Effects of maternal dietary protein source on liver disease development in rat offspring

Abstract

Background: In utero nutrition and other environmental factors may contribute to the alteration of the fetal development process and to risks of diseases in later life. As the liver is responsible for the regulation of metabolic homeostasis, fetal liver growth programming can be affected by the maternal diet, and the latter can therefore have critical long-term health consequences. Soy proteins have been shown to alleviate metabolic diseases by lowering the triacylglycerol and cholesterol levels. In particular, certain amino acid profiles and isoflavones have been suggested to contribute to the beneficial effects of soy protein isolates on the lipid metabolism. However, very few studies have examined the role of the maternal soy protein isolate diet in association with the early liver development and later risk of disease in offspring. Objectives: The present study investigated the short- and long-term effects of maternal dietary protein source on early liver development and the risks of diseases later in life. To this, the study model was designed to compare the effect of soy protein isolate per se with those of a casein (CAS) as a different protein source or a casein supplemented with genistein. Study 1 and 2 (focusing on the short-term effects) investigated whether the maternal consumption of a low-isoflavone soy protein isolate (SPI) diet or a casein plus genistein (250 mg/kg, GEN) diet would alter the liver development of male rat offspring at 3 weeks of age and examined the changes in the gene expression profiles and epigenetic modification. Study 3 (focusing on the long-term effects) investigated whether the adaptive response of the offspring to chronic ethanol consumption would affect the development of liver disease and cholesterol metabolism later in life. Methods: Female Sprague Dawley rats were fed either a CAS diet (200 g/kg), an SPI diet (200 g/kg), or a GEN diet for two weeks before mating, as well as during pregnancy and lactation. Male offspring were studied at 3 weeks of age (Study 1 and 2 groups: CAS, SPI, and GEN) and at 15 weeks of age (Study 3 groups: CAS/CON, CAS/EtOH, SPI/CON, and SPI/EtOH). For the Study 3, male offspring from the dams receiving either a CAS or SPI diet were fed with the standard chow diet from weaning to 8 weeks of age, and pairs of male offspring originated from the same dam were then fed either an ethanol or pair-fed control liquid diet for 6 weeks. Results: In Study 1, offspring of the SPI group had a significantly lower body weight and body fat mass than those of the CAS and GEN groups at 3 weeks of age, whereas the relative liver weight was higher in the SPI group than in the CAS and GEN groups. In the microarray analysis, the gene expression profiles were distinctly altered in the SPI group as compared to the CAS and GEN groups. Interestingly, the most statistically significant genes involved in xenobiotic and drug metabolism were altered by the SPI group compared to the CAS and GEN groups. Moreover, a significant correlation was found between the relative liver weigh and the gene expression related to xenobiotic and drug metabolism. The SPI group showed a significantly higher serum homocysteine level and lower global DNA methylation than the CAS group. The levels of glycine N-methyltransferase and 5-methyltetrahydrofolate-homocysteine methyltransferase related to one-carbon metabolism were significantly lower in the SPI group than in the CAS group. In addition, significantly lower histone H3-Lysine 9 (H3K9) trimethylation and higher H3K9 acetylation levels were observed in the SPI group than in the CAS and GEN groups. In Study 2, serum and hepatic triacylglycerol and cholesterol levels were significantly lowered in dams fed the SPI diet as compared to those fed the CAS diet. Similarly, the SPI group showed lower serum triacylglycerol and cholesterol levels than the CAS group. The specific gene expression responses altered by the SPI diet were associated with the peroxisome proliferator-activated receptor alpha signaling that contributes to the hypolipidemic effect. Interestingly, these gene expression changes were associated with the relative liver weight of the offspring. In Study 3, relatively severe liver damage was observed later in life in the SPI/EtOH group compared to the CAS/EtOH group. The activities of the aminotransferases were higher in the SPI/EtOH group than in the CAS/EtOH group. The expression of the genes involved in the endoplasmic reticulum stress and inflammatory response was higher in the SPI/EtOH group. Moreover, the one-carbon metabolism was more affected in the SPI/EtOH group. Interestingly, serum cholesterol level was lower in the SPI/EtOH group than in the CAS/EtOH group, and that there was a significant correlation between liver damage indicators and the gene expression related to HDL-cholesterol metabolism. However, the lipid-lowering effect observed in the 3-week-old offspring of the SPI group disappeared in the control group at 15 weeks of age. Conclusion: Liver development and growth process of male offspring at 3 weeks of age were affected by the maternal SPI diet. When male offspring were exposed to ethanol later in life, the potential effect of the maternal diet was sustainable, so that offspring from dams fed the SPI diet developed severe liver damage in comparison with offspring from dams fed the CAS diet. Taken together, this study showed that maternal dietary protein source may be responsible for the retarded liver development and growth in early life, which may influence the offsprings susceptibility to the development of liver disease in later life.