<i>In Vivo</i>
            Characterization of the Toxicological Properties of DPhP, One of the Main Degradation Products of Aryl Phosphate Esters

Selmi-Ruby, Samia; Marín-Sáez, Jesús; Fildier, Aurélie; Buleté, Audrey; Abdallah, Myriam; Garcia, Jessica; Deverchère, Julie; Spinner, Loïc; Giroud, Barbara; Ibañez, S.; Granjon, Thierry; Bardel, Claire; Puisieux, Alain; Fervers, Béatrice; Vulliet, Emmanuelle; Payen, Léa; Vigneron, Arnaud

doi:10.1289/ehp6826

Cited by 15 publications

(18 citation statements)

References 52 publications

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“…Similarly, a clear reduction of fatty acid catabolic processes by DPhP exposure was also demonstrated in mice liver. 23 Results presented here were consistent with previous findings but also further revealed the key steps in fatty acid oxidation pathway that was specifically disrupted by DPhP.…”

Section: Metabolomics Responsesupporting

confidence: 92%

“…23 Acylcarnitines and fatty acids were the most affected metabolites in liver of mice after oral exposure to DPhP. 23 Taken together with the current data, fatty acid metabolism and its related biological processes could be substantially disrupted by DPhP.…”

Section: Metabolomics Responsementioning

confidence: 57%

“…29 In addition, results of previous studies indicated that DPhP was most abundant in liver. 23 The sex of the fish was determined by visual inspection of gonadal morphology. The average sex ratio (proportion males) was 59.7%.…”

Section: Methodsmentioning

confidence: 99%

“…17,19−22 Recently, it was reported that chronic exposure to 10 mg/L DPhP through drinking water significantly disrupted the fatty acid catabolic processes and reduced the body mass in mice. 23 To date, most of the studies on toxicity of DPhP have only focused on acute toxicity/short-term effects upon exposure to DPhP at concentrations that are far greater than those found in environmental matrices, which are generally at in the range of μg/L. 4,11,24 For example, DPhP-caused cardiac defects in zebrafish embryo were only observed at concentrations greater than 500 μM (125 mg/L).…”

Section: Introductionmentioning

confidence: 99%

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Life Cycle Exposure to Environmentally Relevant Concentrations of Diphenyl Phosphate (DPhP) Inhibits Growth and Energy Metabolism of Zebrafish in a Sex-Specific Manner

Chen

Lian

et al. 2021

Environ. Sci. Technol.

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Due to commercial uses and environmental degradation of aryl phosphate esters, diphenyl phosphate (DPhP) is frequently detected in environmental matrices and is thus of growing concern worldwide. However, information on potential adverse effects of chronic exposure to DPhP at environmentally realistic concentrations was lacking. Here, we investigated the effects of life cycle exposure to DPhP on zebrafish at environmentally relevant concentrations of 0.8, 3.9, or 35.6 μg/L and employed a dual-omics approach (metabolomics and transcriptomics) to characterize potential modes of action. Exposure to DPhP at 35.6 μg/L for 120 days resulted in significant reductions in body mass and length of male zebrafish, but did not cause those same effects to females. Predominant toxicological mechanisms, including inhibition of oxidative phosphorylation, down-regulation of fatty acid oxidation, and up-regulation of phosphatidylcholine degradation, were revealed by integrated dual-omics analysis and successfully linked to adverse outcomes. Activity of succinate dehydrogenase and protein content of carnitine O-palmitoyltransferase 1 were significantly decreased in livers of male fish exposed to DPhP, which further confirmed the proposed toxicological mechanisms. This study is the first to demonstrate that chronic, low-level exposure to DPhP can retard growth via inhibiting energy output in male zebrafish.

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Section: Metabolomics Responsesupporting

confidence: 92%

Section: Metabolomics Responsementioning

confidence: 57%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Life Cycle Exposure to Environmentally Relevant Concentrations of Diphenyl Phosphate (DPhP) Inhibits Growth and Energy Metabolism of Zebrafish in a Sex-Specific Manner

Chen

Lian

et al. 2021

Environ. Sci. Technol.

