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Maternal Cholesterol Deficiency Predisposes Congenital Heart Defect Risk

ABSTRACT: The relationship between maternal cholesterol deficiency and the risk of congenital heart defects (CHD) in offspring is not fully understood. In a birth cohort study of 5,041 family trios, we found that low maternal cholesterol levels were significantly associated with an increased risk of CHD, with relative risk (RR) of 1.52 in the second trimester and 1.73 in the third trimester. To further investigate this link, we treated pregnant mice with cholesterol-lowering agents, namely ezetimibe or atorvastatin. Both treatments led to a significant increase in the incidence of CHD in their offspring. To identify a pathogenic variant that could provide genetic evidence linking cholesterol synthesis to CHD occurrence and serve as a target for constructing genetic mouse models, we performed whole-genome sequencing (WGS) on 103 CHD cases from the birth cohort. We identified a recurrent functional variant in the CYP51A1 gene (c.1147A>G, p.Ile383Val). We then developed a CYP51A1I383V knock-in mouse model. This variant disrupted cholesterol synthesis, resulting in CHD through impaired hedgehog (Hh) signaling. Most intriguingly, maternal dietary intervention to increase cholesterol intake effectively reduced the risk of CHD in CYP51A1I383V mutant offspring. Our study suggests that low maternal cholesterol during pregnancy increases the risk of CHD in offspring by inhibiting Hh signaling, and that maternal cholesterol supplementation during pregnancy may reduce the occurrence of CHD.

ORGANISM(S): Mus musculus

PROVIDER: GSE307566 | GEO | 2025/09/22

REPOSITORIES: GEO

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Project description:Maternal diet is associated with the development of metabolism-related and other non-communicable diseases in offspring. Underlying mechanisms, functional profiles, and molecular markers are only starting to be revealed. Here, we explored the physiological and molecular impact of maternal Western-style diet on the liver of male and female offspring. C57BL/6 dams were exposed to either a low fat/low cholesterol diet (LFD) or a Western-style high fat/high cholesterol diet (WSD) for six weeks before mating, as well as during gestation and lactation. Dams and offspring were sacrificed at postnatal day 14, and body, liver, and blood parameters were assessed. The impact of maternal WSD on the pups' liver gene expression was characterised by whole-transcriptome microarray analysis. Exclusively male offspring had significantly higher body weight upon maternal WSD. In offspring of both sexes of WSD dams, liver and blood parameters, as well as hepatic gene expression profiles were changed. In total, 686 and 604 genes were differentially expressed in liver (pM-bM-^IM-$0.01) of males and females, respectively. Only 10% of these significantly changed genes overlapped in both sexes. In males, in particular alterations of gene expression with respect to developmental functions and processes were observed, such as Wnt/beta-catenin signalling. In females, mainly genes important for lipid metabolism, including cholesterol synthesis, were changed. We conclude that maternal WSD affects physiological parameters and induces substantial changes in the molecular profile of the liver in two-week-old pups. Remarkably, the observed biological responses of the offspring reveal pronounced sex-specificity. C57BL/6 dams were exposed to either a low fat/low cholesterol diet (LFD) or a Western-style high fat/high cholesterol diet (WSD) as six weeks pre-treatment before mating, as well as during gestation and lactation. Offspring were sacrificed at postnatal week two, livers were removed and RNA samples were subjected to gene expression profiling.

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Maternal Cholesterol Deficiency Predisposes Congenital Heart Defect Risk

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