Embryotoxicity
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Teratology is the study of abnormalities of
physiological development Development of the human body is the process of growth to maturity. The process begins with fertilization, where an egg released from the ovary of a female is penetrated by a sperm cell from a male. The resulting zygote develops through mitosis ...
in organisms during their life span. It is a sub-discipline in
medical genetics Medical genetics is the branch of medicine that involves the diagnosis and management of hereditary disorders. Medical genetics differs from human genetics in that human genetics is a field of scientific research that may or may not apply to me ...
which focuses on the classification of
congenital abnormalities A birth defect is an abnormal condition that is present at birth, regardless of its cause. Birth defects may result in disabilities that may be physical, intellectual, or developmental. The disabilities can range from mild to severe. Birth de ...
in
dysmorphology Teratology is the study of abnormalities of physiological development in organisms during their life span. It is a sub-discipline in medical genetics which focuses on the classification of congenital abnormalities in dysmorphology caused by t ...
caused by teratogens and also in
pharmacology Pharmacology is the science of drugs and medications, including a substance's origin, composition, pharmacokinetics, pharmacodynamics, therapeutic use, and toxicology. More specifically, it is the study of the interactions that occur betwee ...
and
toxicology Toxicology is a scientific discipline, overlapping with biology, chemistry, pharmacology, and medicine, that involves the study of the adverse effects of chemical substances on living organisms and the practice of diagnosing and treating ex ...
. Teratogens are substances that may cause non-heritable
birth defects A birth defect is an abnormal condition that is present at birth, regardless of its cause. Birth defects may result in disabilities that may be physical, intellectual, or developmental. The disabilities can range from mild to severe. Birth de ...
via a
toxic Toxicity is the degree to which a chemical substance or a particular mixture of substances can damage an organism. Toxicity can refer to the effect on a whole organism, such as an animal, bacterium, or plant, as well as the effect on a subst ...
effect on an
embryo An embryo ( ) is the initial stage of development for a multicellular organism. In organisms that reproduce sexually, embryonic development is the part of the life cycle that begins just after fertilization of the female egg cell by the male sp ...
or
fetus A fetus or foetus (; : fetuses, foetuses, rarely feti or foeti) is the unborn offspring of a viviparous animal that develops from an embryo. Following the embryonic development, embryonic stage, the fetal stage of development takes place. Pren ...
. Defects include malformations, disruptions, deformations, and dysplasia that may cause stunted growth, delayed mental development, or other
congenital disorder A birth defect is an abnormal condition that is present at childbirth, birth, regardless of its cause. Birth defects may result in disability, disabilities that may be physical disability, physical, intellectual disability, intellectual, or dev ...
s that lack structural malformations. These defects can be recognized prior to or at birth as well as later during early childhood. The related term
developmental toxicity Developmental toxicity is any developmental malformation that is caused by the toxicity of a chemical or pathogen. It is the structural or functional alteration, reversible or irreversible, which interferes with homeostasis, Auxology, normal growth, ...
includes all manifestations of abnormal development that are caused by environmental
insult An insult is an expression, statement, or behavior that is often deliberately disrespectful, offensive, scornful, or derogatory towards an individual or a group. Insults can be intentional or unintentional, and they often aim to belittle, of ...
. The extent to which teratogens will impact an embryo is dependent on several factors, such as how long the embryo has been exposed, the stage of development the embryo was in when exposed (gestational timing), the genetic makeup of the embryo, and the transfer rate of the teratogen. The dose of the teratogen, the route of exposure to the teratogen, and the chemical nature of the teratogenic agent also contribute to the level of teratogenicity.


Etymology

The term was borrowed in 1842 from the French , where it was formed in 1830 from the
Greek Greek may refer to: Anything of, from, or related to Greece, a country in Southern Europe: *Greeks, an ethnic group *Greek language, a branch of the Indo-European language family **Proto-Greek language, the assumed last common ancestor of all kno ...
(
word stem In linguistics, a word stem is a word part responsible for a word's lexical meaning. The term is used with slightly different meanings depending on the morphology of the language in question. For instance, in Athabaskan linguistics, a verb stem ...
), meaning "sign sent by the gods, portent, marvel, monster", and (''
-ology ''-logy'' is a suffix in the English language, used with words originally adapted from Ancient Greek ending in ('). The earliest English examples were anglicizations of the French '' -logie'', which was in turn inherited from the Latin ''-log ...
''), used to designate a discourse, treaty, science, theory, or study of some topic. Old literature referred to abnormalities of all kinds under the Latin term ''Lusus naturae'' (). As early as the 17th century, ''Teratology'' referred to a discourse on prodigies and marvels of anything so extraordinary as to seem abnormal. In the 19th century, it acquired a meaning more closely related to biological deformities, mostly in the field of botany. Currently, its most instrumental meaning is that of the medical study of teratogenesis,
congenital malformations A birth defect is an abnormal condition that is present at birth, regardless of its cause. Birth defects may result in disabilities that may be physical, intellectual, or developmental. The disabilities can range from mild to severe. Birth de ...
or individuals with significant malformations. Historically, people have used many pejorative terms to describe/label cases of significant physical malformations. In the 1960s, David W. Smith of the
University of Washington The University of Washington (UW and informally U-Dub or U Dub) is a public research university in Seattle, Washington, United States. Founded in 1861, the University of Washington is one of the oldest universities on the West Coast of the Uni ...
Medical School (one of the researchers who became known in 1973 for the discovery of
fetal alcohol syndrome Fetal alcohol spectrum disorders (FASDs) are a group of conditions that can occur in a person who is exposed to alcohol during gestation. FASD affects 1 in 20 Americans, but is highly misdiagnosed and underdiagnosed. The several forms of the ...
), popularized the term ''teratology''. With the growth of understanding of the origins of birth defects, the field of teratology overlaps with other fields of science, including
developmental biology Developmental biology is the study of the process by which animals and plants grow and develop. Developmental biology also encompasses the biology of Regeneration (biology), regeneration, asexual reproduction, metamorphosis, and the growth and di ...
,
embryology Embryology (from Ancient Greek, Greek ἔμβρυον, ''embryon'', "the unborn, embryo"; and -λογία, ''-logy, -logia'') is the branch of animal biology that studies the Prenatal development (biology), prenatal development of gametes (sex ...
, and
genetics Genetics is the study of genes, genetic variation, and heredity in organisms.Hartl D, Jones E (2005) It is an important branch in biology because heredity is vital to organisms' evolution. Gregor Mendel, a Moravian Augustinians, Augustinian ...
. Until the 1940s, teratologists regarded birth defects as primarily hereditary. In 1941, the first well-documented cases of environmental agents being the cause of severe birth defects were reported.


Teratogenesis

Teratogenesis occurs when the development of an embryo is altered negatively due to the presence of teratogens. Teratogens are the causes of teratogenesis. Common examples of teratogens include
genetic disorder A genetic disorder is a health problem caused by one or more abnormalities in the genome. It can be caused by a mutation in a single gene (monogenic) or multiple genes (polygenic) or by a chromosome abnormality. Although polygenic disorders ...
s, maternal nutrition and health, and chemical agents such as drugs and
alcohol Alcohol may refer to: Common uses * Alcohol (chemistry), a class of compounds * Ethanol, one of several alcohols, commonly known as alcohol in everyday life ** Alcohol (drug), intoxicant found in alcoholic beverages ** Alcoholic beverage, an alco ...
. Lesser known examples that will be covered include stress, caffeine, and deficiencies in diet and nutrition. Although teratogens can affect a fetus during any time in the pregnancy, one of the most sensitive time frames for them to be exposed to the developing embryo is during the embryonic period. This period is in effect from about the fourteenth day following when a female's egg is implanted into a specific place in the reproductive organs and sixty days after conception. Teratogens are able to cause abnormal defects through certain mechanisms that occur throughout the development of the embryo.


