Is the PentaBDE replacement, tris (1,3-dichloro-2-propyl) phosphate (TDCPP), a developmental neurotoxicant? Studies in PC12 cells

Abstract

Organophosphate flame retardants (OPFRs) are used as replacements for the commercial PentaBDE mixture that was phased out in 2004. OPFRs are ubiquitous in the environment and detected at high concentrations in residential dust, suggesting widespread human exposure. OPFRs are structurally similar to neurotoxic organophosphate pesticides, raising concerns about exposure and toxicity to humans. This study evaluated the neurotoxicity of tris (1,3-dichloro-2-propyl) phosphate (TDCPP) compared to the organophosphate pesticide, chlorpyrifos (CPF), a known developmental neurotoxicant. We also tested the neurotoxicity of three structurally similar OPFRs, tris (2-chloroethyl) phosphate (TCEP), tris (1-chloropropyl) phosphate (TCPP), and tris (1,3-dibromopropyl) phosphate (TDBPP), and 2,2′,4,4′-tetrabromodiphenyl ether (BDE-47), a major component of PentaBDE. Using undifferentiated and differentiating PC12 cells, changes in DNA synthesis, oxidative stress, differentiation into dopaminergic or cholinergic neurophenotypes, cell number, cell growth and neurite growth were assessed. TDCPP displayed concentration-dependent neurotoxicity, often with effects equivalent to or greater than equimolar concentrations of CPF. TDCPP inhibited DNA synthesis, and all OPFRs decreased cell number, and altered neurodifferentiation. Although TDCPP elevated oxidative stress, there was no adverse effect on cell viability or growth. TDCPP and TDBPP promoted differentiation into both neuronal phenotypes, while TCEP and TCPP promoted only the cholinergic phenotype. BDE-47 had no effect on cell number, cell growth or neurite growth. Our results demonstrate that different OPFRs show divergent effects on neurodifferentiation, suggesting the participation of multiple mechanisms of toxicity. Additionally, these data suggest that OPFRs may affect neurodevelopment with similar or greater potency compared to known and suspected neurotoxicants.

Distribution of organophosphorus flame retardants in sediments from the Pearl River Delta in South China

“…Chlorinated organophosphates, such as tris(2-chloroethyl) phosphate (TCEP), tris(2-chloro-isopropyl) phosphate (TCPP), and tris(2-chloro, 1-chloromethyl-ethyl) phosphate (TDCP) are suspected carcinogens (World Health Organization, 1998). Additionally, TCEP has been linked with incidents of acute death of dogs (Lehner et al, 2010), while TDCP was shown to be more neurotoxic than TCEP and TCPP (Dishaw et al, 2011). Tricresyl phosphate (TCrP), triphenyl phosphate (TPhP), and TDCP are considered as possibly toxic for reproduction (van der Veen and de Boer, 2012;Meeker and Stapleton, 2010).…”

Developmental exposure to the organophosphorus flame retardant tris(1,3-dichloro-2-propyl) phosphate: Estrogenic activity, endocrine disruption and reproductive effects on zebrafish

“…Limited toxicological information indicates that TDCPP may act as an endocrine disruptor (Dishaw et al, 2011;Liu et al, 2013a). adrenocortical carcinoma cells (H295R) exposed to TDCPP have abnormal sex hormone levels (Liu et al, 2012); (2) TDCPP can act as an androgen receptor antagonist (Kojima et al, 2013) and (3) TDCPP can act as an estrogenic receptor (ER) ␣ agonist with estrogenic activity .…”

Multiple bio-analytical methods to reveal possible molecular mechanisms of developmental toxicity in zebrafish embryos/larvae exposed to tris(2-butoxyethyl) phosphate

“…Previous studies have demonstrated that several OP esters cause developmental toxicity and endocrine disruption in vivo and in vitro (Crump et al, 2012;Dishaw et al, 2012;Farhat et al, 2013;Fu et al, 2013;Liu et al, 2012bLiu et al, , 2013McGee et al, 2012McGee et al, , 2013Wang et al, 2013). For example, exposure of zebrafish embryos to tris(1,3-dichloro-2-propyl) phosphate (TDCPP) disrupted embryogenesis and caused larval malformation, with median lethal concentrations (LC 50 ) ranging from 3.7 to 7.0 mg/L (Fu et al, 2013;Liu et al, 2013;McGee et al, 2012;Wang et al, 2013).…”