12 November 2018

Retinoic acid and its relatives - I can't live with or without you

Natural toxin

Retinoic compounds are occurring in freshwater sources frequently as cyanobacterial blooms spread. Despite not being considered toxic, their bioactive potential is huge and already causes malformations in aquatic vertebrates. Also, from dietary sources, the intake of retinoic compounds, e.g. vitamin A, has to be monitored to prevent adverse effects on the development especially during pregnancy.

Fig. 1. Left: cyanobacterial bloom in a hypertrophic lake. Right: Malformations of X. laevis during early development (upper image, adapted from Smutná et al., 20178) caused by exposure to all-trans retinoic acid (structure on lower right side). Click image for interactive 3D model of retinoic acid.

The polyisoprenoid lipid retinoic acid (RA), i.e. all-trans-retinoic acid (atRA), is the biologically active metabolite of vitamin A (retinol) and indispensable for growth and development1.

Especially during the early (embryonic) development of vertebrates, gradients of RA determine the dorso-ventral polarization of tissues and, as one of the first actors determine the formation of limbs and, most notably, the brain1–3.

RA acts in a concentration dependent manner by binding to retinoic acid receptors. Different subtypes of these receptors have different affinities to retinoic metabolites, though the group-representative receptor ligand for the retinoic acid receptor alpha-subfamily is all-trans RA, stimulating the receptor at concentrations as low as 0.43 nM4. Upon binding, the retinoic acid receptor (RAR) recognizes its dimerization partner retinoid X receptor (RXR) and promotes transcription of genes governed by retinoic acid response elements (RAREs). Genes regulated (activated) in this fashion are, amongst others, Hox-genes – determinants for cell proliferation and fate, which is crucial during embryonic morphogenesis1.

However, to enable proper retinoic acid signaling during the fetal development, to some extent vertebrates are able to synthetize retinoic acid on their own, if supplied with vitamin A (with a β-carotene moiety – the reason why you should not skip carroty and other orange-yellow colored vegetables!)2.

Despite being inevitable, the concentration-dependent action of retinoic substances harbors risks of misdosage. Historically both, too much and too little retinoic acid/vitamin A have been linked to malformations, especially of the brain (hindbrain) and large blood vessels (heart, aorta)1. These teratogenic properties range from mild symptoms similar to the fetal alcohol syndrome to severe and fatal cases, leading to loss of the fetus2,3,5,6. As retinoic acid effects have the biggest impact during development, its consumption and exposure is critical during pregnancy in mammals or during the embryo-larval developmental stage (before hatching). In nature, the abundance of structurally related retinoic substances can often be spotted by their color hue ranging from yellow to orange (carrots!). For example, carrots are a prime source of vitamin A, that is protected from light by growing in the soil. In fact, carrots, sweet potatoes and other yellow-orange vegetables are a prime dietary source of vitamin A7.

But retinoic compounds are also produced by aquatic organisms, such as cyanobacteria8. Despite their abundance and ubiquitous presence, retinoic compounds have received very little attention by the scientific community. In aquatic amphibians (Xenopus laevis, toad) and fish cyanobacterial blooms have been linked to malformations and teratogenicity despite low mortalities8–11.

Expecting more hot and dry summers in the northern hemisphere in the next years and decades, clean drinking water resources will become scarce. Additionally, drinking water supplies will be more dependent on surface water, that are very likely to be infested with cyanobacteria. Hence, implications for drinking water treatment have to be investigated, to be able to react to these challenges in a pro-active manner.

SMILES: CC1=C(C(CCC1)(C)C)/C=C/C(=C/C=C/C(=C/C(=O)O)/C)/C

References and further reading:

  1. Zieger, E. & Schubert, M. in International review of cell and molecular biology 330, 1–84 (2017).
  2. Rhinn, M. & Dolle, P. Retinoic acid signalling during development. Development 139, 843–858 (2012).
  3. Cunningham, T. J. & Duester, G. Mechanisms of retinoic acid signalling and its roles in organ and limb development. Nat. Rev. Mol. Cell Biol. 16, 110–123 (2015).
  4. Baker, N. et al. Toxcast Chemical and Bioactivity Profiles for In Vitro Targets in the Retinoid Signaling System (SOT). 2016 SOT Annu. Meet. New Orleans, LA, March 13 - 17 (2016). doi:10.23645/epacomptox.5173810
  5. Duester, G. A hypothetical mechanism for fetal alcohol syndrome involving ethanol inhibition of retinoic acid synthesis at the alcohol dehydrogenase step. Alcohol. Clin. Exp. Res. 15, 568–72 (1991).
  6. Penniston, K. L. & Tanumihardjo, S. A. The acute and chronic toxic effects of vitamin A. Am. J. Clin. Nutr. 83, 191–201 (2006).
  7. Office of Dietary Supplements (ODS), N. I. of H. (NIH). Vitamin A — Health Professional Fact Sheet. website (2018). Available at: https://ods.od.nih.gov/factsheets/VitaminA-HealthProfessional/. (Accessed: 9th November 2018)
  8. Smutná, M., Priebojová, J., Večerková, J. & Hilscherová, K. Retinoid-like compounds produced by phytoplankton affect embryonic development of Xenopus laevis. Ecotoxicol. Environ. Saf. 138, 32–38 (2017).
  9. Smutná, M. et al. Acute, chronic and reproductive toxicity of complex cyanobacterial blooms in Daphnia magna and the role of microcystins. Toxicon 79, 11–18 (2014).
  10. Priebojová, J., Hilscherová, K., Procházková, T., Sychrová, E. & Smutná, M. Intracellular and extracellular retinoid-like activity of widespread cyanobacterial species. Ecotoxicol. Environ. Saf. 150, 312–319 (2018).
  11. Sychrová, E. et al. Characterization of total retinoid-like activity of compounds produced by three common phytoplankton species. Harmful Algae 60, 157–166 (2016).