OP Exposure Research Articles

Maternal exposure to 4-tert-octylphenol causes alterations in the morphology and function of microglia in the offspring mouse brain

4-tert-Octylphenol (OP), an endocrine disrupting chemical is widely used in the production of industrial products. Prenatal exposure to endocrine-disrupting chemicals negatively affects the brain. However, the influence of OP exposure during neurodevelopment in adult offspring remains unclear. Thus, in the present study, we investigated the effects of maternal OP exposure on brain development in adult offspring by analyzing primary glial cell cultures and mice. Our findings revealed that OP exposure led to a specific increase in the mRNA expression of the ionized calcium-binding adapter molecule 1 (Iba-1) and the proportion of amoeboid microglia in the primary glial cell culture and adult offspring mice. Exposure to OP increased the transcriptional activation of Iba-1 and estrogen response element, which were counteracted by estrogen receptor antagonists ICI 182,780. Moreover, OP exposure increased the nuclear localization of the estrogen receptor. Remarkably, OP exposure decreased the mRNA expression levels of proinflammatory cytokines and genes associated with immune response in the brains of the offspring. OP exposure upregulated actin filament-related genes and altered cytoskeletal gene expression, as demonstrated by microarray analysis. The morphological changes in microglia did not result in an inflammatory response following lipopolysaccharide treatment. Taken together, the effects of OP exposure during neurodevelopment persist into adulthood, resulting in microglial dysfunction mediated by estrogen receptor signaling pathways in the brains of adult offspring mice.

Model acetylcholinesterase‐Fc fusion glycoprotein biotechnology system for the manufacture of an organophosphorus toxicant bioscavenging countermeasure

AbstractOrganophosphate (OP) toxicants remain an active threat to public health and to warfighters in the military. Current countermeasures require near immediate administration following OP exposure and are reported to have controversial efficacies. Acetylcholinesterase (AChE) fused to the human immunoglobulin 1 (IgG1) Fc domain (AChE‐Fc) is a potential bioscavenger for OP toxicants, but a reproducible AChE‐Fc biomanufacturing strategy remains elusive. This report is the first to establish a comprehensive laboratory‐scale bioprocessing strategy that can reproducibly produce AChE‐Fc and AChE(W86A)‐Fc which is a mutated AChE protein with reduced enzymatic activity. Characterization studies revealed that AChE‐Fc and AChE(W86A)‐Fc are N‐glycosylated dimeric fusion glycoproteins but only AChE‐Fc had the capability to bind to paraoxon (a model OP). This AChE‐Fc fusion glycoprotein bioprocessing strategy can be leveraged during industrial biomanufacturing development, while the research‐grade AChE‐Fc proteins can be used to determine the potential clinical relevance of the countermeasure against OP toxicants.

Effects of crosstalk between steroid hormones mediated thyroid hormone in zebrafish exposed to 4-tert-octylphenol: Estrogenic and anti-androgenic effects

Alkylphenols, such as nonylphenol and 4-tert-octylphenol (OP), are byproducts of the biodegradation of alkylphenol ethoxylates and present substantial ecological and health risks in aquatic environments and higher life forms. In this context, our study aimed to explore the effect of OP on reproductive endocrine function in both female and male zebrafish. Over a period of 21 days, the zebrafish were subjected to varying concentrations of OP (0, 0.02, 0.1, and 0.5 μg/L), based on the lowest effective concentration (EC10 = 0.48 μg/L) identified for zebrafish embryos. OP exposure led to a pronounced increase in hepatic vitellogenin (vtg) mRNA expression and 17β-estradiol biosynthesis in both sexes. Conversely, OP exhibits anti-androgenic properties, significantly diminishes gonadal androgen receptor (ar) mRNA expression, and reduces endogenous androgen (testosterone and 11-ketotestosterone) levels in male zebrafish. Notably, cortisol and thyroid hormone (TH) levels demonstrated concentration-dependent elevations in zebrafish, influencing the regulation of gonadal steroid hormones (GSHs). These findings suggest that prolonged OP exposure may result in sustained reproductive dysfunction in adult zebrafish, which is largely attributable to the intricate reciprocal relationship between hormone levels and the associated gene expression. Our comprehensive biological response analysis of adult zebrafish offers vital insights into the reproductive toxicological effects of OP, thereby enriching future ecological studies on aquatic systems.

