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Caffeine Alters Human Face Development

Study suggests that consumption of certain substances such as coffee could potentially disrupt human facial development during pregnancy.

A recent study in Toxicological Sciences investigated the impact of five common drugs, encompassing caffeine and the blood thinner warfarin, on zebrafish embryos. All five drugs were observed to hinder the migration of cells responsible for bone formation, leading to facial malformations in the developing fish.

Zebrafish embryos hold significant advantages for studying early development due to their rapid growth, transparency, and external development. This zebrafish model offers a potential tool for efficient screening of potentially harmful substances, minimizing reliance on mammalian testing and empowering expectant parents with informed choices for themselves and their unborn child.

In order to study facial development in zebrafish, researchers employed genetic modification techniques. This modification resulted in the green fluorescence of bone-forming cells within the larvae’s face. These cells are naturally colorless and transparent, making them difficult to observe during this early developmental stage. Zebrafish embryos begin forming their head and tail after only 16 hours, and reach adulthood at a mere 2-5 centimeters in length.

Origins and Frequency

Facial appearances can differ due to both congenital factors and life experiences. Globally, craniofacial anomalies, encompassing the development of a child’s head and facial bones, account for over a third of all birth defects. Cleft lip and/or palate is a well-known example. The precise causes of craniofacial variations remain unclear, but current research suggests a multifactorial etiology. This includes genetics, the gestational environment, dietary factors, certain illnesses, and exposure to specific drugs or chemicals.

Focus on Teratogens and Testing Strategies

Teratogens are substances known to disrupt fetal or embryonic development; pregnant individuals are advised to avoid alcohol and nicotine for this reason. Traditionally, potential teratogens are evaluated using animal models like rodents and rabbits. However, the research community is actively seeking alternative methods that are faster, more cost-effective, and minimize the reliance on mammalian testing.

Unveiling Disruptions in Facial Development

Tiny zebrafish, measuring only 2-5 centimeters, offer a powerful tool for studying embryonic development. Remarkably, these freshwater fish develop as much in a single day as a human embryo does in a month. Due to their transparency and external development, researchers can monitor the behavior of live cells within zebrafish embryos. Over the past decade, zebrafish have emerged as a valuable method for identifying substances that may cause birth defects (teratogens). Scientists are still investigating the precise mechanisms by which teratogens disrupt typical embryonic development.

Investigating the Causes of Facial Malformations

Researchers focused on a specific genetic marker associated with a group of cells involved in craniofacial development in both mammals and fish. These cells contribute to the formation of facial structures like the jaw and nose in humans. A genetic modification was introduced into zebrafish embryos to make bone-forming cells glow green under fluorescence. Subsequently, the embryos were exposed to chemicals known to cause facial defects in human newborns. The researchers then tracked the movements of these bone-forming cells throughout the embryonic stages.

The team investigated five chemicals: valproic acid (used for neurological and psychiatric disorders), warfarin (an anticoagulant), salicylic acid (found in many skin ointments), caffeine, and methotrexate (used in chemotherapy). As expected, all five chemicals induced varying degrees of craniofacial anomalies in the zebrafish embryos 96 hours after fertilization. However, the researchers were surprised by the mechanism responsible for these defects and the rapidity of its onset.

Early Disruption of Cell Migration as a Common Cause

Bone and cartilage-forming cells in the head, known as cranial neural crest cells (CNCCs), typically migrate a long distance from their initial formation site around the back of the neck to their final destinations, such as the jaw or nose. Interestingly, the researchers discovered that irrespective of the specific way each chemical affected the cells on a molecular level, all five chemicals caused disruptions in the migration of bone-forming cells during early embryonic development. This disruption was identified as the common cause of facial malformations in the zebrafish embryos. Notably, these signs were evident within just 24 hours, at a stage when zebrafish and mammalian embryos share highly similar morphological and molecular characteristics.

These findings suggest a potential universal mechanism by which teratogenic chemicals might hinder the early movement of CNCCs, thereby leading to the development of facial variations. The researchers hypothesize that facial differences caused by other substances might also follow the same mechanism.

Future Research and Potential Applications

Future research aims to elucidate the molecular mechanism underlying the impaired cell migration. This will help scientists understand why different chemicals lead to the shared defects in cell migration. The zebrafish-based system proposed by the research team offers a promising new method for testing teratogens across different species. This information could empower parents and healthcare professionals to make informed choices to minimize or avoid exposure to such teratogens during pregnancy.


Craniofacial anomalies are one of the most frequent birth defects worldwide and are often caused by genetic and environmental factors such as pharmaceuticals and chemical agents. Although identifying adverse outcome pathways (AOPs) is a central issue for evaluating the teratogenicity, the AOP causing craniofacial anomalies has not been identified. Recently, zebrafish has gained interest as an emerging model for predicting teratogenicity because of high throughput, cost-effectiveness and availability of various tools for examining teratogenic mechanisms. Here, we established zebrafish sox10-EGFP reporter lines to visualize cranial neural crest cells (CNCCs) and have identified the AOPs for craniofacial anomalies. When we exposed the transgenic embryos to teratogens that were reported to cause craniofacial anomalies in mammals, CNCC migration and subsequent morphogenesis of the first pharyngeal arch were impaired at 24 hours post-fertilization. We also found that cell proliferation and apoptosis of the migratory CNCCs were disturbed, which would be key events of the AOP. From these results, we propose that our sox10-EGFP reporter lines serve as a valuable model for detecting craniofacial skeletal abnormalities, from early to late developmental stages. Given that the developmental process of CNCCs around this stage is highly conserved between zebrafish and mammals, our findings can be extrapolated to mammalian craniofacial development and thus help in predicting craniofacial anomalies in human.

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