Welfare capitalism is capitalism that includes social welfare policies and/or the practice of businesses providing welfare services to their employees. Welfare capitalism in this second sense, or industrial paternalism, was centered on industries that employed skilled labor and peaked in the mid-20th century.
Today, welfare capitalism is most often associated with the
models of capitalism found in Central Mainland and Northern Europe, such
as the Nordic model and social market economy (also known as Rhine capitalism and social capitalism). In some cases welfare capitalism exists within a mixed economy, but welfare states can and do exist independently of policies common to mixed economies such as state interventionism and extensive regulation.
Language
"Welfare
capitalism" or "welfare corporatism" is somewhat neutral language for
what, in other contexts, might be framed as "industrial paternalism",
"industrial village", "company town", "representative plan", "industrial betterment", or "company union".
History
In
the 19th century, some companies—mostly manufacturers—began offering
new benefits for their employees. This began in Britain in the early
19th century and also occurred in other European countries, including
France and Germany. These companies sponsored sports teams, established social clubs,
and provided educational and cultural activities for workers. Some
offered housing as well. Welfare corporatism in the United States
developed during the intense Industrial Revolution development of 1880 to 1900 which was marked by labor disputes and strikes, many violent.
Cooperatives and model villages
Robert Owen
was a utopian socialist of the early 19th century, who introduced one
of the first private systems of philanthropic welfare for his workers at
the cotton mills of New Lanark. He embarked on a scheme in New Harmony, Indiana to create a model cooperative, called the New Moral World, (pictured). Owenites fired bricks to build it, but construction never took place.
One of the first attempts at offering philanthropic welfare to workers was made at the New Lanark mills in Scotland by the social reformerRobert Owen. He became manager and part owner of the mills in 1810, and encouraged by his success in the management of cotton mills in Manchester (see also Quarry Bank Mill),
he hoped to conduct New Lanark on higher principles and focus less on
commercial profit. The general condition of the people was very
unsatisfactory. Many of the workers were steeped in theft and
drunkenness, and other vices were common; education and sanitation were
neglected and most families lived in one room. The respectable country
people refused to submit to the long hours and demoralising drudgery of
the mills. Many employers also operated the truck system,
whereby payment to the workers was made in part or totally by tokens.
These tokens had no value outside the mill owner's "truck shop". The
owners were able to supply shoddy goods to the truck shop and charge top
prices. A series of "Truck Acts" (1831–1887) eventually stopped this abuse, by making it an offence not to pay employees in common currency.
Owen opened a store where the people could buy goods of sound
quality at little more than wholesale cost, and he placed the sale of
alcohol under strict supervision. He sold quality goods and passed on
the savings from the bulk purchase of goods to the workers. These
principles became the basis for the cooperative stores
in Britain that continue to operate today. Owen's schemes involved
considerable expense, which displeased his partners. Tired of the
restrictions on his actions, Owen bought them out in 1813. New Lanark
soon became celebrated throughout Europe, with many leading royals,
statesmen and reformers visiting the mills. They were astonished to find
a clean, healthy industrial environment with a content, vibrant
workforce and a prosperous, viable business venture all rolled into one.
Owen's philosophy was contrary to contemporary thinking, but he was
able to demonstrate that it was not necessary for an industrial
enterprise to treat its workers badly to be profitable. Owen was able to
show visitors the village's excellent housing and amenities, and the
accounts showing the profitability of the mills.
Owen and the French socialist Henri de Saint-Simon were the fathers of the utopian socialist
movement; they believed that the ills of industrial work relations
could be removed by the establishment of small cooperative communities.
Boarding houses were built near the factories for the workers'
accommodation. These so-called model villages
were envisioned as a self-contained community for the factory workers.
Although the villages were located close to industrial sites, they were
generally physically separated from them and generally consisted of
relatively high quality housing, with integrated community amenities and
attractive physical environments.
The first such villages were built in the late 18th century, and
they proliferated in England in the early 19th century with the
establishment of Trowse, Norfolk in 1805 and Blaise Hamlet, Bristol in 1811. In America, boarding houses were built for textile workers in Lowell, Massachusetts in the 1820s. The motive behind these offerings was paternalistic—owners were
providing for workers in ways they felt was good for them. These
programs did not address the problems of long work hours, unsafe
conditions, and employment insecurity that plagued industrial workers
during that period, however. Indeed, employers who provided housing in
company towns (communities established by employers where stores and
housing were run by companies) often faced resentment from workers who
chafed at the control owners had over their housing and commercial
opportunities. A noted example was Pullman, Illinois—a
site of a strike that destroyed the town in 1894. During these years,
disputes between employers and workers often turned violent and led to
government intervention.