Ambient long-term exposure to organophosphorus pesticides and the human gut microbiome: an observational study

BackgroundOrganophosphorus pesticides (OP) have been associated with various human health conditions. Animal experiments and in-vitro models suggested that OP may also affect the gut microbiota. We examined associations between ambient chronic exposure to OP and gut microbial changes in humans.MethodsWe recruited 190 participants from a community-based epidemiologic study of Parkinson’s disease living in a region known for heavy agricultural pesticide use in California. Of these, 61% of participants had Parkinson’s disease and their mean age was 72 years. Microbiome and predicted metagenome data were generated by 16S rRNA gene sequencing of fecal samples. Ambient long-term OP exposures were assessed using pesticide application records combined with residential addresses in a geographic information system. We examined gut microbiome differences due to OP exposures, specifically differences in microbial diversity based on the Shannon index and Bray–Curtis dissimilarities, and differential taxa abundance and predicted Metacyc pathway expression relying on regression models and adjusting for potential confounders.ResultsOP exposure was not associated with alpha or beta diversity of the gut microbiome. However, the predicted metagenome was sparser and less evenly expressed among those highly exposed to OP (p = 0.04). Additionally, we found that the abundance of two bacterial families, 22 genera, and the predicted expression of 34 Metacyc pathways were associated with long-term OP exposure. These pathways included perturbed processes related to cellular respiration, increased biosynthesis and degradation of compounds related to bacterial wall structure, increased biosynthesis of RNA/DNA precursors, and decreased synthesis of Vitamin B1 and B6.ConclusionIn support of previous animal studies and in-vitro findings, our results suggest that ambient chronic OP pesticide exposure alters gut microbiome composition and its predicted metabolism in humans.

Management of organophosphorus poisoning and the role of magnesium sulfate: A scoping review of literature.

Organophosphorus agents are easily absorbed via respiratory, gastrointestinal, and dermal routes, and inhibit the acetylcholine transferase enzyme (AChE), which is responsible for the majority of toxicity caused by organophosphates in the body. A comprehensive search was conducted across three prominent databases, namely Google Scholar, PubMed, and Science Direct, to identify relevant articles published. The search focused on the keywords "MgSO4" or "magnesium sulfate" in conjunction with "organophosphate" or "organophosphate poisoning." Inhibition of AChE results in the accumulation of acetylcholine (ACh) in synapses and stimulation of cholinergic receptors. Considering that several studies have shown the use of magnesium sulfate (MgSO4) in inhibiting the release of ACh in the central and peripheral sympathetic and parasympathetic synapses, this study was conducted to review the role of MgSO4 in the treatment of OP. The intravenous administration of MgSO4 exhibits favorable tolerability and clinical efficacy in alleviating cardiac toxicity associated with OP exposure.

Organophosphorus pesticide exposure from house dust and parent-reported child behavior in Latino children from an orchard community

BackgroundOrganophosphorus pesticide (OP) exposure is known to have adverse effects on the nervous system. Children from agricultural communities are at risk of exposure to these chemicals from their indoor environments that can lead to neurological and developmental problems, including changes in behavior. ObjectiveThe aim of this study is to evaluate whether the take-home pathway exposure is associated with behavioral and emotional problems in Latino Orchid Community children. MethodThe study was implemented over a period of two years (2008–2010) in an orchard farming community with a total of 324 parents who had children between the ages of 5–12 years old. Mothers of the children were asked to complete the Child Behavior Checklist (CBCL) and dust from their carpets was collected. Emotional and behavioral deficits were assessed based on the CBCL and house dust was assessed for OP concentrations. In this study, correlations between OPs in house dust and CBCL subscales were estimated using linear regression models with total OP concentrations classified by tertiles. This study also facilitated the comparison between the agricultural and non-agricultural families in terms of behavioral deficits and house dust concentrations of pesticides. ResultsThe data from the study shows that there was a positive association between the concentration of OP residues in house dust and internalizing behavior (β=2.06, p=0.05) whereas the association with externalizing behavior was not significant after accounting for sociocultural covariates. Significant positive associations of OP residues with somatic problems (p=0.02) and thought problems (p=0.05) were also found. ConclusionThe data support a potential role of OP exposure in childhood development, with a specific focus on internalizing behavior. Future work focused on longitudinal studies may uncover the long-term consequences of OP exposure and behavior.

Evaluation of Midazolam-Ketamine-Allopregnanolone Combination Therapy against Cholinergic-Induced Status Epilepticus in Rats.

