Organophosphorus flame retardant (tricresyl phosphate) trigger apoptosis in HepG2 cells: Transcriptomic evidence on activation of human cancer pathways

Alsalem, Abdulaziz A.; Saquib, Quaiser; Siddiqui, Maqsood A.; Ahmad, Javed; Wahab, Rizwan; Al‐Khedhairy, Abdulaziz A.

doi:10.1016/j.chemosphere.2019.124519

Cited by 30 publications

(26 citation statements)

References 57 publications

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“…Ca 2+ influx and mitochondrial membrane potential (∆Ψm) in TCEP-exposed cells were measured following the previously described method [28]. Before commencing the experiments, HepG2 cells were seeded separately in 24-well plates and allowed to grow overnight at 37 • C in a CO 2 incubator (5%, 95% humidity).…”

Section: Ca 2+ Influx and Mitochondrial Membrane Potential (∆ψM)mentioning

confidence: 99%

“…For quantifying changes in ∆Ψm, cells were stained with 5 µg/mL of Rh123 dye for 1 h at 37 • C in a CO 2 incubator (5%, 95% humidity). Post staining, the fluorescence of 10,000 cells was recorded at 530 nm on a log scale (FL-1) with a flow cytometer [28].…”

Section: Ca 2+ Influx and Mitochondrial Membrane Potential (∆ψM)mentioning

confidence: 99%

“…Intracellular ROS, NO, and esterase level quantifications were done following the previously described method [28]. Firstly, HepG2 cells were seeded separately in 24-well plates and allowed to grow overnight in a CO 2 incubator (5%, 95% humidity) maintained at 37 • C. Later, cell culture medium was aspirated and discarded under sterile conditions.…”

Section: Reactive Oxygen Species (Ros) Nitric Oxide (No) and Esteramentioning

confidence: 99%

“…HepG2 cells were allowed to separately stain with the above dyes for 1 h (37 • C) in a CO 2 incubator (5% CO 2 ). After the specified incubation time, 10,000 cells were analyzed on a flow cytometer at FL-1 channel (530 nm) [28].…”

Section: Reactive Oxygen Species (Ros) Nitric Oxide (No) and Esteramentioning

confidence: 99%

“…qPCR array experiments were done to quantify the transcriptomic alterations by following the previously described methods [27,28]. For the qPCR array, HepG2 cells were first seeded in 6-well plates and allowed to grow overnight in a CO 2 incubator (5%, 95% humidity) maintained at 37 • C. Subsequently, cell culture medium was disposed, and incomplete RPMI-1640 medium containing 100 µM of TCEP was replenished in the replicate wells.…”

Section: Transcriptomic Analysis By Qpcr Arraymentioning

confidence: 99%

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Tris(2-chloroethyl) Phosphate (TCEP) Elicits Hepatotoxicity by Activating Human Cancer Pathway Genes in HepG2 Cells

Alsalem

Saquib

Siddiqui

et al. 2020

Toxics

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Tris(2-chloroethyl) phosphate (TCEP) is one of the organophosphorus flame retardants (OPFRs) used in consumer commodities and have been detected in human body fluids. Research on TCEP-induced transcriptomic alterations and toxicological consequences in liver cells is still lacking. Herein, human hepatocellular (HepG2) cells were treated with 100, 200, and 400 μM TCEP for 3 days to quantify hepatotoxicity by MTT, NRU, and comet assays. Apoptosis, mitochondrial membrane potential (ΔΨm), oxidative stress, and Ca2+ influx were measured by flow cytometry. A qPCR array was employed for transcriptomic analysis. MTT and NRU data showed 70.92% and 75.57% reduction in cell survival at 400 μM. In addition, 20-fold greater DNA damage was recorded at 400 μM. Cell cycle data showed 65.96% subG1 apoptotic peak in 400 μM treated cells. An elevated level of oxidative stress, esterase, Ca2+ influx, and ΔΨm dysfunction were recorded in TCEP-treated cells. Out of 84 genes, the qPCR array showed upregulation of 17 genes and downregulation of 10 key genes belonging to human cancer pathways. Our study endorses the fact that TCEP possesses hepatotoxic potential at higher concentrations and prolonged exposure. Hence, TCEP may act as a cancer-inducing entity by provoking the gene network of human cancer pathways.