Wilson's principles

In 1959 and in his 1973 monograph ''Environment and Birth Defects'', embryologist
James Wilson James Wilson may refer to: Politicians and government officials Canada * James Wilson (Upper Canada politician) (1770–1847), English-born farmer and political figure in Upper Canada * James Crocket Wilson (1841–1899), Canadian MP from Queb ...
put forth six principles of teratogenesis to guide the study and understanding of teratogenic agents and their effects on developing organisms. These principles were derived from and expanded on by those laid forth by zoologist
Camille Dareste Gabriel-Madeleine-Camille Dareste de la Chavanne (22 November 1822, in Paris – 1899, in Paris) was a French zoologist and specialist in experimental embryology particularly in the examination of natural defects as well as the artificial induct ...
in the late 1800s: # Susceptibility to teratogenesis depends on the
genotype The genotype of an organism is its complete set of genetic material. Genotype can also be used to refer to the alleles or variants an individual carries in a particular gene or genetic location. The number of alleles an individual can have in a ...
of the
conceptus A conceptus (from Latin Latin ( or ) is a classical language belonging to the Italic languages, Italic branch of the Indo-European languages. Latin was originally spoken by the Latins (Italic tribe), Latins in Latium (now known as Lazio), ...
and the manner in which this interacts with adverse environmental factors. # Susceptibility to teratogenesis varies with the developmental stage at the time of exposure to an adverse influence. There are critical periods of susceptibility to agents and organ systems affected by these agents. # Teratogenic agents act in specific ways on developing cells and tissues to initiate sequences of abnormal developmental events. # The access of adverse influences to developing tissues depends on the nature of the influence. Several factors affect the ability of a teratogen to contact a developing conceptus, such as the nature of the agent itself, route and degree of maternal exposure, rate of placental transfer and systemic absorption, and composition of the maternal and embryonic/fetal genotypes. # There are four manifestations of deviant development (death, malformation, growth retardation and functional defect). # Manifestations of deviant development increase in frequency and degree as dosage increases from the
No Observable Adverse Effect Level The no-observed-adverse-effect level (NOAEL) denotes the level of exposure of an organism, found by experiment or observation, at which there is no biologically or statistically significant increase in the frequency or severity of any adverse effe ...
(NOAEL) to a dose producing 100% lethality (LD100). The mechanisms of these teratogens lie in specific alterations to genes, cells, and tissues within the developing organism that cause deviation from normal development and can result in functional defects, growth stunts, malformation, and even death. Finally, susceptibility to teratogens is more elevated during specific, critical periods during development.


Oxidative stress

The natural metabolic processes of the human body produce highly reactive oxygen-containing molecules called reactive oxygen species. Being highly reactive, these molecules can oxidatively damage fats, proteins, and DNA, and alter signal transduction. Teratogens such as thalidomide, methamphetamine, and phenytoin are known to enhance ROS formation, potentially leading to teratogenesis ROS damage a certain class of reactions called redox reactions, which are chemical processes in which substances change their oxidation states by donating or accepting electrons. In these reactions, ROS act as strong oxidizing agents. They accept electrons from other molecules, causing those molecules to become oxidized. This shifts the balance of redox reactions in cells, inducing oxidative stress when ROS levels are high, leading to cellular damage. Developmental processes such as rapid cell division, cell differentiation into different types, and apoptosis rely on pathways that involve communication between cells through a process called signal transduction. These pathways' proper functioning is highly dependent on a certain class of reactions called redox reactions; many of these pathways are vulnerable to disruption due to oxidative stress. Therefore, one mechanism by which teratogens induce teratogenesis is by triggering oxidative stress and derailing redox-dependent signal transduction pathways in early development. Folate plays key roles in DNA methylation and in synthesis of nitrogenous bases found in DNA and RNA. These processes are crucial for cell division, cell growth, gene regulation, protein synthesis, and cell differentiation. All these processes ensure normal fetal development. Since the developing fetus requires rapid cell growth and division, the demand for folate increase during pregnancy, which if not met, can lead to teratogenic complications.


Epigenetic modifications

Epigenetic modifications are any heritable modifications to the expression of genes in the DNA that do not include direct code alteration of the base genome. These modifications can include heritable alterations in transcriptional and translational processes of certain genes and even their interactions with other genes. Many known teratogens affect fetal development by inducing these epigenetic modifications including turning on/off transcriptional processes of certain genes, regulating the location and distribution of proteins inside the cell, and regulating cell differentiation by modifying which mRNA molecules are translated into protein. During embryo development, a temporary organ called a placenta forms in the womb, connecting the mother to the fetus. The placenta provides oxygen and nutrients to the developing fetus throughout the pregnancy. Environmental influences such as under-nutrition, drugs, alcohol, tobacco smoke, and even abnormal hormonal activity can lead to epigenetic changes in the placental cells and harm the fetus in the long term, though specific mechanisms by which developmental damage takes place remains unclear.


Causes

Common causes of teratogenesis include: *
Genetic disorder A genetic disorder is a health problem caused by one or more abnormalities in the genome. It can be caused by a mutation in a single gene (monogenic) or multiple genes (polygenic) or by a chromosome abnormality. Although polygenic disorders ...
s and
chromosomal abnormalities A chromosomal abnormality, chromosomal anomaly, chromosomal aberration, chromosomal mutation, or chromosomal disorder is a missing, extra, or irregular portion of chromosomal DNA. These can occur in the form of numerical abnormalities, where ther ...
* Maternal health factors ** Nutrition during pregnancy (e.g.,
spina bifida Spina bifida (SB; ; Latin for 'split spine') is a birth defect in which there is incomplete closing of the vertebral column, spine and the meninges, membranes around the spinal cord during embryonic development, early development in pregnancy. T ...
resulting from
folate Folate, also known as vitamin B9 and folacin, is one of the B vitamins. Manufactured folic acid, which is converted into folate by the body, is used as a dietary supplement and in food fortification as it is more stable during processing and ...
deficiency) ** Metabolic disorders such as
diabetes Diabetes mellitus, commonly known as diabetes, is a group of common endocrine diseases characterized by sustained high blood sugar levels. Diabetes is due to either the pancreas not producing enough of the hormone insulin, or the cells of th ...
and
thyroid disease Thyroid disease is a medical condition that affects the structure and/or function of the thyroid gland. The thyroid gland is located at the front of the neck and produces thyroid hormones that travel through the blood to help regulate many other ...
** Stress * Chemical agents ** Prescription and recreational drugs (e.g.,
alcohol Alcohol may refer to: Common uses * Alcohol (chemistry), a class of compounds * Ethanol, one of several alcohols, commonly known as alcohol in everyday life ** Alcohol (drug), intoxicant found in alcoholic beverages ** Alcoholic beverage, an alco ...
,
thalidomide Thalidomide, sold under the brand names Contergan and Thalomid among others, is an oral administered medication used to treat a number of cancers (e.g., multiple myeloma), graft-versus-host disease, and many skin disorders (e.g., complication ...
) ** Environmental toxins and contaminants (e.g., heavy metals such as mercury and
lead Lead () is a chemical element; it has Chemical symbol, symbol Pb (from Latin ) and atomic number 82. It is a Heavy metal (elements), heavy metal that is density, denser than most common materials. Lead is Mohs scale, soft and Ductility, malleabl ...
,
polychlorinated biphenyl Polychlorinated biphenyls (PCBs) are organochlorine compounds with the formula Carbon, C12Hydrogen, H10−''x''Chloride, Cl''x''; they were once widely used in the manufacture of carbonless copy paper, as heat transfer fluids, and as dielectri ...
s (PCBs)) *
Vertically transmitted infection A vertically transmitted infection is an infection caused by pathogenic bacteria or viruses that use mother-to-child transmission, that is, transmission directly from the mother to an embryo, fetus, or baby during pregnancy or childbirth. It ...
s such as
rubella Rubella, also known as German measles or three-day measles, is an infection caused by the rubella virus. This disease is often mild, with half of people not realizing that they are infected. A rash may start around two weeks after exposure and ...
and
syphilis Syphilis () is a sexually transmitted infection caused by the bacterium ''Treponema pallidum'' subspecies ''pallidum''. The signs and symptoms depend on the stage it presents: primary, secondary, latent syphilis, latent or tertiary. The prim ...
*
Ionizing radiation Ionizing (ionising) radiation, including Radioactive decay, nuclear radiation, consists of subatomic particles or electromagnetic waves that have enough energy per individual photon or particle to ionization, ionize atoms or molecules by detaching ...
such as
X-ray An X-ray (also known in many languages as Röntgen radiation) is a form of high-energy electromagnetic radiation with a wavelength shorter than those of ultraviolet rays and longer than those of gamma rays. Roughly, X-rays have a wavelength ran ...
s and that emitted from
nuclear fallout Nuclear fallout is residual radioactive material that is created by the reactions producing a nuclear explosion. It is initially present in the mushroom cloud, radioactive cloud created by the explosion, and "falls out" of the cloud as it is ...
* Temperatures outside the accepted range for a given organism


