DINP aggravates autoimmune thyroid disease through activation of the Akt/mTOR pathway and suppression of autophagy in Wistar rats

Environ Pollut. 2019 Feb;245:316-324. doi: 10.1016/j.envpol.2018.10.108. Epub 2018 Oct 30.


Di-isononyl phthalate (DINP) is used as a substitute for traditional phthalates, in a wide range of applications. However, there is growing concern regarding its toxicity. Studies have indicated that DINP is related to thyroid hormone disorder and that phthalates can affect thyroid normal function. In this study, we aim to determine any effects of DINP exposure on autoimmune thyroid disease (AITD), the most common autoimmune disease, and to understand the underlying causal mechanism. AITD model Wistar rats were exposed to 0.15 mg/kg, 1.5 mg/kg or 15 mg/kg DINP. We assessed the thyroid globulin antibody levels, Th1/Th2 balance, histopathological changes and caspase-3 levels in the thyroid. The data show that exposure to DINP does indeed aggravate AITD. To explore the underlying mechanisms, we examined the levels of microtubule-associated protein 1 light chain 3 B (LC3B), Sequestosome 1 (SQSTM1) and the appearance of autophagosomes or autolysosomes to assess autophagy in the thyroid. The results show that DINP can suppress normal autophagy. We found that DINP induced an exacerbation of oxidative stress and the activation of the Akt/mTOR pathway, indicating that oxidative stress and activation of mTOR may play a key role in these processes. Moreover, the activation of mTOR also promoted the expression of IL-17. Importantly, blocking oxidative stress with VE or blocking Akt/mTOR with rapamycin mitigated the exacerbation of AITD and the suppression of normal autophagy. All these results indicate that exposure to DINP, especially high doses of DINP, can aggravate oxidative stress and activate the Akt/mTOR pathway. This exposure then leads to a suppression of normal autophagy and expression of IL-17 in the thyroid, resulting in an eventual exacerbation of AITD.

Keywords: Autophagy; Di-isononyl phthalate; Oxidative stress; mTOR.

MeSH terms

  • Animals
  • Autophagy / drug effects*
  • Female
  • Interleukin-17 / metabolism
  • Lysosomes / metabolism
  • Male
  • Oxidative Stress / drug effects
  • Phthalic Acids / toxicity*
  • Proto-Oncogene Proteins c-akt / metabolism*
  • Rats, Wistar
  • Signal Transduction / drug effects
  • TOR Serine-Threonine Kinases / metabolism*
  • Thyroid Gland / drug effects*
  • Thyroid Gland / metabolism
  • Thyroid Gland / pathology
  • Thyroiditis, Autoimmune / chemically induced*
  • Thyroiditis, Autoimmune / metabolism
  • Thyroiditis, Autoimmune / pathology


  • Interleukin-17
  • Phthalic Acids
  • diisononyl phthalate
  • TOR Serine-Threonine Kinases
  • mTOR protein, rat
  • Proto-Oncogene Proteins c-akt