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Toxicological Sciences : An Official... Feb 2023Two organophosphate esters used as flame retardants and plasticizers, triphenyl phosphate (TPHP) and isopropylated phenyl phosphate (IPP), have been detected in...
Reproductive and developmental toxicity following exposure to organophosphate ester flame retardants and plasticizers, triphenyl phosphate and isopropylated phenyl phosphate, in Sprague Dawley rats.
Two organophosphate esters used as flame retardants and plasticizers, triphenyl phosphate (TPHP) and isopropylated phenyl phosphate (IPP), have been detected in environmental samples around the world. Human exposure primarily occurs via oral ingestion with reported higher concentrations in children. Currently, there are no data to evaluate potential risk from exposure to either TPHP or IPP during fetal development. These short-term perinatal studies in rats provide preliminary toxicity data for TPHP and IPP, including information on transfer to fetus/offspring and across the pup blood-brain barrier. In separate experiments, TPHP or IPP were administered via dosed feed at concentrations 0, 1000, 3000, 10 000, 15 000, or 30 000 ppm to time-mated Hsd:Sprague Dawley SD rats from gestation day (GD) 6 through postnatal day (PND) 28; offspring were provided dosed feed at the same concentration as their dam (PND 28-PND 56). TPHP- and IPP-related toxicity resulted in removal of both 30 000 ppm groups on GD 12 and 15 000 ppm IPP group after parturition. Body weight and organ weights were impacted with exposure in remaining dams. Reproductive performance was perturbed at ≥10 000 ppm TPHP and all IPP exposure groups. In offspring, both TPHP- and IPP-related toxicity was noted in pups at ≥10 000 ppm as well as reduction in bodyweights, delays in pubertal endpoints, and/or reduced cholinesterase enzyme activity starting at 1000 ppm TPHP or IPP. Preliminary internal dose assessment indicated gestational and lactational transfer following exposure to TPHP or IPP. These findings demonstrate that offspring development is sensitive to 1000 ppm TPHP or IPP exposure.
Topics: Pregnancy; Female; Child; Rats; Animals; Humans; Rats, Sprague-Dawley; Flame Retardants; Plasticizers; Organophosphates; Phosphates; Esters
PubMed: 36562586
DOI: 10.1093/toxsci/kfac135 -
Applied and Environmental Microbiology May 2023Organophosphate hydrolases (OPH), hitherto known to hydrolyze the third ester bond of organophosphate (OP) insecticides and nerve agents, have recently been shown to...
Organophosphate hydrolases (OPH), hitherto known to hydrolyze the third ester bond of organophosphate (OP) insecticides and nerve agents, have recently been shown to interact with outer membrane transport components, namely, TonB and ExbB/ExbD. In an OPH negative background, Sphingopyxis wildii cells failed to transport ferric enterobactin and showed retarded growth under iron-limiting conditions. We now show the OPH-encoding organophosphate degradation () gene from Sphingobium fuliginis ATCC 27551 to be part of the iron regulon. A -box motif found to be overlapping with the transcription start site (TSS) of the gene coordinates with an iron responsive element (IRE) RNA motif identified in the 5' coding region of the mRNA to tightly regulate gene expression. The -box motif serves as a target for the Fur repressor in the presence of iron. A decrease in iron concentration leads to the derepression of . IRE RNA inhibits the translation of mRNA and serves as a target for apo-aconitase (IRP). The IRP recruited by the IRE RNA abrogates IRE-mediated translational inhibition. Our findings establish a novel, multilayered, iron-responsive regulation that is crucial for OPH function in the transport of siderophore-mediated iron uptake. Sphingobium fuliginis, a soil-dwelling microbe isolated from agricultural soils, was shown to degrade a variety of insecticides and pesticides. These synthetic chemicals function as potent neurotoxins, and they belong to a class of chemicals termed organophosphates. codes for OPH, an enzyme that has been shown to be involved in the metabolism of several organophosphates and their derivatives. Interestingly, OPH has also been shown to facilitate siderophore-mediated iron uptake in and in another Sphingomonad, namely, , implying that this organophosphate-metabolizing protein has a role in iron homeostasis, as well. Our research dissects the underlying molecular mechanisms linking iron to the expression of OPH, prompting a reconsideration of the role of OPH in Sphingomonads and a reevaluation of the evolutionary origins of the OPH proteins from soil bacteria.