Welfare as a business model
The Cadbury factory at Bournville, c. 1903, where workers worked in conditions that were very good for the time
In the early years of the 20th century, business leaders began embracing a different approach. The Cadbury family of philanthropists and business entrepreneurs set up the model village at Bournville,
England in 1879 for their chocolate making factory. Loyal and
hard-working workers were treated with great respect and relatively high
wages and good working conditions; Cadbury pioneered pension schemes, joint works committees and a full staff medical service. By 1900, the estate included 313 'Arts and Crafts' cottages and houses; traditional in design but with large gardens and modern interiors, they were designed by the resident architectWilliam Alexander Harvey.
The Cadburys were also concerned with the health and fitness of
their workforce, incorporating park and recreation areas into the
Bournville village plans and encouraging swimming, walking and indeed all forms of outdoor sports. In the early 1920s, extensive football and hockey
pitches were opened together with a grassed running track. Rowheath
Pavilion served as the clubhouse and changing rooms for the acres of
sports playing fields, several bowling greens, a fishing lake and an
outdoor swimming lido, a natural mineral spring forming the source for
the lido's
healthy waters. The whole area was specifically for the benefit of the
Cadbury workers and their families with no charges for the use of any of
the sporting facilities by Cadbury employees or their families.
Port Sunlight in Wirral, England was built by the Lever Brothers
to accommodate workers in its soap factory in 1888. By 1914, the model
village could house a population of 3,500. The garden village had
allotments and public buildings including the Lady Lever Art Gallery, a cottage hospital, schools, a concert hall, open air swimming pool, church, and a temperance
hotel. Lever introduced welfare schemes, and provided for the education
and entertainment of his workforce, encouraging recreation and
organisations which promoted art, literature, science or music.
Lever's aims were "to socialise and Christianise business
relations and get back to that close family brotherhood that existed in
the good old days of hand labour." He claimed that Port Sunlight was an
exercise in profit sharing,
but rather than share profits directly, he invested them in the
village. He said, "It would not do you much good if you send it down
your throats in the form of bottles of whisky, bags of sweets, or fat
geese at Christmas. On the other hand, if you leave the money with me, I
shall use it to provide for you everything that makes life
pleasant—nice houses, comfortable homes, and healthy recreation."
In America in the early 20th century, businessmen like George F. Johnson and Henry B. Endicott
began to seek new relations with their labor by offering the workers
wage incentives and other benefits. The point was to increase
productivity by creating good will with employees. When Henry Ford
introduced his $5-a-day pay rate in 1914 (when most workers made $11 a
week), his goal was to reduce turnover and build a long-term loyal labor
force that would have higher productivity. Turnover in manufacturing plants in the U.S. from 1910 to 1919 averaged
100%. Wage incentives and internal promotion opportunities were
intended to encourage good attendance and loyalty. This would reduce turnover and improve productivity. The combination of
high pay, high efficiency and cheap consumer goods was known as Fordism, and was widely discussed throughout the world.
Led by the railroads and the largest industrial corporations such as the Pullman Car Company, Standard Oil, International Harvester, Ford Motor Company and United States Steel,
businesses provided numerous services to its employees, including paid
vacations, medical benefits, pensions, recreational facilities, sex
education and the like. The railroads, in order to provide places for
itinerant trainmen to rest, strongly supported YMCA hotels, and built railroad YMCAs. The Pullman Car Company built an entire model town, Pullman, Illinois. The Seaside Institute is an example of a social club built for the particular benefit of women workers. Most of these programs proliferated after World War I—in the 1920s.
The economic upheaval of the Great Depression in the 1930s
brought many of these programs to a halt. Employers cut cultural
activities and stopped building recreational facilities as they
struggled to stay solvent. It wasn't until after World War II that many
of these programs reappeared—and expanded to include more blue-collar
workers. Since this time, programs like on-site child care and
substance abuse treatment have waxed and waned in use/popularity, but
other welfare capitalism components remain. Indeed, in the U.S., the
health care system is largely built around employer-sponsored plans.
