Developmental Exposure to the Flame Retardant Mixture Firemaster 550 Compromises Adult Bone Integrity in Male but not Female Rats

Abstract

Flame retardants (FRs) are used in a variety of common items from furniture to carpet to electronics to reduce flammability and combustion, but the potential toxicity of these compounds is raising health concerns globally. Organophosphate FRs (OPFRs) are becoming more prevalent as older, brominated FRs are phased out, but the toxicity of these compounds, and the FR mixtures that contain them, is poorly understood. Work in a variety of in vitro model systems has suggested that FRs may induce metabolic reprogramming such that bone density is compromised at the expense of increasing adiposity. To address this hypothesis, the present studies maternally exposed Wistar rat dams orally across gestation and lactation to 1000 µg daily of the FR mixture Firemaster 550 (FM 550) which contains a mixture of brominated FRs and OPFRs. At six months of age, the offspring of both sexes were examined for evidence of compromised bone composition. Bone density, composition, and marrow were all significantly affected, but only in males. The fact that the phenotype was observed months after exposure suggests that FM 550 altered some fundamental aspect of mesenchymal stem cell reprogramming. The severity of the phenotype and the human-relevance of the dose employed, affirm this is an adverse outcome meriting further exploration.

Environmentally Relevant Concentrations of Tris(1,3-dichloro-2-propyl) Phosphate Induced a Female-Biased Osteotoxicity in Crucian Carp (Carassius auratus)

“…A decreased trend in bone thickness was also observed after exposure to different concentrations of TDCIPP, but a statistically significant decrease was only observed in PM female individuals of 5000 ng/L group. Several previous studies reported that the reduction of bone thickness was considered as a marker of bone homeostasis imbalance in bone formation and bone resorption. − Therefore, our results indicated that TDCIPP exposure led to skeletal microstructure impairment and a pathological condition of the skeletal system in female crucian carp. Collectively, it was hypothesized that the female malformation in caudal vertebrae occurred because of the reduction of bone thickness, disturbance of bone deposition, and increase of mechanical burden on the spinal column.…”

Prenatal Exposure of Organophosphate Esters and Its Trimester-Specific and Gender-Specific Effects on Fetal Growth

“…For example, one toxicological research found that OPE exposure compromised adult skeletal integrity in male rats. 48 Another study on chicken embryos found that head length and spine length was significantly reduced by tris(2-chloroethyl)phosphate exposure. 49 The above findings could support the negative correlations of prenatal OPE exposure with FL and HC found in this study.…”

“…Several experimental studies have found that OPEs have skeletal development toxicity. For example, one toxicological research found that OPE exposure compromised adult skeletal integrity in male rats . Another study on chicken embryos found that head length and spine length was significantly reduced by tris­(2-chloroethyl)­phosphate exposure .…”

Exposure totert-Butylphenyl Diphenyl Phosphate, an Organophosphate Ester Flame Retardant and Plasticizer, Alters Hedgehog Signaling in Murine Limb Bud Cultures

“…Investigations into the potential effects of OPE exposure on the skeleton are very limited. Macari et al (2020) reported that developmental exposure to Firemaster 550, a commercial FR mixture containing triphenyl phosphate (TPHP) and isopropylated triphenyl phosphate (IPPP), was detrimental to the skeletal health of adult male Wistar rats. Interestingly, increases in urinary OPE concentrations by one quartile were associated with a decrease in birth length z-scores in a recent pregnancy cohort study (Kuiper et al, 2020).…”