Topics: Insecticides; Iron; Siderophores; Organophosphorus Compounds; Organophosphates; RNA; RNA, Messenger
PubMed: 37074175
DOI: 10.1128/aem.01903-22 -
Environmental Research Dec 2022The use of organophosphate esters (OPEs) as flame retardants, which has increased over the past two decades, raises concerns that OPEs may be harmful to humans,...
The use of organophosphate esters (OPEs) as flame retardants, which has increased over the past two decades, raises concerns that OPEs may be harmful to humans, especially children. Animal studies and some human studies have reported that OPEs may adversely impact brain development, but few human studies evaluated OPE exposure during early childhood and neurodevelopmental outcomes. We aimed to fill this knowledge gap with the present study on urinary OPE metabolite concentrations at ages 1-5 years and cognitive abilities at 8 years. We used data of 223 children from the Health Outcomes and Measures of the Environment (HOME) Study, a prospective pregnancy and birth cohort in Cincinnati, Ohio. The point estimates for bis-2-chloroethyl-phosphate (BCEP) and bis(1,3-dichloro-2-propyl)-phosphate (BDCIPP) in association with IQ tended to be small and positive, while the point estimates for diphenyl-phosphate (DPHP) were small and negative, with 95% CIs including the null. However, we did find that socioeconomic status (SES) variables modified associations between OPEs and child IQ, with adverse OPE-IQ associations being stronger in socioeconomically disadvantaged children than in others. We identified an additional 1- to 2-point decrease in Full Scale IQ for every log-unit increase in BDCIPP, BCEP, and DPHP among those with lower maternal education, non-white race, lower income, or living in more deprived neighborhoods. We observed similar results for the Perceptual Reasoning, Verbal Comprehension, and Working Memory Index Scores. We suspect that there is residual confounding related to socioeconomic disadvantage, which was not captured with the available SES variables typically used in epidemiologic studies.
Topics: Child; Child, Preschool; Cognition; Cohort Studies; Esters; Female; Flame Retardants; Humans; Infant; Longitudinal Studies; Organophosphates; Phosphates; Pregnancy; Prospective Studies
PubMed: 36103927
DOI: 10.1016/j.envres.2022.114265 -
The Journal of Pharmacology and... Sep 2021Inhibition of acetylcholinesterase (AChE) by certain organophosphates (OPs) can be life-threatening and requires reactivating antidote accessibility to the peripheral...
Inhibition of acetylcholinesterase (AChE) by certain organophosphates (OPs) can be life-threatening and requires reactivating antidote accessibility to the peripheral and central nervous systems to reverse symptoms and enhance survival parameters. In considering dosing requirements for oxime antidotes in OP exposures that inactivate AChE, clearance of proton ionizable, zwitterionic antidotes is rapid and proceeds with largely the parent antidotal compound being cleared by renal transporters. Such transporters may also control disposition between target tissues and plasma as well as overall elimination from the body. An ideal small-molecule antidote should access and be retained in primary target tissues-central nervous system (brain), skeletal muscle, and peripheral autonomic sites-for sufficient periods to reactivate AChE and prevent acute toxicity. We show here that we can markedly prolong the antidotal activity of zwitterionic antidotes by inhibiting P-glycoprotein (P-gp) transporters in the brain capillary and renal systems. We employ the P-gp inhibitor tariquidar as a reference compound and show that tissue and plasma levels of RS194B, a hydroxyl-imino acetamido alkylamine reactivator, are elevated and that plasma clearances are reduced. To examine the mechanism, identify the transporter, and establish the actions of a transport inhibitor, we compare the pharmacokinetic parameters in a P-glycoprotein knockout mouse strain and see dramatic enhancements of short-term plasma and tissue levels. Hence, repurposed transport inhibitors that are candidate or Food and Drug Administration-approved drugs, should enhance target tissue concentrations of the zwitterionic antidote through inhibition of both renal elimination and brain capillary extrusion. SIGNIFICANCE STATEMENT: We examine renal and brain capillary transporter inhibition as means for lowering dose and frequency of dosing of a blood-brain barrier permanent reactivating antidote, RS194B, an ionizable zwitterion. Through a small molecule, tariquidar, and gene knockout mice, CNS antidote concentrations are enhanced, and total body clearances are concomitantly diminished. RS194B with repurposed transport inhibitors should enhance reactivation of central and peripheral OP-inhibited acetylcholinesterase. Activities at both disposition sites are a desired features for replacing the antidote, pralidoxime, for acute OP exposure.
