Mechanisms and Targeted Prevention of Hepatic Osteodystrophy Caused by a Low Concentration of Di-(2-ethylhexyl)-phthalate

qinming hui ^1,2 xinru du ^1,2 maoxuan li ² sha liu ² zhendong wang ² sisi song ² yancheng gao ² Ye Yang ^2* Zhou Chunxiao ^1* Yuan Li ^1,2*

• ¹ Suzhou Municipal Hospital, Suzhou, Jiangsu Province, China
• ² Nanjing Medical University, Nanjing, China

Hepatic osteodystrophy (HOD) is one of the important public health issues that seriously affect people's health. The pathogeny of HOD is complex, in which, exposure of environmental pollutants plays important roles. Di-(2-ethylhexyl) phthalate (DEHP) is a persistent environmental endocrine toxicant present in many products; and liver is an important target organ for its toxic effects. However, the effects of DEHP on HOD, the underlying mechanisms, and potential key preventive approaches remain largely uninvestigated. Here we found that, in recent years, male and female population were exposed to a relative lower concentration of DEHP, and that only male population exhibited a negative correlation between DEHP exposure and bone mineral density. In vivo study confirmed that low dose of DEHP caused liver lesions, disrupted liver function, and induced osteoporosis in male, but not female C57BL/6J mice. For the molecular mechanisms, low dose of DEHP activated the hepatic 14-3-3η/nuclear factor κB (NF-κB) positive feedback loop, which in turn modified the secretory proteome associated with bone differentiation, leading to the HOD. Finally, we revealed that, targeted 14-3-3η/NF-κB feedback loop by using our novel 14-3-3η inhibitor (imICA) could prevent DEHP-induced HOD. Our present study offered new insights into environmental toxin-induced osteoporosis and suggested a potential key intervention target/approach for the prevention of HOD.