Exposure to 6-PPD quinone suppresses the proliferation and differentiation of osteoblasts by Nr4a1-p38 MAPK signal axis.

6-PPD quinone (6-PPDQ), a new environmental contaminant, has been frequently detected in different environmental matrices and widely identified as causing health hazard. However, most early studies have primarily reported 6-PPDQ-induced toxic effects on visceral organs but do not consider its skeletal toxicity as well as the associated molecular mechanism after 6-PPDQ exposure, which remains largely unknown. This study investigated the impacts of 6-PPDQ on skeleton in vitro and in vivo. Four-week repeated 8 mg/kg 6-PPDQ exposure inhibited the bone formation, possibly by affecting osteoblasts rather than osteoclasts in mice. Moreover, 10 µg/L 6-PPDQ exposure inhibited osteoblast proliferation and differentiation by inhibiting Nr4a1 and p38 MAPK pathway. Additionally, Nr4a1 functioned upstream of p38 MAPK signaling to control the 6-PPDQ-induced suppression on osteoblasts proliferation and differentiation. Briefly, 10 µg/L 6-PPDQ exposure suppressed the activation of Nr4a1-p38 MAPK signal axis to further suppress osteoblasts proliferation and differentiation. Consequently, the present work helps understand possible skeletal toxicity induced by 10 µg/L 6-PPDQ exposure in mammals and provides novel intervention targets for the therapy of skeletal diseases caused by environmental toxicants in humans.