Subchronic exposure to di-(2-ethylhexyl) phthalate (DEHP) elicits blood-brain barrier dysfunction and neuroinflammation in male C57BL/6J mice.

BACKGROUND: Exposure to di-(2-ethylhexyl) phthalate (DEHP) can cause neurotoxicity but the mechanism is not clear. Blood brain barrier (BBB) is one of the most important tissues to protect the brain. However, whether DEHP can disrupt the BBB or not remains unclear. The objective of this study is to investigate the potential effects of subchronic DEHP exposure on BBB integrity and discuss the role of BBB in DEHP inducible neurotoxicity with an emphasis on neuroinflammatory responses. Male adult C57BL/6J mice were orally administered with vehicle or 200 or 750 mg/kg/day DEHP for 90 days. Subchronic exposure to high-dose DEHP increased water intake but decreased body weight and brain weight. The concentrations of DEHP metabolites increased in serum from all DEHP-exposed groups while increased in brain only from the high-dose group. DEHP induced neurobehavioural alterations and damaged hippocampal neurons. DEHP increased BBB permeability by Evans blue (EB) extravasation and decreased tight junction proteins (ZO-1, occludin, and claudin-5) while presenting a neuroinflammatory feature characterized by the upregulated inflammatory mediators TNF-α and the NLRP3/caspase-1/IL-1ß inflammasome pathway. Our data provide new insights into neurotoxicity caused by subchronic DEHP exposure, which is probably involved in BBB dysfunction and neuroinflammatory responses.

Di-(2-ethylhexyl) phthalate inhibits expression and internalization of transthyretin in human placental trophoblastic cells.

During pregnancy, fetal thyroid hormones (THs) are dependent on maternal placental transport and their physiological level is crucial for normal fetal neurodevelopment. Earlier research has shown that Di-(2-ethylhexyl) phthalate (DEHP) disrupts thyroid function and THs homeostasis in pregnant women and fetuses, and affects placental THs transport. However, the underlying mechanisms are poorly understood. The present study, therefore, aimed to systematically investigate the potential mechanisms of DEHP-induced disruption in the placental THs transport using two human placental trophoblastic cells, HTR-8/SVneo cells and JEG-3 cells. While the exposure of DEHP at the doses of 0-400 µM for 24 h did not affect cell viability, we found reduced consumption of T3 and T4 in the culture medium of HTR-8/Svneo cells treated with DEHP at 400 µM. DEHP treatment did not affect T3 uptake and the expression of monocarboxylate transporters 8 (MCT8) and organic anion transporters 1C1 (OATP1C1). However, DEHP significantly inhibited transthyretin (TTR) internalization, down-regulated TTR, deiodinase 2 (DIO2), and thyroid hormone receptors mRNA expression and protein levels, and up-regulated deiodinase 3 (DIO3) protein levels in a dose-dependent manner. These results indicate that DEHP acts on placental trophoblast cells, inhibits its TTR internalization, down-regulates TTR expression and affects the expression of DIO2, DIO3, and thyroid hormone receptor. These may be the mechanisms by which PAEs affects THs transport through placental.