Topics: Acetylcholinesterase; Kinetics; Organophosphates; Pralidoxime Compounds
PubMed: 34145064
DOI: 10.1124/jpet.121.000715 -
Drug Design, Development and Therapy 2022Heavily-treatment-experienced people living with human immunodeficiency virus (HTE-PLWH) represent a population with limited therapeutic options and at high-risk of... (Review)
Review
Heavily-treatment-experienced people living with human immunodeficiency virus (HTE-PLWH) represent a population with limited therapeutic options and at high-risk of clinical progression, morbidity, and mortality. The development of new drugs and new drug classes for the treatment of HIV-1 infection in HTE-PLWH is critical to successfully suppress HIV-1 replication, restore the immune system, and improve quality of life. Fostemsavir is the first attachment inhibitor approved by Food and Drug Administration and European Medicines Agency for the treatment of HIV-1 infection. It is approved in combination with other antiretrovirals, for HTE-PLWH with multi-drug resistant HIV-1 after failing their current antiretroviral regimen due to resistance, intolerance, or safety considerations. In this review, we present and discuss the mechanism of action, the pharmacodynamic and pharmacokinetic properties, and the efficacy and safety of fostemsavir as an antiretroviral agent for the treatment of HIV-1 infection.
Topics: Anti-HIV Agents; HIV Infections; HIV-1; Humans; Organophosphates; Piperazines
PubMed: 35115764
DOI: 10.2147/DDDT.S273660 -
Sensors (Basel, Switzerland) Mar 2022Azamethiphos (AZA) is an insecticide and neurotoxic agent that causes the inhibition of acetylcholinesterase (AChE). AChE is a vital enzyme for neurotransmission because...
Azamethiphos (AZA) is an insecticide and neurotoxic agent that causes the inhibition of acetylcholinesterase (AChE). AChE is a vital enzyme for neurotransmission because it metabolizes acetylcholine neurotransmitter at the synaptic cleft and terminates synaptic transmission. It is worth mentioning that organophosphates and carbamates inhibit AChE. These AChE inhibitors bind to the active site of the enzyme and inactivate it, leading to paralysis and death. Herein, for the first time, we develop a sensitive, low-cost, and rapid electrogenerated chemiluminescence (ECL) system for the detection of AZA. The designed ECL sensor was applied for the highly sensitive detection of AZA with a wide dynamic range (from 0.1 μM to 1000 μM) and low detection limit of 0.07 μM (S/N = 3). The practical utility of the sensor demonstrates high recoveries (96-102%) in real samples of lake water and wastewater.
Topics: 2,2'-Dipyridyl; Acetylcholinesterase; Insecticides; Luminescence; Luminescent Measurements; Organothiophosphates; Ruthenium
PubMed: 35408132
DOI: 10.3390/s22072519 -
Ecotoxicology and Environmental Safety Dec 2023Organophosphorus flame retardants (OPFRs) have been shown to be carcinogenic, neurotoxic, and endocrine disruptive, so it is important to understand the levels of OPFRs...
