The interference of DEHP in precocious puberty of females mediated by the hypothalamic IGF-1/PI3K/Akt/mTOR signaling pathway

Shao, Pu; Wang, Yuzhuo; Zhang, Meng; Wen, Xinggui; Zhang, Jun; Xu, Zhijun; Hu, Min; Jiang, Jinlan; Liu, Te

doi:10.1016/j.ecoenv.2019.06.017

Cited by 36 publications

(27 citation statements)

References 46 publications

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“…The activation of IGF-1R leads to the stimulation of the following two major downstream signalling pathways: (i) the PI3K-AKT-mTOR pathway and (ii) Ras-Raf-MAP pathway 29 . Regarding the relationship between GnRH and the intracellular signalling pathway following IGF-1R, Shao et al investigated the expression of genes and proteins related to the IGF-1 pathway in the rat hypothalamus after combined treatments with di-(2-ethylhexyl) phthalate (DEHP), a common environmental endocrine disruptor 41 . Their study indicated that DEHP might activate the hypothalamic GnRH neurons prematurely through the IGF-1 and IGF-1R/PI3K/AKT/mTOR signalling pathway to promote GnRH release.…”

Section: Discussionmentioning

confidence: 99%

Involvement of IGF-1R-PI3K-AKT-mTOR pathway in increased number of GnRH3 neurons during androgen-induced sex reversal of the brain in female tilapia

Oda

Inoue

Kaneko

et al. 2022

Sci Rep

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The neuroplastic mechanism of sex reversal in the fish brain remains unclear due to the difficulty in identifying the key neurons involved. Mozambique tilapia show different reproductive behaviours between sexes; males build circular breeding nests while females hold and brood fertilized eggs in their mouth. In tilapia, gonadotropin-releasing hormone 3 (GnRH3) neurons, located in the terminal nerve, regulate male reproductive behaviour. Mature males have more GnRH3 neurons than mature females, and these neurons have been indicated to play a key role in the androgen-induced female-to-male sex reversal of the brain. We aimed to elucidate the signalling pathway involved in the androgen-induced increase in GnRH3 neurons in mature female tilapia. Applying inhibitors to organotypic cultures of brain slices, we showed that the insulin-like growth factor (IGF)-1 receptor (IGF-1R)/PI3K/AKT/mTOR pathway contributed to the androgen-induced increase in GnRH3 neurons. The involvement of IGF-1 and IGF-1R in 11-ketotestosterone (11-KT)-induced development of GnRH3 neurons was supported by an increase in Igf-1 mRNA shortly after 11-KT treatment, the increase of GnRH3 neurons after IGF-1 treatment and the expression of IGF-1R in GnRH3 neurons. Our findings highlight the involvement of IGF-1 and its downstream signalling pathway in the sex reversal of the tilapia brain.

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Section: Discussionmentioning

confidence: 99%

Involvement of IGF-1R-PI3K-AKT-mTOR pathway in increased number of GnRH3 neurons during androgen-induced sex reversal of the brain in female tilapia

Oda

Inoue

Kaneko

et al. 2022

Sci Rep

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“…Onuma et al revealed that IGF-1 affects the development of GnRH2 and GnRH3 through IGF-1R in zebra sh embryos. [39] They also examined whether PI3K inhibitors and/or ERK inhibitors disturbed the distribution of GnRH3 neurons in embryos. Treatment of embryos with a PI3K inhibitor (LY294002 or wortmannin) caused abnormal GnRH3 distribution similar to that in IGF signalling-de cient embryos.…”

Section: Discussionmentioning

confidence: 99%

Involvement of IGF-1R-PI3K-AKT-mTOR Pathway in Increased Number of GnRH3 Neurons During Androgen-induced Sex Reversal of the Brain in Female Tilapia