Status epilepticus (SE) is a life-threatening development of self-sustaining seizures that becomes resistant to benzodiazepines when treatment is delayed. Benzodiazepine pharmacoresistance is thought in part to result from internalization of synaptic GABAA receptors, which are the main target of the drug. The naturally occurring neurosteroid allopregnanolone is a therapy of interest against SE for its ability to modulate all isoforms of GABAA receptors. Ketamine, an N-methyl-D-aspartate (NMDA) receptor antagonist, has been partially effective in combination with benzodiazepines in mitigating SE-associated neurotoxicity. In this study, allopregnanolone as an adjunct to midazolam or midazolam-ketamine combination therapy was evaluated for efficacy against cholinergic-induced SE. Adult male rats implanted with electroencephalographic (EEG) telemetry devices were exposed to the organophosphorus chemical (OP) soman (GD) and treated with an admix of atropine sulfate and HI-6 at 1 minute after exposure followed by midazolam, midazolam-allopregnanolone, or midazolam-ketamine-allopregnanolone 40 minutes after seizure onset. Neurodegeneration, neuronal loss, and neuroinflammation were assessed 2 weeks after GD exposure. Seizure activity, EEG power integral, and epileptogenesis were also compared among groups. Overall, midazolam-ketamine-allopregnanolone combination therapy was effective in reducing cholinergic-induced toxic signs and neuropathology, particularly in the thalamus and hippocampus. Higher dosage of allopregnanolone administered in combination with midazolam and ketamine was also effective in reducing EEG power integral and epileptogenesis. The current study reports that there is a promising potential of neurosteroids in combination with benzodiazepine and ketamine treatments in a GD model of SE. SIGNIFICANCE STATEMENT: Allopregnanolone, a naturally occurring neurosteroid, reduced pathologies associated with soman (GD) exposure such as epileptogenesis, neurodegeneration, and neuroinflammation, and suppressed GD-induced toxic signs when used as an adjunct to midazolam and ketamine in a delayed treatment model of soman-induced status epilepticus (SE) in rats. However, protection was incomplete, suggesting that further studies are needed to identify optimal combinations of antiseizure medications and routes of administration for maximal efficacy against cholinergic-induced SE.

Neurobehavioral Effects of Low-Dose Chronic Exposure to Insecticides: A Review.

The modes of action of insecticides frequently involve a neurotoxic effect; therefore, the study of neurotoxic effects caused by long-term and low-dose insecticide exposure is of particular interest. This study looks at whether or not new studies conducted after 2009 and up to 2021 have provided new evidence for a better understanding of the actual neurobehavioral risk associated with long-term insecticide exposure. We selected and reviewed studies carried out on the neurobehavioral effects of neurotoxic insecticides (organophosphates and/or carbamates, pyrethroids, multiple or undefined insecticides, and organochlorines) considering occupational and non-occupational exposures. The articles were also scored and ranked based on seven parameters. Eighty-six studies were chosen for a final review process from among the 950 scientific papers identified. Twenty-six addressed occupational exposure and six environmental exposure. Among the latter group of studies, 17 focused on rural residents, to be assumed exposed because of living in rural areas, and 43 on the general population. Pending doubts have not been resolved in the last ten years due to the presence of contradictory and hardly comparable results and the fact that in most of the studies showing an evident neurobehavioral impairment the frequent presence of a previous episode of poisoning and hospitalization, with severe brain hypoxia, impaired the possibility of confirming the presence of a causal association with insecticide exposure. Interestingly, the most severely exposed groups, such as applicators who did not wear personal protective equipment, performed worse on neurobehavioral tests. As for residential exposure, there is sufficient evidence to suggest that prenatal OP exposure may increase the risk of ADHD in children.

Avian assemblages are maintained after aerial applications of ULV fenitrothion for control of the Australian plague locust (Chortoicetes terminifera (Walker)) in arid and semiarid agroecosystems