Human pregnancy

In
human Humans (''Homo sapiens'') or modern humans are the most common and widespread species of primate, and the last surviving species of the genus ''Homo''. They are Hominidae, great apes characterized by their Prehistory of nakedness and clothing ...
s,
congenital disorder A birth defect is an abnormal condition that is present at childbirth, birth, regardless of its cause. Birth defects may result in disability, disabilities that may be physical disability, physical, intellectual disability, intellectual, or dev ...
s resulted in about 510,000 deaths globally in 2010. About 3% of newborns have a "major physical anomaly", meaning a physical anomaly that has cosmetic or functional significance. Developmental defects manifest in approximately 3% to 5% of newborns in the United States, between 2% to 3% of which are teratogen-induced. Congenital disorders are responsible for 20% of infant deaths. The most common congenital diseases are heart defects, Down syndrome, and neural tube defects. Trisomy 21 is the most common type of Down Syndrome. About 95% of infants born with Down Syndrome have this disorder and it consists of 3 separate copies of chromosomes. Translocation Down syndrome is not as common, as only 3% of infants with Down Syndrome are diagnosed with this type. VSD, ventricular septal defect, is the most common type of heart defect in infants. If an infant has a large VSD it can result into heart failure. Infants with a smaller VSD have a 96% survival rate and those with a moderate VSD have about an 86% survival rate. Lastly, NTD, neural tube defect, is a defect that forms in the brain and spine during early development. If the spinal cord is exposed and touching the skin it can require surgery to prevent an infection.


Medications

Though many pregnancies are accompanied with prescription drugs, there is limited knowledge regarding the potential teratogenic risks. Only medications that are commonly taken during pregnancies that are known to cause structural birth defects are considered teratogenic agents. One common drug in particular that is teratogenic is isotretinoin, known by many as Accutane. It became popular through its success in the care and treatment of skin cancer and severe acne. However, over time it has become clear that it causes severe teratogenic effects with 20-35% of exposed embryos experiencing developmental defects. Exposure of isotretinoin has led to severe skull, facial, cardiovascular, and neurological defects – to name a few. Another drug known as carbamazepine is sometimes prescribed during pregnancy if the mother experiences more extreme concerns regarding epilepsy or bipolar disorder. Unfortunately, this drug can also cause birth and developmental defects especially during the early stages of pregnancy such as defects of the neural tube, which develops into the brain and spinal cord. An example of this is spina bifida. Oral and topical antifungal agents such as fluconazole, ketoconazole, and terbinafine are commonly prescribed in pregnancy. Some fungal infections are asymptomatic and therefore do not really cause discomfort, but some are slightly more severe and can negatively affect a pregnant woman's life quality and even the fetus. This is primarily when antifungal agents are prescribed during pregnancy. Unfortunately, the use of antifungal agents can lead to spontaneous abortions and defects mainly regarding the cardiovascular and musculoskeletal systems, as well as some eye defects. It is safer to avoid taking medications during pregnancy to keep the likelihood of teratogenicity low, as the chances of any pregnancy resulting in birth defects is only 3-5%. However, it is necessary and cannot be avoided in certain cases. As with any medical concern, a doctor should always be consulted in order for the pregnancy to have the best outcome possible for both mother and baby.


Acitretin

Acitretin Acitretin, sold under the brand names Neotigason and Soriatane, is a second-generation retinoid. It is taken orally, and is typically used for psoriasis. Acitretin is an oral retinoid used in the treatment of severe resistant psoriasis. Becaus ...
is a retinoid and vitamin A derivative that is used in the treatment of psoriasis.
Acitretin Acitretin, sold under the brand names Neotigason and Soriatane, is a second-generation retinoid. It is taken orally, and is typically used for psoriasis. Acitretin is an oral retinoid used in the treatment of severe resistant psoriasis. Becaus ...
is highly teratogenic and noted for the possibility of severe birth defects. It was initially suggested as a replacement for Etretinate. It should not be used by pregnant women or women planning to get pregnant within 3 years following the use of acitretin. Sexually active women of childbearing age who use acitretin should also use at least two forms of birth control concurrently. Men and women who use it should not donate blood for three years after using it, because of the possibility that the blood might be used in a pregnant patient and cause birth defects. In addition, it may cause nausea, headache, itching, dry, red or flaky skin, dry or red eyes, dry or chapped lips, swollen lips, dry mouth, thirst, cystic acne or hair loss.


Etretinate

Etretinate Etretinate (trade name Tegison) is a medication developed by Hoffmann–La Roche that was approved by the FDA in 1986 to treat severe psoriasis. It is a second-generation retinoid. It was subsequently removed from the Canadian market in 1996 and t ...
(trade name Tegison) is a
medication Medication (also called medicament, medicine, pharmaceutical drug, medicinal product, medicinal drug or simply drug) is a drug used to medical diagnosis, diagnose, cure, treat, or preventive medicine, prevent disease. Drug therapy (pharmaco ...
developed by
Hoffmann–La Roche F. Hoffmann-La Roche AG, commonly known as Roche (), is a Swiss multinational holding healthcare company that operates worldwide under two divisions: Pharmaceuticals and Diagnostics. Its holding company, Roche Holding AG, has shares listed on ...
that was approved by the FDA in 1986 to treat severe
psoriasis Psoriasis is a long-lasting, noncontagious autoimmune disease characterized by patches of abnormal skin. These areas are red, pink, or purple, dry, itchy, and scaly. Psoriasis varies in severity from small localized patches to complete b ...
. It is a second-generation
retinoid The retinoids are a class of chemical compounds that are natural derivatives of vitamin A or are chemically related to it. Synthetic retinoids are utilized in cosmetic formulations, clinical dermatology, and the treatment of some forms of cancer ...
. It was subsequently removed from the
Canadian Canadians () are people identified with the country of Canada. This connection may be residential, legal, historical or cultural. For most Canadians, many (or all) of these connections exist and are collectively the source of their being ''C ...
market in 1996 and the
United States The United States of America (USA), also known as the United States (U.S.) or America, is a country primarily located in North America. It is a federal republic of 50 U.S. state, states and a federal capital district, Washington, D.C. The 48 ...
market in 1998 due to the high risk of birth defects. It remains on the market in Japan as Tigason.