Oda

Kaneko

et al. 2021

Preprint

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The neuroplastic mechanism of sex reversal in the fish brain remains unclear due to the difficulty in identifying the key neurons involved. Mozambique tilapia show different reproductive behaviours between sexes; males build circular breeding nests while females hold and brood fertilized eggs in their mouth. In tilapia, gonadotropin-releasing hormone 3 (GnRH3) neurons, located in the terminal nerve, regulate male reproductive behaviour. Mature males have more GnRH3 neurons than mature females, and these neurons have been indicated to play a key role in the androgen-induced female-to-male sex reversal of the brain. We aimed to elucidate the signalling pathway involved in the androgen-induced increase in GnRH3 neurons in mature female tilapia. Applying inhibitors to organotypic cultures of brain slices, we showed that the insulin-like growth factor (IGF)-1 receptor (IGF-1R)/PI3K/AKT/mTOR pathway contributed to the androgen-induced increase in GnRH3 neurons. The involvement of IGF-1 and IGF-1R in 11-ketotestosterone (11-KT)-induced development of GnRH3 neurons was supported by an increase in Igf-1 mRNA shortly after 11-KT treatment, the increase of GnRH3 neurons after IGF-1 treatment and the expression of IGF-1 in GnRH3 neurons. Our findings highlight the involvement of IGF-1 and its downstream signalling pathway in the sex reversal of the tilapia brain.

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“…The fetal developing hypothalamus is vulnerable to DEHP exposure. For example, perinatal DEHP exposure may alter hypothalamic–pituitary regulation, resulting in reproductive dysfunction and precocious puberty in young rats [ 40 , 41 ]. The relationship between early-life DEHP exposure and socioemotional disorders has been established in humans and rodents.…”

Section: Introductionmentioning

confidence: 99%

Effects of Prenatal Phthalate Exposure and Childhood Exercise on Maternal Behaviors in Female Rats at Postpartum: A Role of Oxtr Methylation in the Hypothalamus

Lee

Lin

Chaudhary

et al. 2021

IJMS

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Both the detrimental effect of prenatal exposure to di-(2-ethylhexyl)-phthalate (DEHP) and the beneficial effects of physical exercise on brain functions have been reported. The oxytocin pathway has been implicated in the onset of maternal behaviors. Epigenetic modification of the oxytocin receptor gene (OXTR) through DNA methylation has been associated with the pathogenesis of neuropsychiatric disorders. The purpose of this study was to investigate the effects of prenatal DEHP exposure on oxytocin-regulated maternal behaviors and to examine the protective effect of exercise. Pregnant rats (F0) were fed with vehicle or DEHP during gestation and the offspring females (F1) were assessed for their maternal behaviors by pup retrieval test at postpartum. The results showed that reduced pup retrieval activities without significant alteration of stress responses were observed in the prenatally DEHP-exposed females. Prenatal DEHP exposure decreased the expressions of oxytocin, Oxtr mRNA, and oxytocin receptor, and increased Oxtr methylation in the hypothalamus of postpartum female rats. There were no significant effects of exercise on behavioral, biochemical, and epigenetic measurements. These results suggest that prenatal DEHP exposure has a long-term adverse effect on maternal behaviors; Oxtr hyper-methylation may be a potential epigenetic mechanism for this alteration, which cannot be prevented by physical exercise during childhood.

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The interference of DEHP in precocious puberty of females mediated by the hypothalamic IGF-1/PI3K/Akt/mTOR signaling pathway

Cited by 36 publications

References 46 publications

Involvement of IGF-1R-PI3K-AKT-mTOR pathway in increased number of GnRH3 neurons during androgen-induced sex reversal of the brain in female tilapia

Involvement of IGF-1R-PI3K-AKT-mTOR pathway in increased number of GnRH3 neurons during androgen-induced sex reversal of the brain in female tilapia

Involvement of IGF-1R-PI3K-AKT-mTOR Pathway in Increased Number of GnRH3 Neurons During Androgen-induced Sex Reversal of the Brain in Female Tilapia

Effects of Prenatal Phthalate Exposure and Childhood Exercise on Maternal Behaviors in Female Rats at Postpartum: A Role of Oxtr Methylation in the Hypothalamus

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