title: Dietary Chromium Restriction of Pregnant Mice Changes the Methylation Status of Hepatic Genes Involved with Insulin Signaling in Adult Male Offspring.
abstract: Maternal undernutrition is linked with an elevated risk of diabetes mellitus in offspring regardless of the postnatal dietary status. This is also found in maternal micro-nutrition deficiency, especial chromium which is a key glucose regulator. We investigated whether maternal chromium restriction contributes to the development of diabetes in offspring by affecting DNA methylation status in liver tissue. After being mated with control males, female weanling 8-week-old C57BL mice were fed a control diet (CON, 1.19 mg chromium/kg diet) or a low chromium diet (LC, 0.14 mg chromium/kg diet) during pregnancy and lactation. After weaning, some offspring were shifted to the other diet (CON-LC, or LC-CON), while others remained on the same diet (CON-CON, or LC-LC) for 29 weeks. Fasting blood glucose, serum insulin, and oral glucose tolerance test was performed to evaluate the glucose metabolism condition. Methylation differences in liver from the LC-CON group and CON-CON groups were studied by using a DNA methylation array. Bisulfite sequencing was carried out to validate the results of the methylation array. Maternal chromium limitation diet increased the body weight, blood glucose, and serum insulin levels. Even when switched to the control diet after weaning, the offspring also showed impaired glucose tolerance and insulin resistance. DNA methylation profiling of the offspring livers revealed 935 differentially methylated genes in livers of the maternal chromium restriction diet group. Pathway analysis identified the insulin signaling pathway was the main process affected by hypermethylated genes. Bisulfite sequencing confirmed that some genes in insulin signaling pathway were hypermethylated in livers of the LC-CON and LC-LC group. Accordingly, the expression of genes in insulin signaling pathway was downregulated. There findings suggest that maternal chromium restriction diet results in glucose intolerance in male offspring through alterations in DNA methylation which is associated with the insulin signaling pathway in the mice livers.
authors.affiliation: Key Laboratory of Endocrinology, Translational Medicine Centre, Ministry of Health, Department of Endocrinology, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China.
authors.forename: Qian
authors.initials: Q
authors.lastname: Zhang
authors.affiliation: Department of Endocrinology, the Affiliated Hospital of Qingdao University, Qingdao, Shandong, China.
authors.forename: Xiaofang
authors.initials: X
authors.lastname: Sun
authors.affiliation: Key Laboratory of Endocrinology, Translational Medicine Centre, Ministry of Health, Department of Endocrinology, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China.
authors.forename: Xinhua
authors.initials: X
authors.lastname: Xiao
authors.affiliation: Key Laboratory of Endocrinology, Translational Medicine Centre, Ministry of Health, Department of Endocrinology, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China.
authors.forename: Jia
authors.initials: J
authors.lastname: Zheng
authors.affiliation: Key Laboratory of Endocrinology, Translational Medicine Centre, Ministry of Health, Department of Endocrinology, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China.
authors.forename: Ming
authors.initials: M
authors.lastname: Li
authors.affiliation: Key Laboratory of Endocrinology, Translational Medicine Centre, Ministry of Health, Department of Endocrinology, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China.
authors.forename: Miao
authors.initials: M
authors.lastname: Yu
authors.affiliation: Key Laboratory of Endocrinology, Translational Medicine Centre, Ministry of Health, Department of Endocrinology, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China.
authors.forename: Fan
authors.initials: F
authors.lastname: Ping
authors.affiliation: Key Laboratory of Endocrinology, Translational Medicine Centre, Ministry of Health, Department of Endocrinology, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China.
authors.forename: Zhixin
authors.initials: Z
authors.lastname: Wang
authors.affiliation: Key Laboratory of Endocrinology, Translational Medicine Centre, Ministry of Health, Department of Endocrinology, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China.
authors.forename: Cuijuan
authors.initials: C
authors.lastname: Qi
authors.affiliation: Key Laboratory of Endocrinology, Translational Medicine Centre, Ministry of Health, Department of Endocrinology, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China.
authors.forename: Tong
authors.initials: T
authors.lastname: Wang
authors.affiliation: Key Laboratory of Endocrinology, Translational Medicine Centre, Ministry of Health, Department of Endocrinology, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China.
authors.forename: Xiaojing
authors.initials: X
authors.lastname: Wang
mesh_terms: D000818:Animals; D002857:Chromium / Q000172:deficiency*; D019175:DNA Methylation; D005260:Female; D005947:Glucose / Q000378:metabolism; D007328:Insulin / Q000378:metabolism*; D008099:Liver / Q000378:metabolism*; D008297:Male; D039382:Maternal Nutritional Physiological Phenomena / Q000235:genetics*; D051379:Mice; D008810:Mice, Inbred C57BL; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction; D014131:Trace Elements / Q000172:deficiency*
chemical_list: D007328:Insulin; D014131:Trace Elements; D002857:Chromium; D005947:Glucose