Exploring the invisible forces that disrupt embryonic development and cause lasting structural and functional abnormalities
Infants affected by thalidomide tragedy
Average delay in neurodevelopmental studies
Neurodevelopmental alterations in exposed medications
Sensitivity of combined testing methods
In the 1960s, a medical tragedy forever changed how we view pregnancy and medication. The drug thalidomide, prescribed for morning sickness, led to an estimated 10,000 infants worldwide being born with severe physical malformations 1 . This catastrophic event unveiled a disturbing truth: certain substances could slip through the placental barrier and disrupt the delicate dance of human development. These substances, known as teratogens, operate as invisible forces of mutability, capable of altering developmental pathways and reshaping fetal formation.
The story of thalidomide sparked a revolution in prenatal care and toxicology, leading to stricter drug testing protocols and greater awareness of environmental hazards during pregnancy. Yet, more than half a century later, the science of teratogenesis remains full of complexities and unanswered questions. Today, researchers are discovering that teratogens impact far more than physical structures—they can alter brain development, change genetic expression, and cause functional impairments that may not appear until years after birth 1 . As science advances, we're beginning to understand the subtle yet powerful ways these agents influence what they call 'mutability'—the capacity for developmental change—and how we might better protect the most vulnerable among us.
Thalidomide tragedy reveals teratogen risks
Focus on physical malformations
Recognition of neurodevelopmental effects
Genetic susceptibility and advanced testing methods
Teratogens are substances, organisms, or physical conditions that can disrupt normal embryonic and fetal development, causing permanent structural or functional abnormalities 6 . The term derives from the Greek word "teras," meaning monster or marvel—an etymology that reflects the dramatic physical malformations first associated with these agents. Today, we recognize that their effects extend far beyond visible deformities to include growth restriction, functional impairments, and neurodevelopmental disorders 1 .
Teratogens operate through multiple mechanisms. Some directly damage embryonic cells, while others interfere with specific molecular pathways essential for development. The famous acne medication isotretinoin, for instance, disrupts normal craniofacial and neurological development by interfering with neural crest cell migration 7 . Other teratogens, like alcohol, can induce a wide range of effects on the developing brain, leading to attention and working memory difficulties that place infants at risk for early developmental delay 1 .
The impact of a teratogen depends crucially on when during pregnancy exposure occurs. The same substance can cause different effects depending on the developmental stage:
(Early Stage)
Teratogens may inhibit cell division or kill the embryo entirely 6
(Weeks 3-8)
Exposure can cause specific organ malfunctions and major structural defects 6
(Later Pregnancy)
Interference may lead to functional abnormalities, growth restriction, and neurocognitive delays 6
This timing principle explains why a single teratogen can produce such varied effects. For example, angiotensin-converting enzyme (ACE) inhibitors cause fetal malformation when administered early in pregnancy but may cause oligohydramnios and renal failure when exposure occurs later 6 .
Historically, teratogen research focused primarily on physical abnormalities detectable at birth. However, a paradigm shift is occurring as scientists recognize that neurodevelopmental impacts may represent the most common—and often overlooked—consequence of prenatal exposures 1 .
Concerningly, a 2025 scoping review revealed that only 13 of 24 (54%) confirmed structural teratogens have been subject to any empirical investigation of neurodevelopmental outcomes. The mean time between authorization of known structural teratogens and the first empirical study investigating neurodevelopmental outcomes was 33 years, ranging from 11 to 64 years 1 . This critical lag means generations of children may be affected before risks are fully understood.
When neurodevelopmental outcomes are investigated for medication exposures with physical teratogenic signatures, researchers find high levels of neurodevelopmental alterations (77%) 1 . These can include lower IQ, language and motor skill delays, and increased rates of diagnoses such as autism spectrum disorder (ASD) and attention deficit hyperactivity disorder (ADHD) 1 .
Not every embryo exposed to a teratogen develops abnormalities—a variability that stems from the complex interplay between environmental exposures and genetic susceptibility. The principles of teratogenesis, first proposed by Wilson in 1977, established that susceptibility depends on the genotype of both embryo and mother, the timing of exposure, and the developmental stage of the embryo 7 .
Research into pharmacogenetics—how genetics influence drug response—is revealing why some individuals are more vulnerable to specific teratogens. A 2021 systematic review identified several promising genetic associations 7 :
These genetic differences help explain why a medication like valproate, an anti-seizure medication with known teratogenic potential, may cause severe malformations in some children but not others 1 . As one researcher notes, "Teratogens do not produce congenital anomalies in all exposed embryos" 7 , highlighting the role of individual genetic makeup in determining risk.
Despite these advances, studies on genetic teratology remain generally small, heterogeneous, and exhibit inconsistent results 7 . The field faces significant challenges, including:
Limiting statistical power
Complicating comparisons
Across different populations
For many known teratogens
Future studies may be improved by increasing sample sizes and applying genome-wide approaches, potentially leading to clinical implementation of genetic screening to provide safer drug use in pregnant women who need medication 7 .
Historically, in vivo teratogenicity studies relied on mammalian models like adult rodents and rabbits. These models suffer from elevated experimental costs, low throughput, and typically require invasive methods 8 . Today, a paradigm shift is underway toward New Approach Methodologies (NAMs) that can increase throughput while decreasing costs and animal use 8 .
