Sex‐Dependent Metabolic Syndrome Phenotype Produced By Developmental Exposure to Indoor Flame Retardants
Authors: Curras-Collazo Margarita , Kozlova Elena , Stapleton Heather , Gonzalez Gwen , Chinthirla Bhuvana D. , Krum Julia M. 
Published: April 2020

Chronic low level exposure to endocrine disrupting chemicals such as polybrominated diphenyl ethers (PBDEs) have been associated with diabetogenic and obesogenic phenotypes but mechanistic studies are sparse.1–2 In this study, we examined effects of developmental exposure to DE‐71, an industrial mixture of mostly penta‐brominated PBDE congeners3, on cellular, organ and systems level processes associated with metabolic syndrome after adult and developmental exposure to DE‐71 in C57Bl/6 mice. In an effort to link chemical exposure to health effects via key events (KE), we designed experiments using an adverse outcome pathway framework. Toxicant Exposure: C57BI/6 dams were exposed daily to DE‐71 at low dose (LD, 0.1mg/kg/d), or high dose (HD, 0.4mg/kg/d) and compared to corn oil vehicle control (OD) via ingestion of infused corn flakes for 10wk (mating, gestation lactation). GC/ECNI‐MS showed that livers of female offspring at sacrifice (PND 100) contained only BDE‐25 and 153, whereas, other congeners were detected in dams: BDE 99>47=85=100=154=183. Adverse Outcomes: Glucose tolerance test indicated pronounced glucose intolerance in LD females and dams but not male offspring. Insulin tolerance test showed insensitivity in LD and HD female offspring (p<.05; n=5–10). Compared to LD female offspring, DE‐71 exposed male offspring and dams showed less pronounced glucose intolerance and insulin insensitivity. KE – Systems (Metabolic): Fasting hyperglycemia was observed in HD female offspring (p<.001; n=5–12); Only the LD female offspring showed elevated plasma cholesterol and liver lipids although but dams showed greatest fatty liver (p<.05, n=5–8). KE – Systems (Endocrine): Plasma insulin was significantly decreased in LD (p<.05, n=8–19) and HD female (p<.01, n=8–19) but not male offspring or dams. KEs – Molecular: Adult and developmental PBDE exposure at LD and HD produced liver oxidative stress as indicated by elevated glutathione S‐transferase (GST) and reduced glutathione reductase (GR) activity in male offspring, female offspring and dams when compared with OD (n=12–20/group; p<.01). PBDEs may alter hepatic glycogenesis and glyceroneogenesis and glucose oxidation since they reduce phosphenolpyruvate carboxykinase (PEPCK) and glutamate dehydrogenase (GDH) activity, respectively; both were decreased in LD and HD male offspring, female offspring and dams (n=8–11/group, p<.01). Exposed female offspring values were similar except that only HD showed reduced GR and PEPCK. Summary: The following sequence of KEs is proposed downstream of a yet unknown molecular initiating event: (1) Reduced GR and elevated GST (KE1); (2) Reduced GDH and PEPCK (KE2); (3) Liver lipids, Fatty liver; (4) Fasting hyperglycemia, glucose intolerance, insulin insensitivity and hyperlipidemia. Our results indicate that PBDEs promote a metabolic syndrome phenotype in parallel with hepatic oxidative stress injury. Support: UC MEXUS (MC), Sigma Xi Research Society Grant in Aid (EK), MARC fellowship (GG)Support or Funding InformationSupport: UC MEXUS (MC), Sigma Xi Research Society Grant in Aid (EK), MARC fellowship (GG)