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“…Use of ERa-knockout mice has revealed ERa to be a critical part of the hypothalamic disruption mechanism and identified pregnane X receptor (PXR) and constitutive androstane receptor activation in the liver (Krumm et al 2018). These studies support other work identifying OPEs as metabolic disruptors (Boyle et al 2019;Farhat et al 2013;Selmi-Ruby et al 2020;Vail and Roepke 2020;Walley et al 2021) and, critically, identify putative, sex-specific mechanisms of action associated with disrupted brain development.…”

Section: Mammalian Studiessupporting

confidence: 87%

Beyond Cholinesterase Inhibition: Developmental Neurotoxicity of Organophosphate Ester Flame Retardants and Plasticizers

Patisaul

Behl

Birnbaum

et al. 2021

Environ Health Perspect

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Background: To date, the toxicity of organophosphate esters has primarily been studied regarding their use as pesticides and their effects on the neurotransmitter acetylcholinesterase (AChE). Currently, flame retardants and plasticizers are the two largest market segments for organophosphate esters and they are found in a wide variety of products, including electronics, building materials, vehicles, furniture, car seats, plastics, and textiles. As a result, organophosphate esters and their metabolites are routinely found in human urine, blood, placental tissue, and breast milk across the globe. It has been asserted that their neurological effects are minimal given that they do not act on AChE in precisely the same way as organophosphate ester pesticides. Objectives: This commentary describes research on the non-AChE neurodevelopmental toxicity of organophosphate esters used as flame retardants and plasticizers (OPEs). Studies in humans, mammalian, nonmammalian, and in vitro models are presented, and relevant neurodevelopmental pathways, including adverse outcome pathways, are described. By highlighting this scientific evidence, we hope to elevate the level of concern for widespread human exposure to these OPEs and to provide recommendations for how to better protect public health. Discussion: Collectively, the findings presented demonstrate that OPEs can alter neurodevelopmental processes by interfering with noncholinergic pathways at environmentally relevant doses. Application of a pathways framework indicates several specific mechanisms of action, including perturbation of glutamate and gamma-aminobutyric acid and disruption of the endocrine system. The effects may have implications for the development of cognitive and social skills in children. Our conclusion is that concern is warranted for the developmental neurotoxicity of OPE exposure. We thus describe important considerations for reducing harm and to provide recommendations for government and industry decision makers. https://doi.org/10.1289/EHP9285

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Curcumin attenuates diphenyl phosphate‐induced apoptosis in GC‐2spd(ts) cells through activated autophagy via the Nrf2/P53 pathway

Wei,

Li,

et al. 2023

Environmental Toxicology

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Diphenyl phosphate (DPhP) is one of the frequently used derivatives of aryl phosphate esters and is used as a plasticizer in industrial production. Like other plasticizers, DPhP is not chemically bound and can easily escape into the environment, thereby affecting human health. DPhP has been associated with developmental toxicity, reproductive toxicity, neurodevelopmental toxicity, and interference with thyroid homeostasis. However, understanding of the underlying mechanism of DPhP on the reproductive toxicity of GC‐2spd(ts) cells remains limited. For the first time, we investigated the effect of DPhP on GC‐2spd(ts) cell apoptosis. By decreasing nuclear factor erythroid‐derived 2‐related factor (Nrf2)/p53 signaling, DPhP inhibited autophagy and promoted apoptosis. DPhP reduced total antioxidant capacity and nuclear Nrf2 and its downstream target gene expression. In addition, we investigated the protective effects of Curcumin (Cur) against DPhP toxicity. Cur attenuated the DPhP‐induced rise in p53 expression while increasing Nrf2 expression. Cur inhibited DPhP‐induced apoptosis in GC‐2spd(ts) cells by activating autophagy via Nrf2/p53 signaling. In conclusion, our study provides new insights into the reproductive toxicity hazards of DPhP and demonstrates that Cur is an important therapeutic agent for alleviating DPhP‐induced reproductive toxicity by regulating Nrf2/p53 signaling.

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In Vivo Characterization of the Toxicological Properties of DPhP, One of the Main Degradation Products of Aryl Phosphate Esters

Cited by 15 publications

References 52 publications

Life Cycle Exposure to Environmentally Relevant Concentrations of Diphenyl Phosphate (DPhP) Inhibits Growth and Energy Metabolism of Zebrafish in a Sex-Specific Manner

Life Cycle Exposure to Environmentally Relevant Concentrations of Diphenyl Phosphate (DPhP) Inhibits Growth and Energy Metabolism of Zebrafish in a Sex-Specific Manner

Beyond Cholinesterase Inhibition: Developmental Neurotoxicity of Organophosphate Ester Flame Retardants and Plasticizers

Curcumin attenuates diphenyl phosphate‐induced apoptosis in GC‐2spd(ts) cells through activated autophagy via the Nrf2/P53 pathway

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