Aryl- and alkyl-phosphorus-containing flame retardants induced mitochondrial impairment and cell death in Chinese hamster ovary (CHO-k1) cells

Abstract

Phosphorus-containing flame retardants (PFRs) are increasingly in demand worldwide as replacements for brominated flame retardants (BFRs), but insufficient available toxicological information on PFRs makes assessing their health risks challenging. Mitochondria are important targets of various environmental pollutants, and mitochondrial dysfunction may lead to many common diseases. In the present study, mitochondria impairment-related endpoints were measured by a high content screening (HCS) assay for 11 selected non-halogen PFRs in Chinese hamster ovary (CHO-k1) cells. A cluster analysis was used to categorize these PFRs into three groups according to their structural characteristics and results from the HCS assay. Two groups, containing long-chain alkyl-PFRs and all aryl-PFRs, were found to cause mitochondrial impairment but showed different mechanisms of toxicity. Due to the high correlation between cell death and mitochondrial impairment, two PFRs with different structures, trihexyl phosphate (THP) and cresyl diphenyl phosphate (CDP), were selected and compared with chlorpyrifos (CPF) to elucidate their mechanism of inducing cell death. THP (an alkyl-PFR) was found to utilize a similar pathway as CPF to induce apoptosis. However, cell death induced by CDP (an aryl-PFR) was different from classical necrosis based on experiments to discriminate among the different modes of cell death. These results confirm that mitochondria might be important targets for some PFRs and that differently structured PFRs could function via distinct mechanisms of toxicity.

Organophosphorus Flame Retardants Impair Intracellular Lipid Metabolic Function in Human Hepatocellular Cells

“…46 The previous data showed that aryl-and alkyl-OPFRs caused mitochondrial dysfunction on CHO cells at relatively high doses (>100 μM). 47 However, mitochondria are sensitive target for many chemicals at noncytotoxic doses. For example, exposure to OCPs reduced MMP and ATP content, as well as the OCR and TCA cycle in HepG2 cells at noncytotoxic doses.…”

“…was usually observed in chemical-induced metabolic disorder . The previous data showed that aryl- and alkyl-OPFRs caused mitochondrial dysfunction on CHO cells at relatively high doses (>100 μM) . However, mitochondria are sensitive target for many chemicals at noncytotoxic doses.…”

Catalytic Hydrolysis of Tricresyl Phosphate by Ruthenium (III) Hydroxide and Iron (III) Hydroxide towards Sensing Application

“…Long-term exposure to ToCP can induce a delayed neurodegenerative condition recognized as organophosphorous-induced delayed neuropathy (OPIDN) [12][13][14]. The other isomers of TCP have also been found functional on the inhibition of enzymes in human beings [6,[15][16][17][18] and on the formation of axon-like processes, as well as on the disruption of neurofilaments in cultured cells [19].…”

Cytotoxic Screening and Transcriptomics Reveal Insights into the Molecular Mechanisms of Trihexyl Phosphate-Triggered Hepatotoxicity

“…Flame retardants (FRs), as a type of functional additives, are widely used in various synthetic and natural polymer materials, such as plastics, wood, coatings, rubber, building materials, and electronic products, to prevent or slow down the combustion of inflammable substances. , FRs are divided into four major groups according to their chemical and structural composition: inorganic, halogenated organic, nitrogen-containing, and phosphorus-containing compounds. , The most extensively used and universal FRs are brominated flame retardants (BFRs) and organophosphate flame retardants (OPFRs) . However, most FRs may easily release into the environmental media because of nonchemical bonding to the end-use products, causing potential health risks to living organisms. − Indeed, polybrominated diphenyl ethers and polychlorinated biphenyls, as one of the BFRs, have been globally restricted and gradually being abandoned because of persistence, bioaccumulation, and biotoxicity under the Stockholm Convention. , The commercial production and consumption of OPFRs as suitable alternatives to BFRs have gradually increased in recent years because of their stable properties, low corrosion, and good flame retardancy. , …”

“…Trihexyl phosphate (THP) is a typical alkyl-phosphorus-containing FR with a long carbon chain . Similar to other OPFRs, THP is detected in a variety of aquatic organisms, such as grass carp, catfish, eel, carp, trout, and other river fish or sea fish, with sample concentrations ranging from 36.9 to 123 ng/g lipid weight (lw) in a Spanish aquatic ecosystem, from nd (not detected) to 39.6 ng/g lw in three European river basins, and from nd to 1.39 ng/g lw in a southern China river. − Huang et al have recently found through a high-content screening assay of 11 selected nonhalogen PFRs that THP causes mitochondrial impairment and induces cell apoptosis in Chinese hamster ovary cells. Meanwhile, Ji et al reported that THP promotes the proliferation of human breast cancer cells (MCF-7) in a dose-dependent manner and exerts estrogenicity via ERα-independent pathways.…”