TY  - JOUR
A1  - Hocher, Berthold
A1  - Haumann, Hannah
A1  - Rahnenführer, Jan
A1  - Reichetzeder, Christoph
A1  - Kalk, Philipp
A1  - Pfab, Thiemo
A1  - Tsuprykov, Oleg
A1  - Winter, Stefan
A1  - Hofmann, Ute
A1  - Li, Jian
A1  - Püschel, Gerhard Paul
A1  - Lang, Florian
A1  - Schuppan, Detlef
A1  - Schwab, Matthias
A1  - Schaeffeler, Elke
T1  - Maternal eNOS deficiency determines a fatty liver phenotype of the offspring in a sex dependent manner
JF  - Epigenetics : the official journal of the DNA Methylation Society
N2  - Maternal environmental factors can impact on the phenotype of the offspring via the induction of epigenetic adaptive mechanisms. The advanced fetal programming hypothesis proposes that maternal genetic variants may influence the offspring's phenotype indirectly via epigenetic modification, despite the absence of a primary genetic defect. To test this hypothesis, heterozygous female eNOS knockout mice and wild type mice were bred with male wild type mice. We then assessed the impact of maternal eNOS deficiency on the liver phenotype of wild type offspring. Birth weight of male wild type offspring born to female heterozygous eNOS knockout mice was reduced compared to offspring of wild type mice. Moreover, the offspring displayed a sex specific liver phenotype, with an increased liver weight, due to steatosis. This was accompanied by sex specific differences in expression and DNA methylation of distinct genes. Liver global DNA methylation was significantly enhanced in both male and female offspring. Also, hepatic parameters of carbohydrate metabolism were reduced in male and female offspring. In addition, male mice displayed reductions in various amino acids in the liver. Maternal genetic alterations, such as partial deletion of the eNOS gene, can affect liver metabolism of wild type offspring without transmission of the intrinsic defect. This occurs in a sex specific way, with more detrimental effects in females. This finding demonstrates that a maternal genetic defect can epigenetically alter the phenotype of the offspring, without inheritance of the defect itself. Importantly, these acquired epigenetic phenotypic changes can persist into adulthood.
KW  - Epigenetics
KW  - eNOS
KW  - Fetal programming
KW  - fatty liver
KW  - metabolism
Y1  - 2016
U6  - https://doi.org/10.1080/15592294.2016.1184800
SN  - 1559-2294
SN  - 1559-2308
VL  - 11
SP  - 539
EP  - 552
PB  - Routledge, Taylor & Francis Group
CY  - Philadelphia
ER  - 
TY  - JOUR
A1  - Reichetzeder, Christoph
A1  - Chen, Hong
A1  - Foeller, Michael
A1  - Slowinski, Torsten
A1  - Li, Jian
A1  - Chen, You-Peng
A1  - Lang, Florian
A1  - Hocher, Berthold
T1  - Maternal vitamin D deficiency and fetal programming - lessons learned from humans and mice
JF  - Kidney & blood pressure research : official organ of the Gesellschaft für Nephrologie
N2  - Background/Aims: Cardiovascular disease partially originates from poor environmental and nutritional conditions in early life. Lack of micronutrients like 25 hydroxy vitamin D-3 (25OHD) during pregnancy may be an important treatable causal factor. The present study explored the effect of maternal 25OHD deficiency on the offspring. Methods: We performed a prospective observational study analyzing the association of maternal 25OHD deficiency during pregnancy with birth outcomes considering confounding. To show that vitamin D deficiency may be causally involved in the observed associations, mice were set on either 25OHD sufficient or insufficient diets before and during pregnancy. Growth, glucose tolerance and mortality was analyzed in the F1 generation. Results: The clinical study showed that severe 25OHD deficiency was associated with low birth weight and low gestational age. ANCOVA models indicated that established confounding factors such as offspring sex, smoking during pregnancy and maternal BMI did not influence the impact of 25OHD on birth weight. However, there was a significant interaction between 25OHD and gestational age. Maternal 25OHD deficiency was also independently associated with low APGAR scores 5 minutes postpartum. The offspring of 25OHD deficient mice grew slower after birth, had an impaired glucose tolerance shortly after birth and an increased mortality during follow-up. Conclusions: Our study demonstrates an association between maternal 25OHD and offspring birth weight. The effect of 25OHD on birth weight seems to be mediated by vitamin D controlling gestational age. Results from an animal experiment suggest that gestational 25OHD insufficiency is causally linked to adverse pregnancy outcomes. Since birth weight and prematurity are associated with an adverse cardiovascular outcome in later life, this study emphasizes the need for novel monitoring and treatment guidelines of vitamin D deficiency during pregnancy.
KW  - Vitamin D
KW  - Birth weight
KW  - Preterm delivery
KW  - Fetal programming
KW  - Glucose tolerance
KW  - Cardiovascular diseases
Y1  - 2014
U6  - https://doi.org/10.1159/000355809
SN  - 1420-4096
SN  - 1423-0143
VL  - 39
IS  - 4
SP  - 315
EP  - 329
PB  - Karger
CY  - Basel
ER  -