Context Risk assessments currently undertaken to approve pesticides for use against locusts in Australia are predominated by laboratory-generated data, often collected from non-endemic species. Very little information exists concerning the potential ecological effects of insecticides used for locust control. Aim To determine the effect of aerial ultra-low volume (ULV) applications of the organophosphorous insecticide, fenitrothion (used for locust control), on avian assemblages in arid and semiarid agro-ecosystems. Methods Avian abundance was surveyed in pesticide-exposed and unexposed locations during standard locust control operations, using fenitrothion, in western New South Wales and Queensland in the spring and summer of 1996, 1997 and 2000, using a transect-point method. Temporal changes in assemblages were analysed using multi-dimensional ordination (MDS) and permutational analysis of variance (PERMANOVA) with PRIMER (V7). Key results Avian assemblages varied over time, independent of pesticide application, reflecting significant redistribution and mobility of birds across a highly disturbed agricultural landscape, irrespective of pesticide exposure. Additionally, pesticide exposure did not affect species abundance or diversity. Conclusions There was no evidence that ultra-low volume (ULV) applications of fenitrothion, currently used in locust control, are impacting avian assemblages, despite previous research indicating that individual birds co-occurring with spray operations suffer suppressions in the enzymatic biomarker for OP exposure, plasma acetylcholinesterase (AChE). Implications Although the risk to avian assemblages associated with the aerial application of locusticides is reduced by the small proportion of the landscape where locust control activities are focused, any change in spray application parameters would necessitate a re-evaluation of the risks associated with insecticide exposure.

Effects of Pesticide Intake on Gut Microbiota and Metabolites in Healthy Adults.

Animal experiments have indicated that pesticides may affect gut microbiota, which is responsible for the production of short-chain fatty acids (SCFAs) and polyamines. Here, we present a preliminary observation of the relationship between pesticide exposure and fecal SCFAs and polyamines in Japanese adults. In total, 38 healthy adults aged 69 ± 10 years (mean ± SD) were recruited and subjected to stool and spot urine tests. Urinary dialkylphosphates (DAP), 3-phenoxybenzoic acid, and glyphosate were assayed as pesticide exposure markers of organophosphorus insecticide (OP), a pyrethroid insecticide, and glyphosate, respectively. Significant negative correlations (p < 0.05, Spearman’s rank correlation coefficient) were found between urinary DAP, fecal acetate (r = −0.345), and lactate (r = −0.391). Multiple regression analyses revealed that urinary DAP was a significant explanatory variable of fecal acetate concentration (p < 0.001, β = −24.0, SE = 4.9, t = −4.9) with some vegetable intake (adjusted R-square = 0.751). These findings suggest that OP exposure is independently associated with lower fecal acetate levels, which may contribute to human health in middle-aged and older adult groups. Given that the human gut environment has long-term effects on the host, studies on wide-range age groups, including children, are necessary.

Personal exposure to PM2.5 oxidative potential and its association to birth outcomes.

Prenatal exposure to fine particulate matter (PM2.5) assessed through its mass concentration has been associated with foetal growth restriction in studies based on outdoor levels. Oxidative potential of PM2.5 (OP) is an emerging metric a priori relevant to mechanisms of action of PM on health, with very limited evidence to indicate its role on birth outcomes. We investigated the association of OP with birth outcomes and compared it with that of PM2.5 mass concentration. 405 pregnant women from SEPAGES cohort (Grenoble area) carried PM2.5 personal dosimeters for one or two one-week periods. OP was measured using dithiothreitol (DTT) and ascorbic acid (AA) assays from the collected filters. Associations of each exposure metric with offspring weight, height, and head circumference at birth were estimated adjusting for potential confounders. The correlation between PM2.5 mass concentration and [Formula: see text] was 0.7. An interquartile range increase in .. was associated with reduced weight (adjusted change, -64 g, -166 to -11, p = 0.02) and height (-4 mm, -6 to -1, p = 0.01) at birth. PM2.5 mass concentration showed similar associations with weight (-53 g, -99 to -8, p = 0.02) and height (-2 mm, -5 to 0, p = 0.05). In birth height models mutually adjusted for the two exposure metrics, the association with [Formula: see text] was less attenuated than that with mass concentration, while for weight both effect sizes attenuated similarly. There was no clear evidence of associations with head circumference for any metric, nor for [Formula: see text] with any growth parameter. PM2.5 pregnancy exposure assessed from personal dosimeters was associated with altered foetal growth. Personal OP exposure was associated with foetal growth restrictions, specifically decreased weight and height at birth, possibly to a larger extent than PM2.5 mass concentration alone. These results support OP assessed from DTT as being a health-relevant metric. Larger scale cohort studies are recommended to support our findings.

Biological Distribution and Metabolic Profiles of Carbon-11 and Fluorine-18 Tracers of VX- and Sarin-Analogs in Sprague-Dawley Rats.