Isotretinoin

Isotretinoin Isotretinoin, also known as 13-''cis''-retinoic acid and sold under the brand name Accutane among others, is a medication used to treat skin diseases like harlequin-type ichthyosis, and lamellar ichthyosis, and severe cystic acne or moderat ...
is classified as a retinoid drug and is used as a treatment for severe acne, other skin conditions, and some cancer types. In treatment against acne, it functions by hindering the activity of skin's sebaceous glands. It is extremely effective in its use in treatment against severe acne, but does have some negative side effects such as dry skin, nausea, joint and muscle pain, blistering skin, and the development of sores on mucous membranes. Some brand names for isotretinoin are Accutane, Absorica, Claravis, and Myorisan. Accutane is no longer on the market, but many other generic alternatives are available. Prenatal exposure to isotretinoin can cause neurocognitive impairment in some children. Isotretinoin is able to cross the placenta, potentially harming the developing fetus. If a fetus is exposed to isotretinoin during the first trimester of pregnancy, craniofacial, cardiac, and central nervous system malformations can occur. Some prenatal exposures to isotretinoin can result in still births or spontaneous abortions. The use of isotretinoin during pregnancy can increase cell apoptosis, leading to malformations, as well as heart defects.


Vaccination

In
human Humans (''Homo sapiens'') or modern humans are the most common and widespread species of primate, and the last surviving species of the genus ''Homo''. They are Hominidae, great apes characterized by their Prehistory of nakedness and clothing ...
s,
vaccination Vaccination is the administration of a vaccine to help the immune system develop immunity from a disease. Vaccines contain a microorganism or virus in a weakened, live or killed state, or proteins or toxins from the organism. In stimulating ...
has become readily available, and is important for the prevention of various communicable diseases such as
polio Poliomyelitis ( ), commonly shortened to polio, is an infectious disease caused by the poliovirus. Approximately 75% of cases are asymptomatic; mild symptoms which can occur include sore throat and fever; in a proportion of cases more severe ...
and
rubella Rubella, also known as German measles or three-day measles, is an infection caused by the rubella virus. This disease is often mild, with half of people not realizing that they are infected. A rash may start around two weeks after exposure and ...
, among others. There has been no association between congenital malformations and vaccination — for example, a population-wide study in Finland in which expectant mothers received the oral polio vaccine found no difference in infant outcomes when compared with mothers from reference cohorts who had not received the vaccine. However, on grounds of theoretical risk, it is still not recommended to vaccinate for polio while pregnant unless there is risk of infection. An important exception to this relates to provision of the influenza vaccine while pregnant. During the
1918 The ceasefire that effectively ended the World War I, First World War took place on the eleventh hour of the eleventh day of the eleventh month of this year. Also in this year, the Spanish flu pandemic killed 50–100 million people wor ...
and
1957 Events January * January 1 – The Saarland joins West Germany. * January 3 – Hamilton Watch Company introduces the first electric watch. * January 5 – South African player Russell Endean becomes the first batsman to be Dismissal (cricke ...
influenza Influenza, commonly known as the flu, is an infectious disease caused by influenza viruses. Symptoms range from mild to severe and often include fever, runny nose, sore throat, muscle pain, headache, coughing, and fatigue. These sympto ...
pandemics, mortality from influenza in pregnant women was 45%. In a 2005 study of vaccination during pregnancy, Munoz et al. demonstrated that there was no adverse outcome observed in the new infants or mothers, suggesting that the balance of risk between infection and vaccination favored preventative vaccination.


Reproductive hormones and hormone replacement therapy

There are a number of ways that a fetus can be affected in pregnancy, specifically due to exposure to various substances. There are a number of drugs that can do this, specifically drugs such as female
reproductive hormone A hormone (from the Greek participle , "setting in motion") is a class of signaling molecules in multicellular organisms that are sent to distant organs or tissues by complex biological processes to regulate physiology and behavior. Hormones a ...
s or hormone replacement drugs such as
estrogen Estrogen (also spelled oestrogen in British English; see spelling differences) is a category of sex hormone responsible for the development and regulation of the female reproductive system and secondary sex characteristics. There are three ...
and
progesterone Progesterone (; P4) is an endogenous steroid and progestogen sex hormone involved in the menstrual cycle, pregnancy, and embryogenesis of humans and other species. It belongs to a group of steroid hormones called the progestogens and is the ma ...
that are not only essential for reproductive health, but also pose concerns when it comes to the synthetic alternatives to these. This can cause a multitude of congenital abnormalities and deformities, many of which can ultimately affect the fetus and even the mother's reproductive system in the long term. According to a study conducted from 2015 till 2018, it was found that there was an increased risk of both maternal and neonatal complications developing as a result of
hormone replacement therapy Hormone replacement therapy (HRT), also known as menopausal hormone therapy or postmenopausal hormone therapy, is a form of hormone therapy used to treat symptoms associated with female menopause. Effects of menopause can include symptoms such ...
cycles being conducted during pregnancy, especially in regards to hormones such as estrogen,
testosterone Testosterone is the primary male sex hormone and androgen in Male, males. In humans, testosterone plays a key role in the development of Male reproductive system, male reproductive tissues such as testicles and prostate, as well as promoting se ...
and thyroid hormone. When hormones such as estrogen and testosterone are replaced, this can cause the fetus to become stunted in growth, born prematurely with a lower birth weight, develop mental retardation, while in turn causing the mother's ovarian reserve to be depleted while increasing ovarian follicular recruitment.


Chemotherapeutic agents

It is rare for cancer and pregnancy to coincide, occurring in only 1 in 1,000 pregnancies and making up less than 0.1% of all recorded malignant tumors. However, when this does occur, there are many complications and great, although not well understood, risks to the fetus in the event that
chemotherapy Chemotherapy (often abbreviated chemo, sometimes CTX and CTx) is the type of cancer treatment that uses one or more anti-cancer drugs (list of chemotherapeutic agents, chemotherapeutic agents or alkylating agents) in a standard chemotherapy re ...
drugs are used. The majority of these drugs are cytotoxic, meaning that they have the potential to be
carcinogen A carcinogen () is any agent that promotes the development of cancer. Carcinogens can include synthetic chemicals, naturally occurring substances, physical agents such as ionizing and non-ionizing radiation, and biologic agents such as viruse ...
ic, mutagenic, and teratogenic. If used during the first two weeks of pregnancy, they may inhibit implantation of the fetus and led to miscarriage. They may particularly act as teratogenic agents if used from the second to eighth week, as this is a critical stage for tissue differentiation. The highest risk continues through the first trimester, making up 14% of major malformations. Chemotherapeutic drugs are considered safer to use during the second and third trimester, but there is limited research to fully support this.


Thalidomide

Thalidomide Thalidomide, sold under the brand names Contergan and Thalomid among others, is an oral administered medication used to treat a number of cancers (e.g., multiple myeloma), graft-versus-host disease, and many skin disorders (e.g., complication ...
, also known as Thalomid, was used in the mid-1900s primarily, as a sedative. It is a drug that was first introduced in Germany and spread to other countries as a therapeutic prescription from the 1950s to early 1960s in Europe as an anti-nausea medication to alleviate morning sickness among pregnant women. While the exact mechanism of action of thalidomide is not known, it is thought to be related to inhibition of
angiogenesis Angiogenesis is the physiological process through which new blood vessels form from pre-existing vessels, formed in the earlier stage of vasculogenesis. Angiogenesis continues the growth of the vasculature mainly by processes of sprouting and ...
through interaction with the insulin like growth factor(IGF-1) and fibroblast like growth factor 2 (FGF-2) pathways. This drug acted upon the immune system causing the overall blood cell count be reduced after repeated usage and hindered the generation of the cells. In the 1960s, it became apparent that thalidomide altered embryo development and led to limb deformities such as thumb absence, underdevelopment of entire limbs, or
phocomelia Phocomelia is a congenital condition that involves malformations of human arms and legs which result in a flipper-like appendage. A prominent cause of phocomelia is the mother being prescribed the use of the drug thalidomide during pregnancy; ho ...
. It is among the first known drugs that research pointed towards the possibility of it causing birth defects. Thalidomide may have caused teratogenic effects in over 10,000 babies worldwide. As it became more well known, other uses were found, such as its use in
leprosy Leprosy, also known as Hansen's disease (HD), is a Chronic condition, long-term infection by the bacteria ''Mycobacterium leprae'' or ''Mycobacterium lepromatosis''. Infection can lead to damage of the Peripheral nervous system, nerves, respir ...
treatment,
cancer Cancer is a group of diseases involving Cell growth#Disorders, abnormal cell growth with the potential to Invasion (cancer), invade or Metastasis, spread to other parts of the body. These contrast with benign tumors, which do not spread. Po ...
treatment, and
HIV The human immunodeficiency viruses (HIV) are two species of '' Lentivirus'' (a subgroup of retrovirus) that infect humans. Over time, they cause acquired immunodeficiency syndrome (AIDS), a condition in which progressive failure of the im ...
infections.