Organophosphorus flame retardants (OPFRs) have been shown to be carcinogenic, neurotoxic, and endocrine disruptive, so it is important to understand the levels of OPFRs in human body as well as the modes of external exposure. In this study, we investigated the levels of 13 OPFRs and 7 phosphodiester metabolites in paired human blood and urine, as well as the influencing factors (region, age and gender), and studied the relationship between OPFRs and oxidative stress by urinary metabolites. We found that the concentrations of triphenyl phosphate (TPhP) and tris-(2-ethylhexyl) phosphate (TEHP) in the blood of urban populations were higher than those of rural populations, and that younger populations suffered higher TPhP and 2-ethylhexyl diphenyl phosphate (EHDPP) exposures than older populations. In addition, we found that tris-(2-chloroethyl) phosphate (TCEP), tributyl phosphate (TnBP), TPhP and EHDPP exposure induced oxidative stress. The results of the internal load principal component analysis indicated that dust ingestion, skin exposure, respiration and dietary intake may be the most important sources of TCEP, tris(2-butoxyethyl) phosphate (TBOEP), tri(2-chloroisopropyl) phosphate (TCIPP) and TEHP, respectively, and dust ingestion and skin exposure may be the main sources of TPhP for humans.
Topics: Humans; Flame Retardants; Organophosphorus Compounds; Organophosphates; Dust; Phosphates
PubMed: 37979363
DOI: 10.1016/j.ecoenv.2023.115696 -
American Journal of Epidemiology Sep 2021Production of organophosphate esters (OPEs), which represent a major flame-retardant class present in consumer goods, has increased over the past 2 decades. Experimental...
Production of organophosphate esters (OPEs), which represent a major flame-retardant class present in consumer goods, has increased over the past 2 decades. Experimental studies suggest that OPEs may be associated with thyroid hormone disruption, but few human studies have examined this association. We quantified OPE metabolites in the urine of 298 pregnant women from Cincinnati, Ohio, in the Health Outcomes and Measures of the Environment Study (enrolled 2003-2006) at 3 time points (16 and 26 weeks' gestation, and at delivery), and thyroid hormones in 16-week maternal and newborn cord sera. Urinary bis(1,3-dichloro-2-propyl)-phosphate concentrations were generally associated with decreased triiodothyronine and thyroxine levels and increased thyroid-stimulating hormone levels in maternal and newborn thyroid hormones in quartile dose-response analyses and multiple informant models. There was weaker evidence for thyroid hormone alterations in association with diphenyl-phosphate and di-n-butyl-phosphate. Bis-2-chloroethyl-phosphate was not associated with alterations in thyroid hormones in any analyses. We did not observe any evidence of effect modification by infant sex. These results suggest that gestational exposure to some OPEs may influence maternal and neonatal thyroid function, although replication in other cohorts is needed.
Topics: Adolescent; Adult; Environmental Exposure; Female; Fetal Blood; Flame Retardants; Humans; Infant, Newborn; Male; Middle Aged; Organophosphates; Pregnancy; Prenatal Exposure Delayed Effects; Thyroid Hormones; Thyrotropin; Thyroxine; Triiodothyronine; Young Adult
PubMed: 33778842
DOI: 10.1093/aje/kwab086 -
International Journal of Hygiene and... Aug 2019Disentangling the separate and synergistic effects of chemicals poses methodological challenges for accurate exposure assessment and for investigating epidemiologically...
Disentangling the separate and synergistic effects of chemicals poses methodological challenges for accurate exposure assessment and for investigating epidemiologically how chemicals affect reproduction. We investigated combined exposures to ubiquitous contemporary use pesticides, specifically organophosphates (OP) and pyrethroids (PYR), and their association with germ cell abnormalities among adult men. Fluorescence in situ hybridization was used to determine disomy in sperm nuclei and urine was analyzed for concentrations of PYR metabolites (3-phenoxybenzoic acid; 3PBA) and OP dialkyl phosphate (DAP) metabolites. Incidence rate ratios using Poisson models were estimated for each disomy type by exposure quartile of DAP metabolites and 3PBA, controlling for confounders. The shape of the associations between PYRs, OPs and disomy were frequently nonmonotonic. There were consistent interactions between OP and PYR metabolite concentrations and the risk for sperm abnormalities. Taking both chemicals into account simultaneously resulted in quantitatively different associations than what was reported previously for OPs and PYRs separately, demonstrating the importance of modeling multiple concentrations simultaneously. Methods investigating interactions using Poisson models are needed to better quantify chemical interactions and their effects on count-based health outcomes, the importance of which was shown here for germ cell abnormalities.