In the late 19th and early 20th centuries, Germany and Britain created "safety nets" for their citizens, including public welfare and unemployment insurance. These government-operated welfare systems is the sense in which the term 'welfare capitalism' is generally understood today.
Modern welfare capitalism
The 19th century German economist, Gustav von Schmoller, defined welfare capitalism as government provision for the welfare of workers and the public via social legislation. Western Europe, Australia, and New Zealand are regions noted for their welfare state provisions, though other countries have publicly financed universal healthcare and other elements of the welfare state as well.
Esping-Andersen categorised three different traditions of welfare provision in his 1990 book The Three Worlds of Welfare Capitalism; social democracy, Christian democracy (conservatism) and liberalism.
Though increasingly criticised, these classifications remain the most
commonly used in distinguishing types of modern welfare states, and
offer a solid starting point in such analysis.
European welfare capitalism is typically endorsed by Christian democrats and social democrats. In contrast to social welfare provisions found in other industrialized countries (especially countries with the Anglo-Saxon model
of capitalism), European welfare states provide universal services that
benefit all citizens (social democratic welfare state) as opposed to a
minimalist model that only caters to the needs of the poor.
In Northern European countries, welfare capitalism is often combined with social corporatism and national-level collective bargaining arrangements aimed at balancing the power between labor and business. The most prominent example of this system is the Nordic model,
which features free and open markets with limited regulation, high
concentrations of private ownership in industry, and tax-funded
universal welfare benefits for all citizens.
An alternative model of welfare exists in Continental European countries, known as the social market economy or German model,
which includes a greater role for government interventionism into the
macro-economy but features a less generous welfare state than is found
in the Nordic countries.
In France, the welfare state exists alongside a dirigiste mixed economy.
In the United States
Welfare capitalism in the United States refers to industrial relations policies of large, usually non-unionised, companies that have developed internal welfare systems for their employees. Welfare capitalism first developed in the United States in the 1880s and gained prominence in the 1920s.
Promoted by business leaders during a period marked by widespread
economic insecurity, social reform activism, and labor unrest, it was
based on the idea that Americans should look not to the government or to
labor unions but to the workplace benefits provided by private-sector
employers for protection against the fluctuations of the market economy. Companies employed these types of welfare policies to encourage worker
loyalty, productivity and dedication. Owners feared government
intrusion in the Progressive Era,
and labor uprisings from 1917 to 1919—including strikes against
"benevolent" employers—showed the limits of paternalistic efforts. For owners, the corporation was the most responsible social
institution and it was better suited, in their minds, to promoting the
welfare of employees than government. Welfare capitalism was their way of heading off unions, communism, and government regulation.
The benefits offered by welfare capitalist employers were often
inconsistent and varied widely from firm to firm. They included minimal
benefits such as cafeteria plans,
company-sponsored sports teams, lunchrooms and water fountains in
plants, and company newsletters/magazines—as well as more extensive
plans providing retirement benefits, health care, and employee
profit-sharing. Examples of companies that have practiced welfare capitalism include Kodak, Sears, IBM and Facebook
with the main elements of the employment system in these companies
including permanent employment, internal labor markets, extensive
security and fringe benefits, and sophisticated communications and
employee involvement.
In the 1980s, the philosophy of maximizing shareholder value became dominant, and defined contribution plans such as 401(k)s, replaced guaranteed pensions. The average duration of employment at the same firm also decreased significantly.
Anti-unionism
Welfare
capitalism was also used as a way to resist government regulation of
markets, independent labor union organizing, and the emergence of a
welfare state. Welfare capitalists went to great lengths to quash
independent trade union organizing, strikes,
and other expressions of labor collectivism—through a combination of
violent suppression, worker sanctions, and benefits in exchange for
loyalty. Also, employee stock-ownership programs meant to tie workers to the
success of companies (and accordingly to management). Workers would
then be actual partners with owners—and capitalists themselves. Owners
intended these programs to ward off the threat of "Bolshevism" and
undermine the appeal of unions.