Zebrafish embryos have emerged as a particularly promising model for teratogenicity testing because they combine the biological complexity of a whole organism with practical advantages for large-scale screening 8 . Their unique features include:
Research has demonstrated that the predictive teratogenic potential of zebrafish is similar, when not superior, to that obtained using traditional rodent models 8 . In one study, results obtained using an automated zebrafish platform showed a high correlation with results from murine models, with even higher prediction levels for human teratogenicity 8 .
No single test provides perfect prediction of human teratogenicity, but combining approaches significantly improves accuracy. A recent study evaluating three methods—the in silico DART model, devTox quickPredict™ test, and Zebrafish Embryotoxicity Test (ZET)—found that while each method alone had good sensitivity and specificity, their predictive power increased dramatically when used together 9 .
While high-dose teratogen exposure clearly causes severe abnormalities, less is known about the long-term impacts of chronic, low-dose exposure during early development. A fascinating study using Caenorhabditis elegans (C. elegans), a transparent nematode worm, investigated how sub-lethal teratogen exposure during larval development affects reproductive health in adulthood .
The researchers designed an elegant experiment to test the hypothesis that low-dose exposure during early development could impact long-term reproductive health :
The study examined multiple teratogens, including tributyltin-chloride, cadmium-chloride, benzo-α-pyrene, nicotine, bisphenol-A, diethylstilbestrol, arsenic(III) oxide, triclosan, fenthion, and cigarette smoke extract .
Larval exposure to teratogens
Transfer to untreated plates
Egg-laying pattern recording
Embryo viability assessment
The experiment yielded several unexpected findings that challenge simple narratives about teratogen effects:
| Teratogen | Category | Effect on Fecundity | Effect on Fertility | Egg Quality |
|---|---|---|---|---|
| Triclosan | Biocide | Decreased | Decreased | No improvement |
| Fenthion | Biocide | Decreased | Decreased | No improvement |
| Benzo-α-pyrene | Combustion pollutant | Decreased | Decreased | No improvement |
| Nicotine | Combustion pollutant | Increased egg-laying | No effect on hatching | No improvement |
| Cadmium | Heavy metal | Increased egg-laying | No effect on hatching | No improvement |
| Tributyltin | Biocide | Increased egg-laying | No effect on hatching | No improvement |
Surprisingly, despite the overall detrimental effect on fecundity and fertility for some teratogens, many unexpectedly increased egg-laying during the earliest observation period (0-3 hours) compared to controls . This effect was not sustained at later intervals.
Perhaps most importantly, the study found that while egg-laying patterns changed, embryo viability remained unaffected across groups and time points . Many of the eggs (up to 50%) did not hatch, indicating that egg quality had not improved despite the increased laying behavior for some teratogens.
This experiment demonstrates that chronic, low-dose exposures to teratogens during early larval development have subtle, long-term effects on egg laying and egg quality that might be missed in traditional high-dose studies . The findings highlight that:
Teratogen effects can be counterintuitive—some increased egg-laying while decreasing reproductive fitness
Low-dose exposure during development can have effects manifesting in adulthood
Behavioral changes may not correlate with improved reproductive outcomes
These insights are particularly relevant for understanding how chronic low-level environmental teratogen exposure in humans might affect reproductive health and development across generations.
Given the potential risks of teratogen exposure, prevention remains the most effective strategy. Based on current evidence, several approaches can significantly reduce the risk of teratogenic congenital defects:
Approximately 40-80% of women in Western countries use prescribed drugs during pregnancy 7 , making careful risk-benefit assessment essential.
Medications with established teratogenic effects include certain anti-seizure medications (valproate, carbamazepine, phenytoin), isotretinoin, and warfarin 1 .
Early initiation of prenatal care helps identify and manage potential teratogenic exposures 2 .
Proven to reduce the risk of neural tube defects by up to 72% and promote healthy pregnancy 2 .
Alcohol, tobacco, and illicit drugs represent modifiable risk factors for preventable birth defects, with avoidance reducing risks by up to 65% 2 .
Research continues to identify new approaches to prevent teratogenesis:
The science of teratogenesis has come a long way since the thalidomide tragedy of the 1960s, yet we continue to discover how profoundly environmental exposures can shape development. Teratogens act as factors of mutability—not in the genetic sense of changing DNA sequences, but by altering developmental pathways, changing how genes are expressed, and reshaping structures and functions during the most vulnerable period of life.
What makes this field both challenging and fascinating is its complexity: the same exposure can have dramatically different effects depending on timing, genetics, and interacting factors. As research continues, we're moving beyond simply identifying obvious physical malformations to understanding subtle functional impairments, particularly in neurodevelopment, that may not become apparent until years after birth.
The future of teratology lies in developing more sophisticated models that can better predict human outcomes, understanding genetic susceptibilities that make some individuals more vulnerable, and creating robust systems to identify teratogenic risks before medications and chemicals are widely used. As one researcher aptly notes, the goal is "to promote knowledge of the mechanisms of human teratogens" which "may help in health strategies to prevent the occurrence of some congenital anomalies" 5 .
While the landscape of invisible threats may seem daunting, each scientific advance provides new tools to protect developmental vulnerability. Through continued research, thoughtful regulation, and educated choices, we can work toward a future where every pregnancy has the opportunity to unfold according to its own unique genetic blueprint, free from disruptive outside influences.