Organophosphorus esters (OPs) were originally developed as pesticides but were repurposed as easily manufactured, inexpensive, and highly toxic chemical warfare agents. Acute OP toxicity is primarily due to inhibition of acetylcholinesterase (AChE), an enzyme in the central and peripheral nervous system. OP inhibition of AChE can be reversed using oxime reactivators but many show poor CNS penetration, indicating a need for new clinically viable reactivators. However, challenges exist on how to best measure restored AChE activity in vivo and assess the reactivating agent efficacy. This work reports the development of molecular imaging tools using radiolabeled OP analog tracers that are less toxic to handle in the laboratory, yet inhibit AChE in a similar fashion to the actual OPs. Carbon-11 and fluorine-18 radiolabeled analog tracers of VX and sarin OP agents were prepared. Following intravenous injection in normal Sprague–Dawley rats (n = 3–4/tracer), the tracers were evaluated and compared using noninvasive microPET/CT imaging, biodistribution assay, and arterial blood analyses. All showed rapid uptake and stable retention in brain, heart, liver, and kidney tissues determined by imaging and biodistribution. Lung uptake of the sarin analog tracers was elevated, 2-fold and 4-fold higher uptake at 5 and 30 min, respectively, compared to that for the VX analog tracers. All tracers rapidly bound to red blood cells (RBC) and blood proteins as measured in the biodistribution and arterial blood samples. Analysis of the plasma soluble activity (nonprotein/cell bound activity) showed only 1–6% parent tracer and 88–95% of the activity in the combined solid fractions (RBC and protein bound) as early as 0.5 min post injection. Multivariate analysis of tracer production yield, molar activity, brain uptake, brain area under the curve over 0–15 min, and the amount of parent tracer in the plasma at 5 min revealed the [18F]VX analog tracer had the most favorable values for each metric. This tracer was considered the more optimal tracer relative to the other tracers studied and suitable for future in vivo OP exposure and reactivation studies.

Erythrocyte Acetylcholinesterase Enzyme Activity, Serum Interleukin-6 Level and Respiratory Function of Myanmar Agricultural Workers Exposed to Organophosphate Pesticides

Background and Aim: Myanmar is one of the countries in production of agricultural plant commodities. Nowadays, pesticides are commonly used to increase agricultural production and productivity. Organophosphate pesticides exposure can cause many physiological changes within the body including impaired respiratory function. Therefore, the present study aimed to find out the relationship between the erythrocyte acetylcholinesterase enzyme activity, serum interleukin-6 level and respiratory functions such as forced expiratory volume in first second (FEV1), forced vital capacity (FVC), ratio of forced expiratory volume in first second and forced vital capacity (FEV1/FVC), peak expiratory flow (PEF) and average forced expiratory flow between 25% and 75% of FVC (FEF25-75%) among agricultural workers who exposed to organophosphate pesticides and non-exposed control subjects. Methods: A community-based cross-sectional, comparative study was done in agricultural workers (n = 40) who live in A-lal-chaung village, Magway Township and age/BMI matched non-exposed subjects (n = 40) who live in Yan-Way Quarter, Magway Township. All the participants were selected according to inclusion and exclusion criteria by simple random sampling method. Erythrocyte acetylcholinesterase (AchE) enzyme activity was measured by spectrophotometric method and serum interleukin-6 levels were measured by enzymelinked immunosorbent assay (ELISA) method. Respiratory function parameters were measured by Spirobank II spirometer. Results: The mean erythrocyte acetylcholinesterase enzyme activity was significantly lower in exposed group than that of non-exposed group (3354.43±589.81 U/L vs 4515.83±759.33 U/L; p<0.001). The percentage of predicted value of respiratory function parameters of exposed group were significantly lower than that of non-exposed group (FEV1: 72.13±4.40 vs 75.95±4.05; FVC: 66.90±4.40 vs 70.60±4.20; FEV1/FVC: 110.35±2.69 vs 111.32±1.33; PEF: 5.52±8.66 vs 79.40±5.09) (p<0.05). There were significant positive correlation between erythrocyte acetylcholinesterase activity and respiratory function parameters in all groups (n=80) (FEV1: r=0.425, p<0.001; FVC: r=0.301, p<0.05 and PEF: r=0.316, p<0.05). There were significant negative correlation between erythrocyte acetylcholinesterase activity and serum IL-6 level (r= -0.374, n= 80, p<0.05). Serum IL-6 level was significantly higher in exposed group than non-exposed group (34.77±3.3 pg/mL vs 28.75±2.0 pg/mL; p <0.001). There was a significant negative correlation between serum IL-6 level and respiratory function parameters in all group (n=80) such as FEV1 (r= 0.300, p<0.05) and FVC (r= 0.331, p<0.05). Conclusion: It was concluded that agricultural workers who exposed to organophosphate pesticides have higher serum IL-6 level and lower respiratory functions than that of non-exposed subjects. The present findings highlighted that there has an impact of chronic low dose OP exposure on respiratory health and there has a role of IL-6 in respiratory function decline.

