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

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. Tris(2-chloroethyl) phosphate (TCEP) and its less well-studied analogue, tris(2-chloroisopropyl) phosphate (TCIPP) were investigated for their modes of action that may give rise to adverse health effects using a transcriptomics approach in human HepG2 cells. Both compounds were found to elicit similar effects, with alterations immune function, steroid hormone biosynthesis and xenobiotic metabolism being common. Alterations to expression of additional immunity effector proteins and inflammatory regulators highlight TCIPP and TCEP effects on immune responses.