In the present study, the neurotoxicity and mechanisms of di-(2-ethylhexyl)
phthalate (
DEHP) exposure on pubertal normal (P-normal) and pubertal
type 2 diabetes mellitus (P-T2DM) mice were investigated by typical neurobehavioral methods and transcriptome analysis. Pubertal male ICR mice were orally exposed to
DEHP (0.18, 1.8, 18 and 180 mg/kg/d) for 3 weeks. In Open field test,
DEHP significantly increased the time in central area staying and decreased the total distance and clockwise (CW) rotation of P-normal and P-T2DM mice. Morris water maze showed that
DEHP significantly increased the latency in locating platform and decreased the original platform quadrant and residence time in target quadrant of P-normal and P-T2DM mice. Transcriptome analysis results revealed the effects of
DEHP exposure on neural signaling pathway including
biogenic amines neurotransmitters, nerve receptors, neurobiological processes, etc.
Enzyme-linked
immunosorbent assay (ELISA) and western blotting results showed that
DEHP significantly decreased the contents of
5-HT, cAMP,
GABA and Ca2+, the levels of CREB, phosphorylation of PKA, ERK1/2 and CREB, increased the levels of CaM and phosphorylation of
CaMKII in P-normal and P-T2DM mice. Factorial analysis results showed that P-T2DM mice were more sensitive than those of P-normal mice. The potential neurotoxicity mechanism of
DEHP may be synergistically mediated by the cAMP-PKA-ERK1/2-CREB signaling and the Ca2+ signaling pathway.