Abstract
This study was to determine the impact of maternal exposure to di-n-butyl phthalate (DBP) on renal development and fibrosis in adult offspring. Pregnant rats received DBP at a dose of 850 mg/kg BW/day by oral perfusion during gestational days 14–18. In DBP exposed newborn offspring, gross observation and histopathological examination revealed the dysplasia of kidney. The expression of genes related to renal development was also changed. In DBP exposed adult offspring, histopathological examination and Masson's trichrome staining revealed the pathological changes of renal fibrosis. Furthermore, higher expression levels of transforming growth factor- β (TGF-β) and alpha-smooth muscle actin (α-SMA) were also detected. In vitro studies reveal that DBP promoted the activation of NRK49F cells and G2/M arrest in NRK52E cells at a sublethal dose. The effect of DBP on these cell lines was linked to the generation of oxidative stress. In addition, DBP induced oxidative stress in both renal fibroblasts and tubular epithelial cells, whereas vitamin C ameliorated the changes caused by DBP. In conclusion, our results showed that prenatal exposure to DBP may generate oxidative stress in both renal fibroblasts and tubular epithelial cells, leading to kidney dysplasia and renal fibrosis.
Highlights
It is estimated that 8–16% of adults in the world have chronic kidney disease (CKD), which is characterized by relentless deposition of extracellular matrix and progressive tubulointerstitial fibrosis (TIF)
The effect of di-n-butyl phthalate (DBP) on these cell lines was linked to the generation of oxidative stress
Maternal DBP exposure led to upregulation of the mRNA expression of other genes, including bone morphogenetic protein 4 (Bmp4), cadherin 11 (Cdh11), tyrosine 3-monooxygenase/tryptophan 5-monooxygenase activation protein, beta (Ywhab) and calmodulin 1 (Calm1) (Figure 1E)
Summary
It is estimated that 8–16% of adults in the world have chronic kidney disease (CKD), which is characterized by relentless deposition of extracellular matrix and progressive tubulointerstitial fibrosis (TIF). In addition to the two conventional factors, genes and the environment, which contribute to the etiology of diseases, increasing evidence suggests that prenatal (intrauterine) procedures have a profound effect on subsequent organ function and adult disease [5]. The ‘Developmental Origins of Health and Adult Disease’ (DOHAD) hypothesis proposes that environmental stimulation on organ development in uterus may have permanent adverse effects and increase risks of specific diseases in adult life [6,7]. The role of an adverse intrauterine environment in developmental programming can be applied to CKD in the adult [12]. It is reported that LBW is related to the increased risk of adultonset diseases (including renal function disorder) [13]
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