Rosmarinic acid alleviates di-2-ethylhexyl phthalate (DEHP) -induced thyroid dysfunction via multiple inflammasomes activation

J Toxicol Sci. 2020;45(7):373-390. doi: 10.2131/jts.45.373.


DEHP (di-2-ethylhexyl phthalate), an environmental endocrine disruptor, is widely used in industrial products, particularly as plasticizers and softeners which could disrupt the function of the hypothalamic-pituitary-thyroid (HPT) axis. Rosmarinic acid (RA) possesses potential antioxidant and anti-inflammatory capacities in disease models. Nevertheless, evidence on the association between DEHP-induced thyroid dysfunction and inflammation, as well as the molecular mechanism underlying the protective effects of RA-mitigated DEHP-induced thyroid injury remains inconclusive. Male Sprague Dawley (SD) rats were intragastrically administered DEHP (150 mg/kg, 300 mg/kg, 600 mg/kg) once a day for 90 consecutive days. Also, FRTL-5 cells were treated with a wide range of DEHP concentrations (10-8, 10-7, 10-6, 10-5, 10-4, 10-3, 10-2 M) for 24 hr. Subsequently, RA (50 μM) was administered for 24 hr before 10-4 M DEHP challenge. We found that DEHP induced thyroid damage and inflammatory infiltration in vivo. In addition, we showed that DEHP triggered inflammatory cell death, which is mediated by multiple inflammasomes. Moreover, RA, pyroptosis inhibitor (Ac-YVAD-cmk) and antioxidant inhibitor (NAC) treatment significantly alleviated DEHP-induced thyrocyte death, suppressing pro-inflammatory cytokine production, inhibiting multiple inflammasomes activation and attenuating thyrocyte death, respectively. Collectively, our results reveal that a critical role of inflammasomes activation in DEHP-induced thyroid injury, and suggest that RA confers protection against DEHP-induced thyroid inflammation, and facilitating control of the effects of DEHP after given pyroptosis inhibitor or antioxidant inhibitor. These results indicate that it should be possible to provide novel insights into toxicologically and pharmacologically targeting this molecule to DEHP-induced inflammation.

Keywords: DEHP; Inflammasomes; Inhibitor; Rosmarinic acid; Thyroid.

MeSH terms

  • Animals
  • Anti-Inflammatory Agents*
  • Antioxidants*
  • Boraginaceae
  • Cell Death / drug effects
  • Cells, Cultured
  • Cinnamates / pharmacology*
  • Cinnamates / therapeutic use*
  • Cytokines / metabolism
  • Depsides / pharmacology*
  • Depsides / therapeutic use*
  • Diethylhexyl Phthalate / adverse effects*
  • Diethylhexyl Phthalate / toxicity
  • Disease Models, Animal
  • Dose-Response Relationship, Drug
  • Endocrine Disruptors / adverse effects*
  • Endocrine Disruptors / toxicity
  • Hypothyroidism / chemically induced*
  • Hypothyroidism / drug therapy*
  • Hypothyroidism / metabolism
  • Inflammasomes / metabolism*
  • Inflammation Mediators / metabolism
  • Male
  • Phytotherapy*
  • Rats, Sprague-Dawley
  • Thyroid Epithelial Cells / drug effects


  • Anti-Inflammatory Agents
  • Antioxidants
  • Cinnamates
  • Cytokines
  • Depsides
  • Endocrine Disruptors
  • Inflammasomes
  • Inflammation Mediators
  • Diethylhexyl Phthalate
  • rosmarinic acid