4-Nonylphenol and 4-tert-octylphenol induce anxiety-related behaviors through alternation of 5-HT receptors and transporters in the prefrontal cortex

Environmental endocrine disruptors 4-nonylphenol (NP) and 4-tert-octylphenol (OP) may cast huge harm to human health. We used a rat model to observe the influence of NP or/and OP exposure on anxiety-related behaviors and the underlying mechanisms. Eighty male Sprague-Dawley (SD) rats were randomly divided into 10 groups: control group (corn oil), NP groups [30, 90, 270 mg/kg], OP groups [40, 120, 360 mg/kg] and NO groups [(mixed with the corresponding NP, OP alone exposed low, medium and high dose according to the natural environment exists NP:OP = 4:1]. The rats were orally administered every other day for 30 days. The neurobehaviors of rats were evaluated by open-field test (OFT) and elevated plus-maze test (EPM), and the concentrations of 5-HT, monoamine oxidase (MAOA), serotonin transporter (SERT), vesicular monoamine transporter 2 (VAMT2), 5-hydroxytryptamine 1A (5-HT1A), 5-hydroxytryptamine 2A (5-HT2A)，and 5-hydroxytryptamine 2C (5-HT2C) in the rat prefrontal cortex were analyzed by ELISA. OFT and EPM tests showed that NP or/and OP exposure induced anxiety-related behaviors in rats. 5-HT levels were significantly increased compared with the control group. The levels of MAOA, SERT, VAMT2, 5-HT1A, 5-HT2A, and 5-HT2C in the prefrontal cortex reduced in different degrees by high-doses NP or/and OP exposure. In summary, NP or/and OP exposure might cause anxiety-related behaviors in rats through regulating neurotransmitter 5-HT levels by altering the expression of 5-HT decomposition enzyme MAOA, transporters SERT and VMAT2, and 5-HT receptors 5-HT1A, 5-HT2A, and 5-HT2C.

Exposure to Organophosphate Pesticides and Menstrual Cycle Characteristics in Chinese Preconceptional Women.

Organophosphates (OPs) are the most heavily used pesticides in China. The Chinese population, including preconceptional women, is highly exposed, yet little is known regarding the associations between OP exposure and menstruation in humans. We conducted a cross-sectional analysis in women preparing for pregnancy to investigate the relationship between biomarkers of OP exposure and menstrual cycle characteristics. From 2013 to 2015, 627 women visiting free preconception-care clinics at 2 maternity hospitals in Shanghai, China, were included. Information on menstrual cycle characteristics was obtained through questionnaires. OP exposure was assessed by measuring urine concentrations of 6 dialkylphosphate metabolites (dimethylphosphate, dimethylthiophosphate, dimethyldithiophosphate, diethylphosphate, diethylthiophosphate, and diethyldithiophosphate). The relationship between concentrations of dialkylphosphate metabolites and menstrual cycle characteristics was analyzed using multiple linear regression models and logistic regression models. Log-transformed levels of diethyl phosphate metabolites (the sum of diethylphosphate and diethylthiophosphate levels) were related to a higher risk of irregularity of menstrual cycles (adjusted odds ratio=2.36, 95% confidence interval: 1.28, 4.34). Subjects with a higher concentration of diethyl phosphate metabolites (log-transformed) had a shorter duration of menstrual bleeding (adjusted β=-0.33, 95% confidence interval: -0.64, -0.02). The findings suggest that OP exposure may be associated with alterations in menstrual function in preconceptional women.

