DEHP induces apoptosis and autophagy of the thyroid via Rap1 signaling pathway: In vivo and in vitro study

Abstract

Objective: DEHP has thyroid toxicity and affects thyroid function. However, the mechanism is unclear.

Methods: The offspring of SD rats were gavaged with different doses of DEHP from in utero to 8 or 12 weeks old. We observed the thyroid morphology with HE and autophagosomes with TEM. The THs levels were tested with ELISA. The apoptosis level was tested by flow cytometry. The levels of apoptosis-related genes, autophagy-related genes and Rap1 pathway genes, were measured with qRT-PCR and Western blot. We established an MEHP-treated Nthy-ori 3-1 cell model and inhibited the Rap1 to verify the mechanism.

Results: DEHP could cause pathological damage and ultrastructure damage of thyroids in offspring rats. After DEHP exposure, the THs levels were altered, the apoptosis levels increased, and autophagosomes appeared. DEHP significantly affected the levels of apoptosis-related genes and autophagy-related genes. DEHP also affected the levels of Rap1 pathway, which was correlated with the levels of apoptosis and autophagy. After inhibiting Rap1 in Nthy-ori 3-1 cells, the THs levels were altered. Rap1 pathway was inhibited and the levels of apoptosis and autophagy were down-regulated.

Conclusion: DEHP could induce the apoptosis and autophagy of the thyroid, and Rap1 signaling pathway may play a significant role.

Keywords: Apoptosis; Autophagy; DEHP; Rap1 signaling pathway; Thyroid.