TPhP exposure disturbs carbohydrate metabolism, lipid metabolism, and the DNA damage repair system in zebrafish liver

Abstract

Triphenyl phosphate is a high production volume organophosphate flame retardant that has been detected in multiple environmental media at increasing concentrations. The environmental and health risks of triphenyl phosphate have drawn attention because of the multiplex toxicity of this chemical compound. However, few studies have paid close attention to the impacts of triphenyl phosphate on liver metabolism. We investigated hepatic histopathological, metabolomic and transcriptomic responses of zebrafish after exposure to 0.050 mg/L and 0.300 mg/L triphenyl phosphate for 7 days. Metabolomic analysis revealed significant changes in the contents of glucose, UDP-glucose, lactate, succinate, fumarate, choline, acetylcarnitine, and several fatty acids. Transcriptomic analysis revealed that related pathways, such as the glycosphingolipid biosynthesis, PPAR signaling pathway and fatty acid elongation, were significantly affected. These results suggest that triphenyl phosphate exposure markedly disturbs hepatic carbohydrate and lipid metabolism in zebrafish. Moreover, DNA replication, the cell cycle, and non-homologous end-joining and base excision repair were strongly affected, thus indicating that triphenyl phosphate hinders the DNA damage repair system in zebrafish liver cells. The present study provides a systematic analysis of the triphenyl phosphate-induced toxic effects in zebrafish liver and demonstrates that low concentrations of triphenyl phosphate affect normal metabolism and cell cycle.

Gestational triphenyl phosphate exposure in C57Bl/6 mice perturbs expression of insulin‐like growth factor signaling genes in maternal and fetal liver

“…Insulin and insulin‐like growth factors are peptide hormones that initiate a cascade of downstream signaling resulting in regulation of growth and metabolism in most bodily tissues. Evidence to date suggests that TPhP can interfere with expression of genes and proteins involved in metabolic control (Du et al, ; Green et al, ; Liu et al, ), however to the best of our knowledge, Igf signaling has yet to be investigated as a target of gestational TPhP exposure.…”

“…Further indications that TPhP may have endocrine disrupting properties include evidence suggesting that exposure may interfere with metabolic pathways. Disruption of carbohydrate and lipid metabolism was found in the liver of both zebrafish and C57Bl/6 mice following exposure to TPhP (Du et al, ; Morris et al, ). Additionally, perinatal TPhP exposure in UCD type 2 diabetes mellitus rats accelerated the onset of type 2 diabetes in male offspring, as well as increased body and fat mass in both male and female offspring (Green et al, ).…”

Flame retardants and their metabolites in the homes and urine of pregnant women residing in California (the CHAMACOS cohort)

“…For example, several recent toxicological studies have linked TPHP exposure with reproductive and developmental toxicity, neurotoxicity, metabolic disruption, endocrine effects, and genotoxicity (Du et al 2016; Mendelsohn et al 2016; Q Zhang et al 2016). TPHP has also been found to induce significant estrogenic activity in vitro (Krivoshiev et al 2016; Zhang et al 2014).…”

Prioritization of hazards of novel flame retardants using the mechanistic toxicology information from ToxCast and Adverse Outcome Pathways

“…Considering liver-related AOs (hepatotoxicity and liver cancer), evidence for TDCIPP, TCEP, TMPP, TBBPA, TPhP and TNBP relied exclusively on animal studies [9,10,15,67,68,72]. Our search identified AOP 144 (all AOPs listed in Table 4) as a plausible mechanism for TMPP-, TBBPA-, TPhP-, TNBP-and TDCIPP-induced hepatotoxicity, and AOP 220 as a plausible mechanism for TCEP-, TBBPA-, TNBP-and TDCIPP-induced liver cancer.…”