Treatment of Organophosphate Poisoning with Experimental Oximes: A Review

Standard therapy of Organophosphorus Compound (OPC) poisoning with oxime-type acetylcholinesterase (AChE) reactivators is unsatisfactory. New bispyridinium oximes have therefore been synthesized. This review summarizes in vitro characteristics of established (pralidoxime, obidoxime, trimedoxime, HI-6) and experimental (K-)oximes, and compares their protective efficacy in vivo, when administered shortly after exposure to Diisopropylfluorophosphate (DFP) and three OPC pesticides (ethyl-paraoxon, methylparaoxon, azinphos-methyl) in the same experimental setting.In addition to reactivating cholinesterase, oximes also inhibit this enzyme; strongest AChE inhibition (IC50 rat blood: 1-9 µM) is observed in vitro for the oximes with a xylene linker (K-107, K-108, K-113). AChE inhibition is weakest for K-27, K-48 and HI-6 (IC50 &gt;500 µM). Intrinsic AChE inhibition of oximes in vitro (IC50, rat) is strongly correlated with their LD50 (rat): oximes with a high IC50 (K-27, K-48, pralidoxime, obidoxime) also show a high LD50, making them relatively non-toxic, whereas oximes K-107, K-108 and K-113 (low IC50 and LD50) are far more toxic.When given in vivo after OP exposure, best protection is conferred by K-27, reducing the relative risk of death to 16-58% of controls, which is significantly superior to pralidoxime in DFP-, ethyl-paraoxon- and methylparaoxon- exposure, and to obidoxime in ethyl-paraoxon- and methyl-paraoxon-exposure. Marked reduction in mortality is also achieved by K-48, K-53, K-74 and K-75, whereas K-107, K-108 and K-113 have no or only a very weak mortality-reducing effect. K-27 is the most promising K-oxime due to its strong reactivation potency, weak cholinesterase inhibition and high LD50, allowing administration in large, very efficacious dosages.

An educational intervention on the risk perception of pesticides exposure and organophosphate metabolites urinary concentrations in rural school children in Maule Region, Chile

BackgroundOrganophosphate (OP) pesticides can be hazardous to human health if not applied with appropriate precautions. There is evidence in the Maule region of Chile that rural schoolchildren are exposed to OP pesticides. ObjectiveTo evaluate the effectiveness of an educational intervention on OP exposure and understanding of pesticides and their hazards (risk perception) in two school communities in the Maule Region of Chile during 2016. MethodWe conducted a quasi-experimental study about the effects on OP pesticide exposure of a community outreach and education program (COEP) administered in four 2-h sessions that's included hands-on activities among 48 schoolchildren from two rural schools. The intervention was directed to groups of parents and school-children separately, and aimed to educate them about the risks of exposure to pesticides and their effects on health. We measured 3,5,6-trichloro-2-pyridinol (TCPy), 2-isopropyl-4-methyl-6-hydroxypyrimidine (IMPY), malathion dicarboxylic acid (MDA), p-nitrophenol (PNP), specific urinary metabolites of the OP pesticides chlorpyrifos, diazinon, malathion and parathion, respectively, as well as the non-specific diethylakylphosphates (DEAPs) and dimethylalkylphosphates (DMAPs) in 192 urine samples of schoolchildren collected before and after the intervention. The risk perception of school children and their parents was also assessed through a questionnaire before and after the intervention. Generalized Estimated Equations were used to account for each child’s repeated measures during four sessions, two in September 2016 (pre-intervention) and two in November 2016 (post-intervention). ResultsThe intervention level had significant effect on the risk perception of adults and children, which increased after the intervention. However, the intervention was not associated with reduced of urinary metabolites levels, with no significant differences between the pre and post measures. The detection frequencies were 1.1% (MDA), 71.4% (TCPy), 43.3% (IMPY), 98.96% (PNP), and 100% (DEAPs and DMAPs). Higher DEAPs urine concentrations were associated with eating more fruit at school (p = 0.03), a younger age (p = 0.03), and being male (p = 0.01). DMAPs showed no associations with potential predictor variables (e.g. OPs applied at home, fruit consumption at school, among others). Higher TCPy was associated with attending a school closer to farms (p = 0.04) and living in a home closer to farm fields (p = 0.01); higher PNP was marginally associated with children younger age (p = 0.035). ConclusionEnvironmental exposure to OP pesticides was unchanged even after behavior changes. It is possible that a longer time period is needed to observe changes in both behavior and urinary metabolites. The levels of DEP and DMP metabolites found here are above the reference population of the US, and our findings indicate exposure to a wide variety of OP pesticides. Given that individual-level interventions were not associated with lower exposures, efforts to reduce exposure must occur upstream and require stricter regulation and control of pesticide use by government agencies.

Within-individual and interlaboratory variability analyses of urinary metabolites measurements of organophosphorus insecticides.