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Section: Ca 2+ Influx and Mitochondrial Membrane Potential (∆ψM)mentioning

confidence: 99%

Section: Ca 2+ Influx and Mitochondrial Membrane Potential (∆ψM)mentioning

confidence: 99%

Section: Reactive Oxygen Species (Ros) Nitric Oxide (No) and Esteramentioning

confidence: 99%

Section: Reactive Oxygen Species (Ros) Nitric Oxide (No) and Esteramentioning

confidence: 99%

Section: Transcriptomic Analysis By Qpcr Arraymentioning

confidence: 99%

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Tris(2-chloroethyl) Phosphate (TCEP) Elicits Hepatotoxicity by Activating Human Cancer Pathway Genes in HepG2 Cells

Alsalem

Saquib

Siddiqui

et al. 2020

Toxics

Self Cite

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Choline ameliorates tris (2‐chloroisopropyl) phosphate‐induced hepatocellular carcinoma metastasis by inhibiting ROS/Nrf2/Keap1‐mediated autophagy

Wang,

Li,

Huang

et al. 2024

Food Frontiers

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Tris (2‐chloroisopropyl) phosphate (TCPP) is an emerging environmental pollutant associated with liver diseases. However, its effects on hepatocellular carcinoma (HCC) remain unknown. Choline, a necessary dietary nutrient, has previously demonstrated inhibitory effects on HCC. Therefore, elucidating the underlying mechanism of TCPP exposure on HCC development and investigating whether choline could mitigate these effects may improve the prognosis of HCC patients. In this study, we examined the tumor‐promoting effects of TCPP on HCC and explored the protective effects of choline. Our findings revealed that choline treatment attenuated the tumor‐promoting effects of TCPP exposure on HCC cells’ epithelial‐mesenchymal transition (EMT) and lung metastasis. Further investigation showed that TCPP exposure induced ROS production via NOX4 upregulation, while choline inhibited ROS generation, thereby mitigating the effects of TCPP on EMT and metastasis in HCC cells. Mechanistic analysis demonstrated that excessive ROS inhibited levels of Keap1, leading to upregulation and nuclear translocation of Nrf2, which promoted autophagy flux and accelerated EMT and metastasis of HCC cells. However, choline treatment significantly impaired TCPP‐induced autophagy by attenuating the ROS/Nrf2/Keap1 pathway. Overall, our data illustrate the adverse effects of TCPP on the malignant progression of HCC and suggest that choline may serve as a potential nutrient to counteract the tumor‐promoting effects of TCPP on HCC.

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Maternal organophosphate flame‐retardant exposure alters offspring energy and glucose homeostasis in a sexually dimorphic manner in mice

Walley

Krumm

Yasrebi

et al. 2020

J of Applied Toxicology

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Persistent organic pollutants such as organophosphate flame retardants (OPFRs) can accumulate in the body and interact with nuclear receptors that control energy homeostasis. One sensitive window of exposure is during development, either in utero or neonatal. Therefore, we investigated if maternal exposure to a mixture of OPFRs alters metabolism on a low-fat diet (LFD) or a high-fat diet (HFD) in both male and female offspring. Wild-type C57Bl/6J dams were orally dosed with vehicle (sesame oil) or an OPFR mixture (1 mg/kg each of tris(1,3-dichloro-2-propyl) phosphate, triphenyl phosphate, and tricresyl phosphate) from gestation day 7 to postnatal day 14. After weaning, pups were fed LFD or HFD. To assess metabolism, we measured body weight and food intake weekly and determined body composition, metabolism, activity, and glucose homeostasis at 6 months of age. Although maternal OPFR exposure did not alter body weight or adiposity, OPFR exposure altered substrate utilization and energy expenditure depending on diet in both sexes. Systolic and diastolic blood pressure was increased by OPFR in male offspring. OPFR exposure interacted with HFD to increase fasting glucose in females and alter glucose and insulin tolerance in male offspring. Plasma leptin was reduced in male and female offspring when fed HFD, whereas liver expression of Pepck was increased in females and Esr1 (estrogen receptor α) was increased in both sex. The physiological implications indicate maternal exposure to OPFRs programs peripheral organs including the liver and adipose tissue, in a sex-dependent manner, thus changing the response to an obesogenic diet and altering adult offspring energy homeostasis.

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Organophosphorus flame retardant (tricresyl phosphate) trigger apoptosis in HepG2 cells: Transcriptomic evidence on activation of human cancer pathways

Cited by 30 publications

References 57 publications

Tris(2-chloroethyl) Phosphate (TCEP) Elicits Hepatotoxicity by Activating Human Cancer Pathway Genes in HepG2 Cells

Tris(2-chloroethyl) Phosphate (TCEP) Elicits Hepatotoxicity by Activating Human Cancer Pathway Genes in HepG2 Cells

Choline ameliorates tris (2‐chloroisopropyl) phosphate‐induced hepatocellular carcinoma metastasis by inhibiting ROS/Nrf2/Keap1‐mediated autophagy

Maternal organophosphate flame‐retardant exposure alters offspring energy and glucose homeostasis in a sexually dimorphic manner in mice

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