The risks of taking statins during pregnancy
Researchers show malformations in fish embryos

Ulm University

Millions of Germans are taking cholesterol-lowering drugs on a daily basis - not just seniors. Up to now, so-called statins were thought to have few side effects. Researchers around Professor Melanie Philipp in Ulm, however, urge caution during pregnancy. The group has been studying the role of cholesterol during the embryonic development: They showed in zebrafish embryos that lowering cholesterol levels with statins leads to grave malformations. The scientists' findings have been published in the science journal 'Communications Biology'.

The fat molecule cholesterol does not have a particularly positive reputation: Elevated cholesterol levels are associated with arteriosclerosis as well as an increased risk for heart attacks and strokes, among other things. On the other hand, cholesterol has an important function in the body as it stabilises cell membranes and serves as a building block for hormones. To what extent cholesterol levels affect the development of the embryo in the womb is not yet fully understood.

Previous findings on the use of statins during pregnancy have been inconclusive and indicated at least in the animal model a potential risk for developmental anomalies in the unborn baby. This uncertainty as well as a rare condition called Smith-Lemli-Opitz syndrome (SLOS) motivated the researchers around Professor Melanie Philipp to take a closer look at the role of cholesterol in embryonic development. Patients with an inherited inability to synthesise sufficient amounts of cholesterol (SLOS) are born with a deformed skull as well as heart defects and abnormal kidney development. 'We wanted to know if the developmental defects are caused by the significantly lowered cholesterol production in SLOS patients and what the underlying cellular mechanisms are,' explains first author Lars Maerz, academic staff member at the Institute of Biochemistry and Molecular Biology.

To get to the bottom of these questions the molecular biologists and physiologists treated zebrafish embryos with cholesterol-lowering substances. This resulted in malformations in the zebrafish embryos that were similar to those found in SLOS. The scientists observed skeletal deformations, particularly of the head, as well as anomalies in various organs including heart and kidneys, among other things. Interestingly, the development of all affected body parts depends on functional cilia. Cilia are fine hairlike organelles that are found on almost all cells and play a role in signal transmission and the movement of body fluids such as the liquor in the brain. Cholesterol is an important component of any cell membrane and is therefore also present in cilia. Dysfunctional cilia can lead to various clinical pictures ('ciliopathies'), which had thus far not been associated with cholesterol.

Using human cells - including those of SLOS patients - as well as mouse cells and unicellular organisms, the researchers were able to confirm their findings from zebrafish embryos that statins can trigger malformations, which demonstrates that the discovery is applicable also to other models, and presumably even to humans.

'Our studies have shown that sufficiently high cholesterol levels are essential for the formation of healthy cilia. Ciliary dysfunctions can in turn lead to severe birth defects in embryos,' explains Professor Melanie Philipp, group leader at the Institute of Biochemistry and Molecular Biology.

Overall, the researchers were able to prove that it is problematic for embryos if the cholesterol level is lowered too much - by taking statins for example. Moreover, the group has demonstrated the important role of cholesterol in the formation of cilia and thus many organs.

The researchers consequently urge to follow the manufacturer's instructions, who recommends a critical assessment of statin intake during pregnancy. However, further studies are needed in order to determine the precise effects of statins on the development of human embryos.

The article in 'Communications Biology' is the result of a collaboration between the Institute of Biochemistry and Molecular Biology and the Institute of General Physiology at Ulm University. The authors were supported by the German Research Foundation (DFG) and the Boehringer Ingelheim Ulm University Biocenter (BIU).

Text and media contact: Annika Bingmann

Lars D. Maerz, Martin D. Burkhalter, Carolin Schilpp, Oliver H. Wittekindt, Manfred Frick, Melanie Philipp. Pharmacological cholesterol depletion disturbs ciliogenesis and ciliary function in developing zebrafish. Communications Biology. https://doi.org/10.1038/s42003-018-0272-7

[Translate to english:] Lichtmikroskopische Aufnahme von zwei Tage alten Zebrafischembryonen. Behandlung mit dem Cholesterinsenker Atorvastatin führt zu stark deformierten Zebrafischembryonen
Light microscopic image depicting two-day-old zebrafish embryos. Treatment with the cholesterol-lowering agent Atorvastatin results in severely malformed zebrafish embryos (image: Lars Maerz)
Prof. Melanie Philipp und der Wissenschaftliche Mitarbeiter Lars Maerz forschen am Institut für Biochemie und Molekulare Biologie der Universität Ulm
Prof. Melanie Philipp and academic staff member Lars Maerz conduct research at Ulm University's Institute of Biochemistry and Molecular Biology (photo: Julian Gerhards)
Zebrafische an der Universität Ulm
Zebrafish at Ulm University (photo: Eberhardt/Uni Ulm)