G6PD) and gamma-glutamyl transferase (GGT) activities, associated with altered glutamate and neutral amino acids uptake could somehow affect the GSH turnover, the antioxidant defense system, as well as the glutamate-glutamine cycle. Reduced levels of S100B and glial fibrillary acidic protein (GFAP) take part of the hypothyroid condition, suggesting a compromised astroglial/neuronal neurometabolic coupling which is probably related to the neurotoxic damage in hypothyroid brain.
Pesticide exposure during brain development represents an important risk factor for the onset of brain-aging processes. Here, the impact of permethrin administered to rats from 6(th) to 21(st) day of life, at a dose near to "no observed adverse effect level" (NOAEL), was studied when animals reached 500 day-old. The permethrin treatment induced a decrease in Nurr1 gene expression in striatum, an increase in hippocampus and cerebellum, while the protein level changed only in striatum where it was increased. NF-kB p65 gene expression was increased in cerebellum, while its protein level augmented in cerebellum and in prefrontal cortex and decreased in hippocampus of treated rats compared to control ones. Nrf-2 gene expression resulted significantly higher only in cerebellum of treated animals. The results suggest that early life permethrin treatment induces long-lasting effects leading to dopaminergic neuronal disorders, monitored by Nurr1 alteration. Moreover the impairment of NF-kB and Nrf-2, important for the balance between pro- and anti-inflammatory systems, confirms that the neonatal permethrin treatment can influence genes involved with the onset of brain-ageing processes.
Pesticides are always used in formulations as mixtures of an active principle with adjuvants. Glyphosate, the active ingredient of the major pesticide in the world, is an herbicide supposed to be specific on plant metabolism. Its adjuvants are generally considered as inert diluents. Since side effects for all these compounds have been claimed, we studied potential active principles for toxicity on human cells for 9 glyphosate-based formulations. For this we detailed their compositions and toxicities, and as controls we used a major adjuvant (the polyethoxylated tallowamine POE-15), glyphosate alone, and a total for-mulation without glyphosate. This was performed after 24 h exposures on hepatic (HepG2), embryonic (HEK293) and placental (JEG3) cell lines. We measured mitochondrial activities, membrane degradations, and caspases 3/7 activities. The compositions in adjuvants were analyzed by mass spectrometry. Here we demonstrate that all formulations are more toxic than glyphosate, and we separated experimen-tally three groups of formulations differentially toxic according to their concentrations in ethoxylated adjuvants. Among them, POE-15 clearly appears to be the most toxic principle against human cells, even if others are not excluded. It begins to be active with negative dose-dependent effects on cellular respiration and membrane integrity between 1 and 3 ppm, at environmental/occupational doses. We demonstrate in addition that POE-15 induces necrosis when its first micellization process occurs, by contrast to glyphosate which is known to promote endocrine disrupting effects after entering cells. Alto-gether, these results challenge the establishment of guidance values such as the acceptable daily intake of glyphosate, when these are mostly based on a long term in vivo test of glyphosate alone. Since pesti-cides are always used with adjuvants that could change their toxicity, the necessity to assess their whole formulations as mixtures becomes obvious. This challenges the concept of active principle of pesticides for non-target species.
A 7 x 7 foot space was marked off into 49 squares. The central square (25) contained a circular wire-mesh barrier. The animals were introduced into the field at a particular square. When food was present in the center of the field the animals made circular movements around the barrier, gradually reducing the number of movements on the edges of the field. When no food was present there was less of a tendency to circle the enclosed area and more of a tendency to explore the whole field than when food was present. The advantages of this method of observing behavior for the study of motivation are indicated. (PsycINFO Database Record (c) 2012 APA, all rights reserved)
Prenatal exposure to chlorpyrifos (CPF) leads to cognitive impairments in adulthood. The cytoarchitectural basis is unclear. In the present study, we assessed the effects of prenatal CPF exposure on T-maze delayed alternation task and the win-shift/lose-shift responses associated with the morphology of the dorsal hippocampus (dHPC) and the medial prefrontal cortex (mPFC) in adult animals. Gestational ICR female mice were exposed to 0, 1 or 5mg/kg/d of CPF through gestational days 13-17. Behavioral experiments were performed on postnatal days (PD) 45-60 of the male and female offsprings; morphological samples were collected on PD 60. Our behavioral study results showed a gradual increase in the number of lose-shift errors on increased memory loads in the 5mg/kg/d CPF-treated males. A weak initial increase in the number of lose-shift errors was observed in the females. In all of the groups, no significant differences were observed in the number of win-shift errors and correct of the first choice. The morphological studies showed extensive condensed nucleus and enlarged intercellular spaces in the CA1 and DG sub-regions in the dHPC of the CPF-treated males and the DG sub-region of the CPF-treated females. The cell count was significantly reduced in these sub-regions. The morphological studies showed no obvious abnormalities at PrL and IL of mPFC in the CPF-treated males and females, but the cell count was reduced. Our findings suggest that prenatal CPF exposure at 5mg/kg/d induces selective cognitive impairments, which based on the morphological deficits in the dHPC and the mPFC.