DEHP is reported to cause
precocious puberty of females in both humans and rodents, but the underlying mechanisms were largely unknown. This study was designed to clarify the effects and the mechanisms of
DEHP on the pathogenesis of
sexual precocity. Prepubertal female rats were treated with
DEHP for 4 weeks. Key organs were analyzed in control conditions and after exposure to 0.2, 1, and 5 mg/kg/day
DEHP in pubertal female rats. To determine the role of the IGF-1/PI3K/Akt/mTOR signaling pathway in
DEHP-induced female
precocious puberty, 36 rats were treated with 5 mg/kg/day
DEHP to establish a model of female
precocious puberty. And we investigated the expression of genes and
proteins related to
IGF-1 pathway in rat hypothalamus
after treatment with inhibitors. In the present study, we observed that
DEHP treatment resulted in earlier vaginal opening time, higher number of Nissl bodies in the hypothalamus neurons, lower apoptosis of hypothalamic cells, higher
IGF-1 and
GnRH levels in the serum and hypothalamus.
DEHP could also upregulated the expression of IGF-1/PI3K/Akt/mTOR pathway and
GnRH in the hypothalamus of adolescent female rats, and inhibition of IGF-1R and mTOR in hypothalamus could block the activation of Kiss-1, GPR54, and
GnRH by
DEHP. In summary, our study suggested that
DEHP might activate the hypothalamic
GnRH neurons prematurely through the
IGF-1 signaling pathway and promote
GnRH release, leading to the initiation of female sexual development. Our results provide a new molecular mechanism underlying reproductive and developmental toxicity in pubertal female rats induced by
DEHP.