Two intrauterine programming mechanisms of adult hypercholesterolemia induced by prenatal nicotine exposure in male offspring rats

Abstract

Epidemiologic studies showed that low birth weight is associated with high cholesterol and an increased risk of cardiovascular diseases in adulthood. This study aimed to elucidate the intrauterine programming mechanisms of adult hypercholesterolemia. The results showed that prenatal nicotine exposure (PNE) caused intrauterine growth retardation and hypercholesterolemia in male adult offspring rats. Hepatic cholesterol synthesis and output were deceased in utero but increased in adults; hepatic reverse cholesterol transport (RCT) persistently deceased before and after birth. Meanwhile, PNE elevated serum corticosterone level and decreased hepatic IGF1 pathway activity in male fetuses, whereas converse changes were observed in male adults. The chronic stress model and cortisol-treated HepG2 cells verified that excessive glucocorticoid (GC)-induced GC-IGF1 axis programming enhanced hepatic cholesterol synthesis and output. In addition, PNE decreased the expression of specific protein 1 and P300 enrichment and H3K27 acetylation at the promoter region of genes responsible for RCT both in fetal and adult, male livers and reduced expression of those genes, similar alterations were also confirmed in cortisol-treated HepG2 cells, suggesting that excessive GC-related programming induced continuous RCT reduction by epigenetic modification. Taken together, the "2-programming" approach discussed above may ultimately contribute to the development of hypercholesterolemia in male adult offspring.-Zhou, J., Zhu, C., Luo, H., Shen, L., Gong, J., Wu, Y., Magdalou, J., Chen, L., Guo, Y., Wang, H. Two intrauterine programming mechanisms of adult hypercholesterolemia induced by prenatal nicotine exposure in male offspring rats.

Synergistic effects of prenatal nicotine exposure and post‐weaning high‐fat diet on hypercholesterolaemia in rat offspring of different sexes

“…A series of our previous studies confirmed that PNE enhances maternal serum GC level, inhibits GC inactivation in placenta barrier, and subsequently raises maternal‐originated GC concentration in foetal blood, and consequently inhibits development of neuroendocrine metabolic function. Our recent study found that expression of SR‐B1 and LDLR in PNE foetal liver was significantly lower than that in the control, and we also detected low histone acetylation at promoter regions of these two genes, which indicated that epigenetic modification was probably involved in PNE‐induced programming alteration of cholesterol reverse transportation genes. Intrauterine programming of neuroendocrine metabolism results in glucose and lipid metabolic disorder, which may continue after birth and increase progeny susceptibility to MS …”

“…Our recent work found that serum corticosterone of PNE pup increased significantly in uterine, but decreased in adulthood. In contrast, IGF1 level increased after birth, accompanied by an enhanced mRNA expression of HMGCR and ApoB . Incubation with IGF1 also increased ApoB expression in HepG2 cells …”

Paternal Nicotine/Ethanol/Caffeine Mixed Exposure Induces Offspring Rat Dysplasia and Its Potential “GC-IGF1” Programming Mechanism

“…Reproductive function inhibition of male rats under long-term chronic stress is associated with increased serum corticosterone levels [ 60 , 61 ]. Our previous study found that prenatal exposure to nicotine, ethanol, or caffeine induced multi-organ dysplasia in offspring mainly attributed to an activated maternal HPA axis [ 62 , 63 , 64 ]. In this study, we found that the body weight and growth rate of paternal rats in the PME group were gradually decreased in a time-dependent manner but the activity of the HPA axis and the function of adrenal steroid synthesis were significantly increased.…”

Prenatal Nicotine Exposure Induces Low Birthweight and Hyperinsulinemia in Male Rats

“…Pumps were loaded with nicotine (Wako Pure Chemical Industries, Ltd., Kyoto, Japan), formulated in saline, at a concentration designed to deliver the drug at an initial dose rate of 3 mg nicotine/kg bodyweight/day for 28 days (starting from one week before the projected mating day through the day of delivery). Several previous papers have reported administration of nicotine to pregnant rat dams at doses ranging from 1 to 5 mg/kg bodyweight/day (19)(20)(21). For the present study, we selected a nicotine dose level of 3 mg nicotine/kg bodyweight/day per pregnant rat dams based on preliminary experiments at various dose level; notably, these data (not shown) are not detected a difference in mean food intake, and gestational age between dams maintained on vehicle compared to those maintained on nicotine at 3 mg nicotine/kg bodyweight/day.…”