Topics: Adult; Biological Monitoring; Chromosome Aberrations; Environmental Pollutants; Humans; Male; Organophosphates; Pesticides; Pyrethrins; Risk; Spermatozoa
PubMed: 31311690
DOI: 10.1016/j.ijheh.2019.07.001 -
Journal of Acquired Immune Deficiency... Feb 2020In the Promoting Maternal and Infant Survival Everywhere (PROMISE) trial, tenofovir disoproxil fumarate (TDF) use was associated with moderate or severe adverse... (Clinical Trial)
Clinical Trial Randomized Controlled Trial
Antenatal Intracellular Concentrations of Tenofovir Diphosphate and Emtricitabine Triphosphate and Associations Between Tenofovir Diphosphate and Severe Adverse Pregnancy Outcomes: IMPAACT-PROMISE (1077BF) Trial.
BACKGROUND
In the Promoting Maternal and Infant Survival Everywhere (PROMISE) trial, tenofovir disoproxil fumarate (TDF) use was associated with moderate or severe adverse pregnancy/neonatal outcomes. This study characterized tenofovir diphosphate (TFV-DP) and emtricitabine triphosphate (FTC-TP) concentrations in dried blood spots (DBS) and assessed association between severe adverse pregnancy/neonatal outcomes and TFV-DP concentration.
METHODS
Retrospective case-control study of PROMISE trial arm-C women randomized to receive TDF, FTC, and ritonavir-boosted lopinavir (LPV/r), who took at least 1 dose of TDF + FTC and had week-4 postrandomization DBS drawn before delivery. Cases, defined as severe adverse pregnancy/neonatal outcomes (very preterm delivery before 34 weeks of gestation, stillbirth ≥20 weeks of gestation, or infant death before 14 days-of-age), were matched to controls (1:2 ratio) by site and gestational age at entry. Week 4 and week 8 DBS samples were assayed for TFV-DP and FTC-TP by liquid chromatography and tandem mass spectrometry. Associations were tested using Wilcoxon rank test and conditional logistic regression.
RESULTS
Of 447 PROMISE arm-C women, 33 met case definitions, and overall, 22 cases and 44 controls were analyzed. Median (interquartile range) concentrations of TFV-DP at weeks 4 and 8 were 706 (375-1023) fmol/punch and 806 (414-1265) fmol/punch, respectively. Odds ratio (95% confidence interval) for severe adverse pregnancy/neonatal outcome with natural log of TFV-DP concentrations as the predictor were 1.27 (0.74 to 2.18) and 1.74 (0.66 to 4.60) at weeks 4 and 8, respectively. Median (interquartile range) concentrations of FTC-TP at weeks 4 and 8 were 0.27 (0.05-0.36) pmol/punch and 0.29 (0.05-0.40) pmol/punch, respectively.
CONCLUSIONS
TFV-DP concentrations in DBS appeared not to be associated with severe adverse pregnancy/neonatal outcomes, although sample size was limited.
Topics: Adenine; Anti-HIV Agents; Case-Control Studies; Chromatography, Liquid; Drug Combinations; Emtricitabine; Female; HIV Infections; Humans; Logistic Models; Lopinavir; Medication Adherence; Organophosphates; Polyphosphates; Pregnancy; Pregnancy Complications; Pregnancy Outcome; Retrospective Studies; Ritonavir; Tenofovir
PubMed: 31929405
DOI: 10.1097/QAI.0000000000002247