Recreational drugs


Alcohol

In the US,
alcohol Alcohol may refer to: Common uses * Alcohol (chemistry), a class of compounds * Ethanol, one of several alcohols, commonly known as alcohol in everyday life ** Alcohol (drug), intoxicant found in alcoholic beverages ** Alcoholic beverage, an alco ...
is subject to the FDA drug labeling
Pregnancy Category The pregnancy category of a medication is an assessment of the risk of fetal injury due to the pharmaceutical, if it is used as directed by the mother during pregnancy. It does ''not'' include any risks conferred by pharmaceutical agents or their ...
X (''Contraindicated in pregnancy''). Alcohol is known to cause
fetal alcohol spectrum disorder Fetal alcohol spectrum disorders (FASDs) are a group of conditions that can occur in a person who is exposed to alcohol during gestation. FASD affects 1 in 20 Americans, but is highly misdiagnosed and underdiagnosed. The several forms of the ...
. There are a wide range of affects that Prenatal Alcohol Exposure (PAE) can have on a developing fetus. Some of the most prominent possible outcomes include the development of Fetal Alcohol Syndrome, a reduction in brain volume, still births, spontaneous abortions, impairments of the nervous system, and much more. Fetal Alcohol Syndrome has numerous symptoms which may include cognitive impairments and impairment of the facial features. PAE remains the leading cause of birth defects and neurodevelopmental abnormalities in the United States, affecting 9.1 to 50 per 1000 live births in the U.S. and 68.0 to 89.2 per 1000 in populations with high levels of alcohol use.


Tobacco and Nicotine

Consuming
tobacco Tobacco is the common name of several plants in the genus '' Nicotiana'' of the family Solanaceae, and the general term for any product prepared from the cured leaves of these plants. More than 70 species of tobacco are known, but the ...
products while pregnant or breastfeeding can have significant negative impacts on the health and development of the unborn child and newborn infant. In a research study conducted in 1957, the relationship between tobacco consumption during pregnancy and premature births was studied. The research showed that there was significant evidence that tobacco consumption during pregnancy can cause the mother to go into labor and deliver earlier than determined due date. Some of the data showed conflicting evidence because tobacco reduces premature birth via
gestational hypertension Gestational hypertension or pregnancy-induced hypertension (PIH) is the development of new hypertension in a pregnant woman after 20 weeks of gestation without the presence of protein in the urine or other signs of pre-eclampsia. Gestational hype ...
but increases other symptom risks. From 1957 to 1986 there were over 500,000 babies observed in studies that showed pregnant mothers intaking tobacco have increased probability that the baby birthed will weigh less than babies birthed by non-smoking mothers. A research study was conducted on six year old's and found a correlation between lower birth weights and lower IQ levels. This can be harmful to the child potentially affecting their brain development overtime as the fetus was not able to have the development of the neurological pathways needed to grow. Tobacco use can also cause stillbirths in mothers who are pregnant, increasing the probability up to three times more risk than non tobacco users. Research shows that the earlier in the pregnancy the mother is the higher chance of a still birth baby being born. Babies that are exposed to nicotine and tobacco can develop an addiction to this substance while still developing, causing addict-like behavioral patterns when born.


= E-Cigarettes

= E-Cigarettes are electronic devices that contain a heating device as well as a cartage to hold liquid in. The liquid in the cartages contain nicotine in about one-third to two-thirds the amount in regular cigarettes. This means that the nicotine still crosses the
placenta The placenta (: placentas or placentae) is a temporary embryonic and later fetal organ that begins developing from the blastocyst shortly after implantation. It plays critical roles in facilitating nutrient, gas, and waste exchange between ...
, and can be detected in the fetus' blood and plasma at higher levels than the maternal concentrations. It can be harmful to the developing fetus' brain and lungs. The liquid also contains artificial flavoring agents that can be harmful to the body. A pregnant mother can have issues that form during development of the baby due to nicotine like birth deformities or retardation. Many of the deformities can include the skull not fully forming, limbs forming partially, or
cardiovascular In vertebrates, the circulatory system is a system of organs that includes the heart, blood vessels, and blood which is circulated throughout the body. It includes the cardiovascular system, or vascular system, that consists of the heart a ...
issues.


Cocaine

Cocaine can act as a teratogen, having various effects on the developing fetus. Some common teratogenic defects caused by cocaine include
hydronephrosis Hydronephrosis is the hydrostatic dilation of the renal pelvis and Renal calyx, calyces as a result of obstruction to urine flow downstream. Alternatively, hydroureter describes the dilation of the ureter, and hydronephroureter describes the dila ...
,
cleft palate A cleft lip contains an opening in the upper lip that may extend into the nose. The opening may be on one side, both sides, or in the middle. A cleft palate occurs when the palate (the roof of the mouth) contains an opening into the nose. The ...
,
polydactyly Polydactyly is a birth defect that results in extra fingers or toes. The hands are more commonly involved than the feet. Extra fingers may be painful, affect self-esteem, or result in clumsiness. It is associated with at least 39 genetic mut ...
, and down syndrome. Cocaine as a drug has a low molecular weight and high water and lipid solubility which enables it to cross the
placenta The placenta (: placentas or placentae) is a temporary embryonic and later fetal organ that begins developing from the blastocyst shortly after implantation. It plays critical roles in facilitating nutrient, gas, and waste exchange between ...
and fetal blood-brain barrier. Because cocaine is able to pass through the placenta and enter the fetus, the fetus' circulation can be negatively affected. With restriction of fetal circulation, the development of organs in the fetus can be impacted, even resulting in intestines developing outside of the fetus' body. Cocaine use during pregnancy can also result in
obstetric labor complication An obstetric labor complication is a difficulty or abnormality that arises during the process of labor or delivery. The Trust for America's Health reports that as of 2011, about one third of American births have some complications; many are direc ...
s such as
preterm birth Preterm birth, also known as premature birth, is the Childbirth, birth of a baby at fewer than 37 weeks Gestational age (obstetrics), gestational age, as opposed to full-term delivery at approximately 40 weeks. Extreme preterm is less than 28 ...
or delivery,
uterine rupture Uterine rupture is when the muscular wall of the uterus tears during pregnancy or childbirth. Symptoms, while classically including increased pain, vaginal bleeding, or a change in contractions, are not always present. Disability or death of the ...
,
miscarriage Miscarriage, also known in medical terms as a spontaneous abortion, is an end to pregnancy resulting in the loss and expulsion of an embryo or fetus from the womb before it can fetal viability, survive independently. Miscarriage before 6 weeks ...
, and
stillbirth Stillbirth is typically defined as fetus, fetal death at or after 20 or 28 weeks of pregnancy, depending on the source. It results in a baby born without vital signs, signs of life. A stillbirth can often result in the feeling of guilt (emotio ...
.


