The mechanism underlying dibutyl phthalate induced shortened anogenital distance and hypospadias in rats

Li, Ning; Chen, Xuyong; Zhou, Xuefeng; Zhang, Wen; Yuan, Jianming; Feng, Jiexiong

doi:10.1016/j.jpedsurg.2015.08.046

Cited by 21 publications

(9 citation statements)

References 19 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In this study, DBP was used to treat pregnant SD rats to induce hypospadias, and we observed the decreased birth weight, shortened AGD, as well as the reduced ratio of AGD/ weight, meanwhile, the incidence of hypospadias was 43.49% in the fetal male rats induced by DBP, suggesting that the hypospadias model was successfully constructed via prenatal exposure to DBP in rats, thereby verifying the toxicity of DBP to offspring development, which was in accordance with previous studies [20,21]. In addition, the apoptosis in the GT of fetal male rats with hypospadias by TUNEL method were also found to be significantly decreased than normal fetal rats.…”

Section: Discussionsupporting

confidence: 90%

Role of PERK‐eIF2α signaling pathway in fetal male rats with hypospadias induced by di‐n‐butyl phthalate

Zhao

Liu

2018

The Kaohsiung J of Med Scie

View full text Add to dashboard Cite

This study aims to explore the role of PERK-eIF2α signaling pathway in fetal male rats with hypospadias induced by maternal exposure to di-n-butyl phthalate (DBP). DBP was used to treat pregnant SD rats by gastric intubation from gestation day (GD) 14-18 to construct a hypospadias rat model. The amount, weight, anogenital distance (AGD), and hypospadias incidence of rats were recorded and the genital tubercle (GT) of fetal male rats was collected on GD 19. Western blotting was performed to detect the expressions of PERK-eIF2α pathway- and autophagy-related proteins, and cell apoptosis was detected using TUNEL method. Then, GT fibroblasts of fetal rats were obtained and transfected with PERK-siRNA to detect cell apoptosis and autophagy in each transfected group. The incidence of hypospadias was 43.49% in fetal male rats induced by DBP. The fetal rats in DBP group presented the decreased birth weight and anogenital distance (AGD)/body weight ratio than the Control group (all P < 0.05). Further, p-PERK, p-eIF2α and ATF4 protein expressions and the ratio of LC3-II/LC3-I were greatly increased in the GTs of fetal rats, while apoptosis index (AI) and P62 protein expression were evidently decreased (all P < 0.05). In addition, the apoptosis rate was increased in GT fibroblasts after transfection of PERK-siRNA with the increased P62 and reduced LC3-II/LC3-I ratio (all P < 0.05). Activation of PERK-eIF2α signaling pathway can influence the GT development of fetal male rats with hypospadias induced by DBP through activation of autophagy and inhibition of apoptosis.

show abstract

Section: Discussionsupporting

confidence: 90%

Role of PERK‐eIF2α signaling pathway in fetal male rats with hypospadias induced by di‐n‐butyl phthalate

Zhao

Liu

2018

The Kaohsiung J of Med Scie

View full text Add to dashboard Cite

show abstract

“…Such sex-specific toxicity may be due to anti-androgen effects of DBP. DBP exposure can induce testicular dysgenesis, delay testicular development, and affect testosterone secretion in rat embryos (Li et al 2015 ) . It is known that male genitalia development is androgen-dependent and disruption of the androgen signaling pathway leads to feminization of male external genitalia, such as hypospadias (Mylchreest et al 2000 ;Steinhardt 2004; Wang and Baskin 2008).…”

Section: Discussionmentioning

confidence: 99%

Di-n-butyl phthalate induced hypospadias relates to autophagy in genital tubercle via the PI3K/Akt/mTOR pathway

Zhang

et al. 2017

Journal of Occupational Health

View full text Add to dashboard Cite

Objective:To explore the mechanisms of hypospadias induced by in utero exposure to din-butyl phthalate (DBP ) . Methods : Timed-pregnant SpragueDawley rats were administered 750 mg / kg of DBP by gavage from GD (gestation days) 13 to GD 18, whereas control group received corn oil. Genital tubercles (GTs) and blood samples were collected from male fetuses on GD 19. The serum testosterone concentration, apoptosis activity, autophagosomes and their related proteins (light chain 3 (LC3-I, LC3-II) ), and sequestosomes (SQSTM1/ p62) in the GTs were then measured. Protein expression of protein kinase B (Akt), Beclin 1, phosphorylated Akt (p-Akt), p-S6, and phosphorylated mammalian target of rapamycin (p-mTOR) in the GTs were analyzed by Western blotting. Results: The incidence of hypospadias induced by DBP was 43.64% in male fetuses. The GT volume and GT volume/body weight of fetuses were significantly reduced in the hypospadias and the nonhypospadias groups. Apoptotic cell number was significantly decreased in the GTs of the hypospadias group, but unchanged in the non-hyposadias group. The ratio of LC3-II/LC3-I was higher in the GTs from DBP exposed fetuses compared to the control group. The ratio of LC3-II/LC3-I in the GTs was higher in the hypospadias group than in the non-hypospadias group. The number of autophagosomes was increased in the GTs of the hypospadias group. Protein expression of p-S6, p-mTOR, and p-Akt were significantly decreased in the GTs of hypospadiac rats. Conclusions: DBP-induced hypospadias might be associated with apoptosis and autophagy mediated by the PI3K/Akt/mTOR signaling pathway in the GT.

show abstract

“…In the rat model, various substances have been administered to pregnant females to evaluate the impact on reproductive organ development in the offspring. [23,24,25]. When the pregnant female rat received flutamide (androgen receptor antagonist) or dibutylphthalate [24,25] the AGD at birth was shorter in male offspring.…”

Section: Discussionmentioning

confidence: 99%

“…[23,24,25]. When the pregnant female rat received flutamide (androgen receptor antagonist) or dibutylphthalate [24,25] the AGD at birth was shorter in male offspring. Exposure to phthalates was also associated with a higher prevalence of cryptorchidism and hypospadias [24].…”

Section: Discussionmentioning

confidence: 99%

First-trimester determination of fetal gender by ultrasound: measurement of the ano-genital distance

Arfi

Cohen

Canlorbe

et al. 2016

European Journal of Obstetrics & Gynecology and Reproductiv

View full text Add to dashboard Cite

show abstract

The mechanism underlying dibutyl phthalate induced shortened anogenital distance and hypospadias in rats

Cited by 21 publications

References 19 publications

Role of PERK‐eIF2α signaling pathway in fetal male rats with hypospadias induced by di‐n‐butyl phthalate

Role of PERK‐eIF2α signaling pathway in fetal male rats with hypospadias induced by di‐n‐butyl phthalate

Di-n-butyl phthalate induced hypospadias relates to autophagy in genital tubercle via the PI3K/Akt/mTOR pathway

First-trimester determination of fetal gender by ultrasound: measurement of the ano-genital distance

Contact Info

Product

Resources

About