The least popular of the welfare capitalism programs were the
company unions created to stave off labor activism. By offering
employees a say in company policies and practices and a means for
appealing disputes internally, employers hoped to reduce the lure of
unions. They called these employee representation plans "industrial democracy."
Efficacy
In the end, welfare capitalism programs benefited white-collar workers far more than those on the factory floor in the early 20th century. The average annual bonus payouts at U.S. Steel Corporation from 1929 to 1931 were approximately $2,500,000; however, in 1929, $1,623,753 of that went to the president of the company. Real wages for unskilled and low-skilled workers grew little in the
1920s, while long hours in unsafe conditions continued to be the norm.
Further, employment instability due to layoffs
remained a reality of work life. Welfare capitalism programs rarely
worked as intended, company unions only reinforced that authority of
management over the terms of employment.
Wage incentives (merit raises and bonuses) often led to a speed-up in production for factory lines. As much as these programs meant to encourage loyalty to the company,
this effort was often undermined by continued layoffs and frustrations
with working conditions. Employees
soured on employee representation plans and cultural activities, but
they were eager for opportunities to improve their pay with good work
and attendance and to gain benefits like medical care. These programs
gave workers new expectations for their employers. They were often
disappointed in the execution of them but supported their aims. The post-World War II
era saw an expansion of these programs for all workers, and today,
these benefits remain part of employment relations in many countries.
Recently, however, there has been a trend away from this form of welfare
capitalism, as corporations have reduced the portion of compensation
paid with health care, and shifted from defined benefit pensions to
employee-funded defined contribution plans.
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 teratogens and also in pharmacology and toxicology. Teratogens are substances that may cause non-heritable birth defects via a toxic effect on an embryo or fetus. Defects include malformations, disruptions, deformations, and dysplasia
that may cause stunted growth, delayed mental development, or other congenital disorders 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 includes all manifestations of abnormal development that are caused by environmental insult. 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 tératologie, where it was formed in 1830 from the Greekτέραςteras (word stemτέρατ-terat-), meaning "sign sent by the gods, portent, marvel, monster", and -ologie (-ology), 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 (lit.'freak of nature'). 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
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 Medical School (one of the researchers who became known in 1973 for the discovery of fetal alcohol syndrome), popularized the term teratology. With the growth of understanding of the origins of birth defects, the field of teratology as of 2015 overlaps with other fields of science, including developmental biology, embryology, and genetics.
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 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 disorders, maternal nutrition and health, and chemical agents such as drugs and alcohol. 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
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 in the late 19th century:
Susceptibility to teratogenesis depends on the genotype of the conceptus 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 (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.
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% and 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 three 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. 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 is a retinoid and vitamin A derivative that is used in the treatment of psoriasis. Acitretin
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 (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 the United States market in 1998 due to the high risk of birth defects. It remains on the market in Japan as Tigason.
Isotretinoin
Isotretinoin 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.
Image of isotretinoin chemical structure.
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 humans, vaccination has become readily available, and is important for the prevention of various communicable diseases such as polio and rubella,
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 and 1957influenza
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 hormones or hormone replacement drugs such as estrogen and progesterone
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 cycles being conducted during pregnancy, especially in regards to hormones such as estrogen, testosterone 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 drugs are used. The majority of these drugs are cytotoxic, meaning that they have the potential to be carcinogenic, 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 chemical structure. The chemical structure of thalidomide allows it to act as a DNA intercalating agent.
Thalidomide, 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 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. 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 treatment, cancer treatment, and HIV infections.
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
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 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 over time 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, 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 issues.
Cocaine
Chemical Structure of Cocaine
Cocaine can act as a teratogen, having various effects on the developing fetus. Some common teratogenic defects caused by cocaine include hydronephrosis, cleft palate, polydactyly, 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 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 complications such as preterm birth or delivery, uterine rupture, miscarriage, and stillbirth.
Marijuana
There is currently no reliable data to suggest that marijuana
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 neurodevelopmental 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
Only
mothers who are deemed 'sensitive' will have negative effects of
caffeine during pregnancy, while the rest of the population will have
normal pregnancies.
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 break down 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
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 poisoning—and the impacts it can have on a community—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
Chemical structure of di(2-ethylhexyl) phthalate.
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
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.
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 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, the tip of whose jaw was twisted. Another notably deformed fossil was a specimen of the ChoristoderaHyphalosaurus, which had two heads- the oldest known example of polycephaly.