Marijuana

There is currently no reliable data to suggest that
marijuana Cannabis (), commonly known as marijuana (), weed, pot, and ganja, List of slang names for cannabis, among other names, is a non-chemically uniform psychoactive drug from the ''Cannabis'' plant. Native to Central or South Asia, cannabis has ...
consistently acts as a teratogen. However, some studies show that it may have negative effects on the development of the fetus and consequent neurobehavioral outcomes. Frequent use of marijuana during pregnancy has been related to a reduction in birth weight, although the association is not strong.  The
neurodevelopment The development of the nervous system in humans, or neural development, or neurodevelopment involves the studies of embryology, developmental biology, and neuroscience. These describe the cellular and molecular mechanisms by which the complex ...
al effects include sleep disturbances, hyperactivity, increased delinquency, and worsened problem-solving. However, this data is not conclusive because there are a variety of other factors that tend to be associated with prenatal use of marijuana, including poorer economic status and exposure to other illicit drugs. Complications with maternal use of cannabis also stem from the fact that it is excreted into breast milk in small quantities and may harm motor development if fetal exposure is regular. It is advised that mothers refrain from using any products containing THC while they are breastfeeding or pregnant.


Caffeine

Caffeine consumption during pregnancy has been linked to intrauterine growth retardation and spontaneous abortion during the first trimester. Other teratogenic effects include low birthweight, problems with neural tube development, decreased head circumference, excessive infant growth, and cognitive impairments at birth. Caffeine's chemical structure allows it to be transmitted across biological membranes, including the placental barrier, which is then transmitted to the developing embryo. The inability to breakdown caffeine results in a build up of caffeine in the embryo. The build up of caffeine in embryos can produce teratogenic effects by blocking adenosine receptors, which regulate several neurotransmitters, including dopamine, serotonin, norepinephrine, and GABA. The teratogenic effects of caffeine are variable, and affects individuals differently depending on their sensitivity to caffeine. One mother may not have any teratogenic effects from caffeine consumption during pregnancy, while another could have significant complications.


Physical Agents as Teratogenic Agents


Heat

One example of a physical agent which may give rise to developmental complications is heat. Women may be exposed to heat from external sources such as extreme heat conditions and hot-tub exposures. External temperatures that exceed 102 °Fahrenheit can give rise to fetal complications via the mechanism of neural tube malformation. The exact mechanisms relating heat to neural tube defects are not well-known. A potential theory connects heat to multiple cell-related issues, including cell movement, cell division, and apoptosis. The disruption in these normal processes may ultimately feed into the mechanism of neural tube malformation. Another method of exposure to heat can be seen as a result of the pregnancy itself. This phenomenon can be associated with maternal weight gain as well the heat produced via fetal metabolism, both of which may cause dysregulation of heat escape. The exact mechanisms beyond these surface-level causes are not clear. One theory associates this heat with producing heat-shock proteins, which then disrupt a certain normal protein balance. This deviation from a normal protein balance may then interfere with fetal development. Another theory draws potential connections between elevated temperature, oxidative stress, and inflammation with blood flow restriction to the fetus.


Radiation

Although large exposures to radiation during pregnancies are often rare, when such exposures occur the resulting teratogenic complications occur due to various factors and/or mechanisms. The negative effects associated with radiation in general have to do with the interaction of said radiation with the stem cells of the developing fetus. There are also associations with DNA damage, oxidative stress responses, and changes in protein expression. In terms of ionizing radiation in particular, such forms of radiation often cause chemical changes to occur that yields abnormal chemical species. These chemical materials can then act on two different structures: they can either alter specific tissue-level structures in a predictable way, or act on DNA structures in a more random fashion.


Noise

While some ranges of sound are kept from reaching the fetus due to the presence of the mother's abdomen and uterus as barrier of sorts, there is still evidence that both high intensity sounds and continuous exposure to sound can be harmful to the fetus. Such sounds may bring about many potential problems within the fetus, including chromosomal abnormalities, altered social behavior after birth, and issues with hearing. In terms of hearing damage specifically, it is thought that these external sounds cause damage to the developing fetal cochlea and its constituent parts, particularly the inner and outer hairs of the structure.


Lead exposure

Long before modern science, it was understood that heavy metals could cause negative effects to those who were exposed. The Greek physician
Pedanius Dioscorides Pedanius Dioscorides (, ; 40–90 AD), "the father of pharmacognosy", was a Greek physician, pharmacologist, botanist, and author of (in the original , , both meaning "On Medical Material") , a 5-volume Greek encyclopedic pharmacopeia on he ...
described the effects of lead exposure as something that "makes the mind give way". Lead exposure in adults can lead to cardiological, renal, reproductive, and cognitive issues that are often irreversible, however, lead exposure during pregnancy can be detrimental to the long-term health of the fetus. Exposure to lead during pregnancy is well known to have teratogenic effects on the development of a fetus. Specifically, fetal exposure to lead can cause cognitive impairment, premature births, unplanned abortions, ADHD, and much more. Lead exposure during the first trimester of pregnancy leads to the greatest predictability of cognitive development issues after birth. Low socioeconomic status correlates to a higher probability of lead exposure. A well-known recent example of lead and the impacts it can have on a was the 2014 water crisis in Flint, Michigan. Researchers have found that female fetuses developed at a higher rate than male fetuses in Flint when compared to surrounding areas. The higher rate of female births indicated a problem because male fetuses are more sensitive to pregnancy hazards than female fetuses.


Phthalate exposure

Phthalate acid esters (PAEs) are a classification of chemical plasticizers used to increase flexibility in commercial plastics, such as polyethylene terephthalate (PET) and polyvinyl chloride (PVC). Phthalates are currently used in several consumer goods, including food packaging, cosmetics, clothing, fragrance, and toys. Additionally, they have wide-spread use in pharmaceutical and medical products, including in coatings and fillers of extend-release medications, blood bag packaging, tubes used in blood transfers, and hemodialysis units. The most common phthalates include di(2-ethylhexyl) phthalate and di-n-butyl phthalate. As of 2017, di(2-ethylhexyl) phthalate is estimated to make up 30% of plastic produced in the United States and European Union, and up to 80% of plastic produced in China. Several animal studies have been conducted to observe the specific effects of DEHP in vitro, including rats, mice, and chick embryos. Observed effects of high phthalate exposure in utero included neural tube malformations, encephalopathy, limb malformations, decreased vasculature, vascular malformations, decreased bodyweight and interuterine death at high concentrations. Higher concentrations of phthalates and phthalate metabolites have also been observed in the urine of mothers to children with neural tube malformations. Phthalate exposure induces teratogenic effects through multiple mechanisms of action. High levels of di-(2-ethylhexyl)-phthalate create oxidative stress in utero, which results in cellular apoptosis in developing fetuses. In vivo, di-(2-ethylhexyl)-phthalate is hydrolyzed into 2-ethylhexanol. It's hypothesized that the metabolic byproduct of 2-ethylhexanol, ethylhexanoic acid, is the primary teratogen responsible for developmental defects in embryos exposed to di-(2-ethylhexyl)-phthalate. The use of di-n-butyl phthalate in children's products was restricted in the United States in 2008, and is restricted in cosmetics in the European Union. Several phthalates, including di-n-butyl phthalate, di-n-hexyl phthalate, and butyl benzyl phthalate, were issued a Proposition 65 warning by the state of California in March, 2005 following evidence of reproductive toxicity and teratogenic effects.