Single-spot urine is often used to estimate organophosphorus insecticide (OP) exposure. However, variations of urinary metabolite concentrations during the day are considerable as OP half-lives are short and as diet is their main exposure source. In addition, quality control is indispensable for institutions that analyze these metabolites. This study aimed to clarify (1) adequate frequencies of urine collection for estimating OP exposure and (2) interlaboratory variation in measured concentrations of OP metabolites, dialkylphosphates (DAPs). To quantify intra-individual variations, urine was collected eight times during a period that spanned 5 consecutive days from nine children aged 5-6 years. For interlaboratory variations, 41 spot samples from 14 pregnant women and 13 three-year-old children were used. Intraclass correlation coefficients for the DAPs were moderate but misclassification occurred in > 50% of the surrogate category analyses using single measurements. The misclassification frequency decreased to satisfactory levels when three temporal measurements were conducted. Values of four DAPs measured in the two laboratories correlated well except in the cases of urine samples obtained from two pregnant women. In conclusion, urinary DAPs should be measured from spot urine samples obtained during 3 different days. Sharing matrix-contained standards and quality control samples should minimize interlaboratory variations.

β-Glucuronidase and Its Relationship With Clinical Parameters and Biomarkers of Pesticide Exposure.

This study determined β-glucuronidase activity and its relationship with clinical, biochemical, and pesticide-exposure biomarkers in workers occupationally exposed mainly to OP insecticides. A cross-sectional study was conducted in pesticide applicators. Three study groups were established: reference group, moderate-exposure group, and high-exposure group. Blood samples were obtained to determine the activity of β-glucuronidase. Clinical analysis was conducted in a certified laboratory. The activity of β-glucuronidase was associated with clinical variables such as glucose, cholesterol, triglycerides, LDL, VLDL, HDL, atherogenic index, transaminases, and BuChE activity, but not with AChE activity. The activity of this enzyme exhibited a significant increase in the group of moderate exposure to pesticides but not in the group of high exposure. β-Glucuronidase activity is a sensitive biomarker under certain scenarios of OP exposure.

Poisoning with Soman, an Organophosphorus Nerve Agent, Alters Fecal Bacterial Biota and Urine Metabolites: a Case for Novel Signatures for Asymptomatic Nerve Agent Exposure.

The experimental pathophysiology of organophosphorus (OP) chemical exposure has been extensively reported. Here, we describe an altered fecal bacterial biota and urine metabolome following intoxication with soman, a lipophilic G class chemical warfare nerve agent. Nonanesthetized Sprague-Dawley male rats were subcutaneously administered soman at 0.8 (subseizurogenic) or 1.0 (seizurogenic) of the 50% lethal dose (LD50) and evaluated for signs of toxicity. Animals were stratified based on seizing activity to evaluate effects of soman exposure on fecal bacterial biota and urine metabolites. Soman exposure reshaped fecal bacterial biota by altering Facklamia, Rhizobium, Bilophila, Enterobacter, and Morganella genera of the Firmicutes and Proteobacteria phyla, some of which are known to hydrolyze OP chemicals. However, analogous changes were not observed in the bacterial biota of the ileum, which remained the same irrespective of dose or seizing status of animals after soman intoxication. However, at 75 days after soman exposure, the bacterial biota stabilized and no differences were observed between groups. Interestingly, in considering just the seizing status of animals, we found that the urine metabolomes were markedly different. Leukotriene C4, kynurenic acid, 5-hydroxyindoleacetic acid, norepinephrine, and aldosterone were excreted at much higher rates at 72 h in seizing animals, consistent with early multiorgan involvement during soman poisoning. These findings demonstrate the feasibility of using the dysbiosis of fecal bacterial biota in combination with urine metabolome alterations as forensic evidence for presymptomatic OP exposure temporally to enable administration of neuroprotective therapies of the future.IMPORTANCE The paucity of assays to determine physiologically relevant OP exposure presents an opportunity to explore the use of fecal bacteria as sentinels in combination with urine to assess changes in the exposed host. Recent advances in sequencing technologies and computational approaches have enabled researchers to survey large community-level changes of gut bacterial biota and metabolomic changes in various biospecimens. Here, we profiled changes in fecal bacterial biota and urine metabolome following a chemical warfare nerve agent exposure. The significance of this work is a proof of concept that the fecal bacterial biota and urine metabolites are two separate biospecimens rich in surrogate indicators suitable for monitoring OP exposure. The larger value of such an approach is that assays developed on the basis of these observations can be deployed in any setting with moderate clinical chemistry and microbiology capability. This can enable estimation of the affected radius as well as screening, triage, or ruling out of suspected cases of exposures in mass casualty scenarios, transportation accidents involving hazardous materials, refugee movements, humanitarian missions, and training settings when coupled to an established and validated decision tree with clinical features.