A toxicogenomics approach to screen chlorinated flame retardants tris(2‐chloroethyl) phosphate and tris(2‐chloroisopropyl) phosphate for potential health effects

Abstract

Tris(2-chloroethyl) phosphate (TCEP) is a pervasive flame retardant that has been identified as a chemical of concern given its health effects and therefore its use has since been tightly regulated. Tris(2-chloroisopropyl) phosphate (TCIPP), an analogue of TCEP, is believed to be its replacement. However, compared to TCEP, little is known of the toxicological impacts of TCIPP. We used RNA sequencing as unbiased and sensitive tool to identify and compare effects on a transcriptome level of TCEP and TCIPP in the human hepatocellular carcinoma cell line, HepG2. We identified that compared to other flame retardants, TCEP and TCIPP had little cytotoxicity. Treatment with sub-cytotoxic concentrations of the two compounds revealed that both chemicals elicited similar effects; both compounds were found to affect genes involved in immune responses and steroid hormone biosynthesis, while also affecting xenobiotic metabolism pathways in a similar manner. Specifically for effects on immune responses, both compounds were shown to alter the expression of the receptor of the potent and pleiotropic complement component, C5a. Additionally, expression of genes encoding for effector proteins involved in the complement cascade along with other potent inflammatory regulators were found altered in response to TCEP and TCIPP, further emphasizing their potential effects on immune function. Taken together, given that TCIPP elicited similar effects compared to TCEP, and at lower concentrations, the potential health effects of TCIPP need to be further studied for a complete risk assessment of the compound.

Early Life Exposure to Tris(2-butoxyethyl) Phosphate (TBOEP) Is Related to the Development of Childhood Asthma

“…Evidence from in vitro studies suggest that exposure to >50 μM OPEs, including TPhP and TDCiPP, can modulate oxidative stress biomarkers and are immunotoxic for dendritic cells from mice, which elicit immune responses to pathogens in the airway . Similarly, human exposure studies have demonstrated that urinary metabolites of TCEP, TnBP, and TPhP among adults and urinary metabolites of TBOEP, TPhP, and EHDPP among children have been associated with higher levels of oxidative stress biomarkers such as 4-hydroxynonenal (HNE), hexanoyl-lysine (HEL), and 8-hydroxy-2′-deoxyguanosine (8-OHdG). , Toxicogenomic studies have also demonstrated that OPEs, such as TBOEP, can alter genes involved in immune response. , …”

“…54,55 Toxicogenomic studies have also demonstrated that OPEs, such as TBOEP, can alter genes involved in immune response. 56,57 Implications. This study examined early life exposure to a wide range of OPEs and their association with childhood asthma diagnosed at age 5.…”

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

“…Human hepatocellular (HepG2) cells exposed to a combined mixture of TCEP and benzo (a) pyrene demonstrated the release of inflammatory responses (IL-6 and IL-8) via activation of the EGFR-ERK1/2 pathway [18]. RNA sequencing (RNA-Seq) of HepG2 cells exposed to TCEP at sublethal concentrations affected several genes related to xenobiotic metabolism, immune responses, and steroid hormone biosynthesis [19]. Furthermore, HepG2 cells exposed to TCEP demonstrated cytotoxicity and growth arrest through attenuation of the SIRT1-independent PI3K/Akt/mTOR pathway [20].…”

The impact of oral exposure to low‐dose tris(2‐butoxyethyl) phosphate in allergic asthmatic mice

“…Canbaz et al (Canbaz, Logiantara, van Ree, & van Rijt, 2017) revealed that TDCIPP and triphenyl phosphate may promote DC activation and proinflammatory cytokine production in vitro. Krivoshiev et al reported that TBEP, tris(2‐chloroethyl) phosphate, and TCIPP had a significant impact on the expression of immune response genes and steroid hormone biosynthesis‐related genes in HepG2 cells (Krivoshiev, Beemster, Sprangers, Blust, & Husson, 2018; Krivoshiev, Beemster, Sprangers, Cuypers, et al, 2018). An epidemiological study revealed a strong positive association between TBEP metabolites in urine and eczema (Araki et al, 2018).…”