Stress

Maternal stress has been associated with an increased risk of various birth defects, though a direct causal relationship has not been conclusively established. Studies suggest that the exposure to significant psychological stress or traumatic events during pregnancy may correlate with a higher incidence of congenital anomalies, such as oral facial cleft (cleft lip and palate), neural tube defects and conotruncal heart defects. One proposed mechanisms involves the dysregulation of maternal stress hormones, particularly glucocorticoids, which include cortisol and other corticosteroids. These hormones, often referred to as "stress hormones", are capable of crossing the placental barrier, but their effects on the fetus depends on the timing, duration, and intensity of exposure. The placenta expresses various enzymes, which metabolizes active cortisol into its inactive form, protecting the fetus. However extreme physiological responses or chronic stress could overwhelm this protective factor. Additionally, stress-induced changes in maternal physiology, such as reduced uteroplacental blood flow, inflammation, and oxidative stress, may further contribute to developmental disruptions. Sometimes, corticosteroids are used therapeutically to promote fetal lung maturation in preterm labor, excessive or prolonged exposure has been linked to intrauterine growth restriction and altered fetal programming. Further research is needed to clarify the exact role of maternal stress in teratogenesis and to determine the potential long-term impacts on offspring health.


Nutrient Deficiencies

Micronutrient deficiencies during pregnancy can contribute to teratogenesis by disrupting essential developmental processes. Deficiencies in folate, iodine, vitamin A, and other key nutrients have been linked to congenital anomalies, miscarriage, and impaired fetal growth. These deficiencies impair cellular differentiation, gene expression, and organogenesis, making proper maternal nutrition crucial for fetal development. Prevention strategies include dietary supplementation and food fortification programs to reduce the incidence of birth defects worldwide.


Folate Deficiency

Folate deficiency increases the risk of neural tube defects. It has been shown that supplementation of folate before, during, and after conception is able to reduce the risk of a fetus developing neural tube defects, cardiovascular malformations, cleft lip and palate, urogenital abnormalities, and reduced limb size.


Iodine Deficiency

In mothers, an iodine deficiency can lead to hypothyroidism, increasing the chances for miscarriage to occur.
Hypothyroidism Hypothyroidism is an endocrine disease in which the thyroid gland does not produce enough thyroid hormones. It can cause a number of symptoms, such as cold intolerance, poor ability to tolerate cold, fatigue, extreme fatigue, muscle aches, co ...
can also potentially cause growth problems in the baby, increasing the chances for preterm delivery. If the iodine deficiency is severe, the likelihood of stillbirth is increased as well as the child having the potential for increased hearing problems. Iodine deficiency has been associated with craniofacial and heart defects. The most severe cases of iodine deficiency caused hypothyroidism can result in cretinism.


Zinc Deficiency

Zinc deficiency can result in fetal death, intrauterine growth retardation, and teratogenesis. It can also have postnatal effects, such as behavioral abnormalities, elevated risk of high blood pressure, or impaired cognitive abilities.


Other animals


Fossil record

Evidence for congenital deformities found in the fossil record is studied by paleopathologists, specialists in ancient disease and injury. Fossils bearing evidence of congenital deformity are scientifically significant because they can help scientists infer the evolutionary history of life's developmental processes. For instance, because a ''
Tyrannosaurus rex ''Tyrannosaurus'' () is a genus of large theropoda, theropod dinosaur. The type species ''Tyrannosaurus rex'' ( meaning 'king' in Latin), often shortened to ''T. rex'' or colloquially t-rex, is one of the best represented theropods. It live ...
'' specimen has been discovered with a block vertebra, it means that vertebrae have been developing the same basic way since at least the most recent common ancestor of dinosaurs and mammals. Other notable fossil deformities include a hatchling specimen of the bird-like dinosaur, ''
Troodon ''Troodon'' ( ; ''Troödon'' in older sources) is a controversial genus of relatively small, bird-like theropod dinosaurs definitively known from the Campanian age of the Late Cretaceous period (about 77 million years ago). It includes at l ...
'', the tip of whose jaw was twisted. Another notably deformed fossil was a specimen of the
Choristodera Choristodera (from the Greek χωριστός ''chōristos'' + δέρη ''dérē'', 'separated neck') is an extinct order of semiaquatic diapsid reptiles that ranged from the Middle Jurassic, or possibly Triassic, to the Miocene (168 to 20 or p ...
''
Hyphalosaurus ''Hyphalosaurus'' (meaning "submerged lizard") is a genus of freshwater aquatic reptiles, belonging to the extinct order Choristodera. They lived during the early Cretaceous period (late Barremian to early Aptian age), about 123-120 million year ...
'', which had two heads- the oldest known example of
polycephaly Polycephaly is the condition of having more than one head. The term is derived from the Greek stems ''poly'' (Greek: "πολύ") meaning "many" and ''kephalē'' (Greek: "κεφαλή") meaning "head". A polycephalic organism may be thought ...
.


Thalidomide and chick limb development

Thalidomide Thalidomide, sold under the brand names Contergan and Thalomid among others, is an oral administered medication used to treat a number of cancers (e.g., multiple myeloma), graft-versus-host disease, and many skin disorders (e.g., complication ...
is a teratogen known to be significantly detrimental to organ and limb development during embryogenesis. It has been observed in chick embryos that exposure to thalidomide can induce limb outgrowth deformities, due to increased
oxidative stress Oxidative stress reflects an imbalance between the systemic manifestation of reactive oxygen species and a biological system's ability to readily detoxify the reactive intermediates or to repair the resulting damage. Disturbances in the normal ...
interfering with the
Wnt signaling pathway In cellular biology, the Wnt signaling pathways are a group of signal transduction pathways which begin with proteins that pass signals into a cell through cell surface receptors. The name Wnt, pronounced "wint", is a portmanteau created from the ...
, increasing apoptosis, and damaging immature blood vessels in developing
limb bud The limb bud is a structure formed early in vertebrate limb development. As a result of interactions between the ectoderm and underlying mesoderm, formation occurs roughly around the fourth week of development. In human embryonic development, the ...
s.


Retinoic acid and mouse limb development

Retinoic acid Retinoic acid (simplified nomenclature for all-''trans''-retinoic acid) is a metabolite of vitamin A1 (all-''trans''-retinol) that is required for embryonic development, male fertility, regulation of bone growth and immune function. All-''trans ...
(RA) is significant in embryonic development. It induces the function of limb patterning of a developing embryo in species such as mice and other vertebrate limbs. For example, during the process of regenerating a newt limb an increased amount of RA moves the limb more proximal to the distal blastoma and the extent of the proximalization of the limb increases with the amount of RA present during the regeneration process. A study looked at the RA activity intracellularly in mice in relation to human regulating CYP26 enzymes which play a critical role in metabolizing RA. This study also helps to reveal that RA is significant in various aspects of limb development in an embryo, however irregular control or excess amounts of RA can have teratogenic impacts causing malformations of limb development. They looked specifically at
CYP26B1 Cytochrome P450 26B1 is a protein that in humans is encoded by the ''CYP26B1'' gene. This gene encodes a member of the cytochrome P450 superfamily of enzymes. The cytochrome P450 proteins are monooxygenases that catalyze many reactions involved ...
which is highly expressed in regions of limb development in mice. The lack of CYP26B1 was shown to cause a spread of RA signal towards the distal section of the limb causing proximo-distal patterning irregularities of the limb. Not only did it show spreading of RA but a deficiency in the CYP26B1 also showed an induced
apoptosis Apoptosis (from ) is a form of programmed cell death that occurs in multicellular organisms and in some eukaryotic, single-celled microorganisms such as yeast. Biochemistry, Biochemical events lead to characteristic cell changes (Morphology (biol ...
effect in the developing mouse limb but delayed
chondrocyte Chondrocytes (, ) are the only cells found in healthy cartilage. They produce and maintain the cartilaginous matrix, which consists mainly of collagen and proteoglycans. Although the word '' chondroblast'' is commonly used to describe an immatu ...
maturation, which are cells that secrete a cartilage matrix which is significant for limb structure. They also looked at what happened to development of the limbs in wild type mice, that are mice with no CYP26B1 deficiencies, but which had an excess amount of RA present in the embryo. The results showed a similar impact to limb patterning if the mice did have the CYP26B1 deficiency meaning that there was still a proximal distal patterning deficiency observed when excess RA was present. This then concludes that RA plays the role of a morphogen to identify proximal distal patterning of limb development in mice embryos and that CYP26B1 is significant to prevent apoptosis of those limb tissues to further proper development of mice limbs in vivo.


