Prenatal nicotine exposure-induced intrauterine programming alteration increases the susceptibility of high-fat diet-induced non-alcoholic simple fatty liver in female adult offspring rats

Abstract

Previous studies have indicated that the intrauterine growth retardation (IUGR) fetus is faced with a high susceptibility to adult metabolic syndrome (MS). Non-alcoholic simple fatty liver (NAFL) is considered to be the hepatic manifestation of MS. In the present study, we evaluated the susceptibility of high-fat dietinduced NAFL in female adult IUGR offspring rats, induced by prenatal nicotine exposure, and we further explored the underlying intrauterine programming mechanism for this phenomenon. The IUGR rat model was established by prenatal exposure to nicotine (2 mg kg −1 d −1 ), the liver tissues from female fetuses and female adult offspring fed with normal or high-fat diets were collected. The female adult offspring in the nicotine-exposed group showed low birth weights and postnatal catch-up growth, as well as severe NAFL under high-fat diets. Moreover, increased gene expression involved in the hepatic insulin-like growth factor 1 (IGF1) pathway, gluconeogenesis and lipid synthesis, and decreased gene expression of lipid output accompanied with elevated serum triglyceride levels, was observed. The female fetuses in the nicotine-exposed group showed down-regulated hepatic IGF1 pathways, and also exhibited similar patterns of increased gluconeogenesis, lipid synthesis and decreased lipid output to those in the adults. The present study demonstrates the intrauterine origin of increased susceptibility to high-fat diet-induced NAFL in female offspring rats by prenatal nicotine exposure, which is most likely mediated by "two intrauterine programming". That is, the first glucocorticoid-IGF1 axis programming induces postnatal catch-up growth, aggravates glucose and lipid metabolic disorders, and leads to an increased susceptibility to adult NAFL, while the second hepatic glucose and lipid metabolic programming enhances hepatic lipogenesis and reduces lipid oxidation and output, promoting NAFL. † Electronic supplementary information (ESI) available. See

Prenatal caffeine exposure-induced adrenal developmental abnormality in male offspring rats and its possible intrauterine programming mechanisms

“…35,36 Recently, combined with our previous reports that prenatal caffeine, nicotine and ethanol exposure could cause fetal rats' over-exposure to maternal GC and increase the susceptibility to adult MS-related NAFLD in IUGR offspring, we proposed a "GC-IGF1 axis programming" hypothesis in the liver of IUGR offspring. 12,37,38 In the present study, we also found that the PCE male offspring in utero showed a high serum GC level but a lower serum IGF1 level; after birth, the serum CORT level increased but the serum IGF1 level reduced from PD1 to PD35, and then the serum CORT level gradually decreased but the serum IGF1 level gradually increased from PD60 to PD168. Meanwhile, there were good opposite changes between the serum CORT levels and adrenal IGF1 signaling pathway expression before or after birth.…”

Prenatal nicotine exposure induced GDNF/c-Ret pathway repression-related fetal renal dysplasia and adult glomerulosclerosis in male offspring

“…"The glucocorticoid and insulin-like growth factor 1 (GC-IGF1) axis programming" was a hypothesis we proposed to explain the susceptibility to metabolic diseases in adult offspring by prenatal xenobiotics exposure. 25,26,28,69,70 Accordingly, PNE could result in the over-exposure of the fetus to maternal GC levels, and thereby down-regulates the IGF1 signaling pathway and gives rise to IUGR; after birth, the offspring are exposed to a low-GC-level environment due to the low function of the hypothalamic-pituitary-adrenal (HPA) axis, which in turn enhances the IGF1 signaling pathway and leads to "catch-up" growth as well as increased susceptibility to NAFLD. 28 In this study, there was a moderate "catch-up" growth in the PNE offspring.…”

“…25,26,28,69,70 Accordingly, PNE could result in the over-exposure of the fetus to maternal GC levels, and thereby down-regulates the IGF1 signaling pathway and gives rise to IUGR; after birth, the offspring are exposed to a low-GC-level environment due to the low function of the hypothalamic-pituitary-adrenal (HPA) axis, which in turn enhances the IGF1 signaling pathway and leads to "catch-up" growth as well as increased susceptibility to NAFLD. 28 In this study, there was a moderate "catch-up" growth in the PNE offspring. As the renal IGF1 signaling pathway is critical for fetal kidney development and has a direct effect on the postnatal compensatory renal growth of IUGR individuals, 71 accompanied by the evidence that IGF1 could increase AT 1 R and AT 2 R expressions in vascular smooth muscle cells, [72][73][74] we speculate that renal ATR expression may be regulated by the renal IGF1 signaling pathway.…”

“…Our previous studies indicated that prenatal nicotine exposure (PNE) could lead to IUGR and increase the susceptibility to the metabolic syndrome, such as non-alcoholic fatty liver disease (NAFLD), in offspring rats. [24][25][26][27][28] Some studies also suggested that PNE might enhance angiotensin II-induced vasoconstriction in adult offspring by stimulating ATR, 29,30 which may produce glomerular hypertension, thereby decreasing renal function. 31,32 In the present study, we were interested in whether PNE could lead to glomerulosclerosis of adult offspring and in the underlying mechanism through renal ATR dysregulation.…”

A study of the consequences of early gestational ethanol and/or nicotine exposure in the mouse

“…Prenatal exposure to nicotine has been reported to result in changes to offspring growth (Wang et al, 2008), metabolic outcomes (Gao et al, 2005;Holloway et al, 2005;Somm et al, 2008Somm et al, , 2009Ma et al, 2014;Xu et al, 2015), cognitive behaviour (Ernst et al, 2001;Alkam et al, 2013), locomotor activity (Pauly et al, 2004), nicotine preference (Klein et al, 2003), genital development (Gyekis et al, 2010), vulnerability to hypoxia (Li et al, 2012), asthma (Rehan et al, 2012), neuroanatomy (Chen et al, 2005;Mychasiuk et al, 2014), and immune function (Basta et al, 2000). Given the increasing usage of nicotine substitutes within the Australian population, it is imperative to better establish the safety, or lack thereof for the use of these products during pregnancy.…”