Rat development and lead exposure

There has been evidence of teratogenic effects of lead in rats as well. An experiment was conducted where pregnant rats were given drinking water, before and during pregnancy, that contained lead. Many detrimental effects, and signs of teratogenesis were found, such as negative impacts on the formation of the cerebellum, fetal mortality, and developmental issues for various parts of the body.


Plants

In
botany Botany, also called plant science, is the branch of natural science and biology studying plants, especially Plant anatomy, their anatomy, Plant taxonomy, taxonomy, and Plant ecology, ecology. A botanist or plant scientist is a scientist who s ...
, teratology investigates the theoretical implications of abnormal specimens. For example, the discovery of abnormal flowers—for example, flowers with leaves instead of petals, or flowers with staminoid pistils—furnished important evidence for the "
foliar theory The ABC model of flower development is a scientific model of the process by which flowering plants produce a pattern of gene expression in meristems that leads to the appearance of an organ oriented towards sexual reproduction, a flower. There a ...
", the theory that all flower parts are highly specialised leaves. In plants, such specimens are denoted as 'lusus naturae' ('
sports Sport is a physical activity or game, often competitive and organized, that maintains or improves physical ability and skills. Sport may provide enjoyment to participants and entertainment to spectators. The number of participants in ...
of nature', abbreviated as 'lus.'); and occasionally as 'ter.', 'monst.', or 'monstr.'.


Types of deformations in plants

Plants can have mutations that leads to different types of deformations such as: *
Fasciation Fasciation (pronounced , from the Latin root meaning "band" or "stripe"), also known as cresting, is a relatively rare condition of abnormal growth in vascular plants in which the apical meristem (growing tip), which normally is concentrated aro ...
: Development of the apex (growing tip) in a flat plane perpendicular to the axis of elongation *
Variegation '' Cryptocarya williwilliana'' showing leaf venation and variegated leaves Variegation is the appearance of differently coloured zones in the foliage, flowers, and sometimes the stems and fruit of plants, granting a speckled, striped, or patch ...
: Degeneration of genes, manifesting itself among other things by anomalous pigmentation *
Virescence Virescence is the abnormal development of green pigment (biology), pigmentation in plant parts that are not normally green, like Plant shoots, shoots or flowers (in which case it is known as floral virescence). Virescence is closely associated with ...
: Anomalous development of a green pigmentation in unexpected parts of the plant *
Phyllody Phyllody is the teratology, abnormal development of flower, floral parts into leafy structures. It is generally caused by phytoplasma or virus infections, though it may also be because of Physiological plant disorders, environmental factors that ...
: Floral organs or fruits transformed into leaves *
Witch's broom Witch's broom or witches' broom is a deformity in a woody plant, typically a tree, where the natural structure of the plant is changed. A dense mass of shoots grows from a single point, with the resulting structure resembling a broom or a bi ...
: Unusually high multiplication of branches in the upper part of the plant, mainly in a tree * Pelorism: Zygomorphic flower regress to their ancestral actinomorphic symmetry * Proliferation: Repetitive growth of an entire organ, such as a flower


Research

Studies designed to test the teratogenic potential of environmental agents use animal model systems (e.g., rat, mouse, rabbit, dog, and monkey). Early teratologists exposed pregnant animals to environmental agents and observed the fetuses for gross visceral and skeletal abnormalities. While this is still part of the teratological evaluation procedures today, the field of Teratology is moving to a more
molecular A molecule is a group of two or more atoms that are held together by attractive forces known as chemical bonds; depending on context, the term may or may not include ions that satisfy this criterion. In quantum physics, organic chemistry, ...
level, seeking the mechanism(s) of action by which these agents act. One example of this is the use of mammalian animal models to evaluate the molecular role of teratogens in the development of embryonic populations, such as the
neural crest The neural crest is a ridge-like structure that is formed transiently between the epidermal ectoderm and neural plate during vertebrate development. Neural crest cells originate from this structure through the epithelial-mesenchymal transition, ...
, which can lead to the development of
neurocristopathies Neurocristopathy is a diverse class of pathologies that may arise from defects in the development of tissues containing cells commonly derived from the embryonic neural crest cell lineage. The term was coined by Robert P. Bolande in 1974. After th ...
.
Genetically modified Genetic engineering, also called genetic modification or genetic manipulation, is the modification and manipulation of an organism's genes using technology. It is a set of technologies used to change the genetic makeup of cells, including th ...
mice are commonly used for this purpose. In addition, pregnancy registries are large, prospective studies that monitor exposures women receive during their pregnancies and record the outcome of their births. These studies provide information about possible risks of medications or other exposures in human pregnancies. Prenatal alcohol exposure (PAE) can produce craniofacial malformations, a phenotype that is visible in
Fetal Alcohol Syndrome Fetal alcohol spectrum disorders (FASDs) are a group of conditions that can occur in a person who is exposed to alcohol during gestation. FASD affects 1 in 20 Americans, but is highly misdiagnosed and underdiagnosed. The several forms of the ...
. Current evidence suggests that craniofacial malformations occur via: apoptosis of neural crest cells, interference with neural crest cell migration, as well as the disruption of sonic hedgehog (shh) signaling. Understanding how a teratogen causes its effect is not only important in preventing congenital abnormalities but also has the potential for developing new therapeutic drugs safe for use with pregnant women.


See also

*
Carcinogen A carcinogen () is any agent that promotes the development of cancer. Carcinogens can include synthetic chemicals, naturally occurring substances, physical agents such as ionizing and non-ionizing radiation, and biologic agents such as viruse ...
*
Congenital abnormalities A birth defect is an abnormal condition that is present at birth, regardless of its cause. Birth defects may result in disabilities that may be physical, intellectual, or developmental. The disabilities can range from mild to severe. Birth de ...
*
Mutagen In genetics, a mutagen is a physical or chemical agent that permanently changes genetic material, usually DNA, in an organism and thus increases the frequency of mutations above the natural background level. As many mutations can cause cancer in ...
*
Polydactyly Polydactyly is a birth defect that results in extra fingers or toes. The hands are more commonly involved than the feet. Extra fingers may be painful, affect self-esteem, or result in clumsiness. It is associated with at least 39 genetic mut ...
*
Retinoic acid Retinoic acid (simplified nomenclature for all-''trans''-retinoic acid) is a metabolite of vitamin A1 (all-''trans''-retinol) that is required for embryonic development, male fertility, regulation of bone growth and immune function. All-''trans ...
*
Teratoma A teratoma is a neoplasia, tumor made up of several types of biological tissue, tissue, such as hair, muscle, Human tooth, teeth, or bone. Teratomata typically form in the tailbone (where it is known as a sacrococcygeal teratoma), ovary, or test ...
*
Thalidomide Thalidomide, sold under the brand names Contergan and Thalomid among others, is an oral administered medication used to treat a number of cancers (e.g., multiple myeloma), graft-versus-host disease, and many skin disorders (e.g., complication ...


References


Sources

*


External links


Society of Teratology

European Teratology Society

Organization of Teratology Information Specialists

March of Dimes Foundation

A Telling of Wonders: Teratology in Western Medicine through 1800 (New York Academy of Medicine Historical Collections)

The Reproductive Toxicology Center Database
{{Authority control Alcohol and health Developmental biology Radiation health effects Substance-related disorders Teratogens