Thalidomide and chick limb development
Thalidomide 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 interfering with the Wnt signaling pathway, increasing apoptosis, and damaging immature blood vessels in developing limb buds.
Retinoic acid and mouse limb development
Retinoic acid
(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 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 effect in the developing mouse limb but delayed chondrocyte 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,
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 theory that all flower parts are highly specialised leaves. In plants, such specimens are denoted as 'lusus naturae' ('sports 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: Development of the apex (growing tip) in a flat plane perpendicular to the axis of elongation
Variegation: Degeneration of genes, manifesting itself among other things by anomalous pigmentation
Virescence: Anomalous development of a green pigmentation in unexpected parts of the plant
Phyllody: Floral organs or fruits transformed into leaves
Witch's broom: 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
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, which can lead to the development of neurocristopathies. Genetically modified
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. 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.
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 animals, such mutagens can therefore be carcinogens, although not all necessarily are. All mutagens have characteristic mutational signatures with some chemicals becoming mutagenic through cellular processes.
The process of DNA becoming modified is called mutagenesis. Not all mutations are caused by mutagens: so-called "spontaneous mutations" occur due to spontaneous hydrolysis, errors in DNA replication, repair and recombination.
Discovery
The first mutagens to be identified were carcinogens, substances that were shown to be linked to cancer. Tumors were described more than 2,000 years before the discovery of chromosomes and DNA; in 500 B.C., the Greek physicianHippocrates named tumors resembling a crab karkinos (from which the word "cancer" is derived via Latin), meaning crab. In 1567, Swiss physician Paracelsus suggested that an unidentified substance in mined ore (identified as radon gas in modern times) caused a wasting disease in miners, and in England, in 1761, John Hill made the first direct link of cancer to chemical substances by noting that excessive use of snuff may cause nasal cancer. In 1775, Sir Percivall Pott wrote a paper on the high incidence of scrotal cancer in chimney sweeps, and suggested chimney soot as the cause of scrotal cancer. In 1915, Yamagawa and Ichikawa showed that repeated application of coal tar to rabbit's ears produced malignant cancer. Subsequently, in the 1930s the carcinogen component in coal tar was identified as a polyaromatic hydrocarbon (PAH), benzo[a]pyrene. Polyaromatic hydrocarbons are also present in soot, which was suggested
to be a causative agent of cancer over 150 years earlier.
The association of exposure to radiation and cancer had been
observed as early as 1902, six years after the discovery of X-ray by Wilhelm Röntgen and radioactivity by Henri Becquerel. Georgii Nadson and German Filippov were the first who created fungi mutants under ionizing radiation in 1925. The mutagenic property of mutagens was first demonstrated in 1927, when Hermann Muller discovered that x-rays can cause genetic mutations in fruit flies, producing phenotypic mutants as well as observable changes to the chromosomes, visible due to the presence of enlarged "polytene" chromosomes in fruit fly salivary glands. His collaborator Edgar Altenburg also demonstrated the mutational effect of UV radiation in 1928. Muller went on to use x-rays to create Drosophila mutants that he used in his studies of genetics. He also found that X-rays not only mutate genes in fruit flies, but also have effects on the genetic makeup of humans. Similar work by Lewis Stadler also showed the mutational effect of X-rays on barley in 1928, and ultraviolet (UV) radiation on maize in 1936. The effect of sunlight had previously been noted in the nineteenth
century where rural outdoor workers and sailors were found to be more
prone to skin cancer.
Chemical mutagens were not demonstrated to cause mutation until the 1940s, when Charlotte Auerbach and J. M. Robson found that mustard gas can cause mutations in fruit flies. A large number of chemical mutagens have since been identified, especially after the development of the Ames test in the 1970s by Bruce Ames that screens for mutagens and allows for preliminary identification of carcinogens. Early studies by Ames showed around 90% of known carcinogens can be
identified in Ames test as mutagenic (later studies however gave lower
figures), and ~80% of the mutagens identified through Ames test may also be carcinogens.
Difference between mutagens and carcinogens
Mutagens are not necessarily carcinogens, and vice versa. Sodium azide for example may be mutagenic (and highly toxic), but it has not been shown to be carcinogenic. Meanwhile, compounds which are not directly mutagenic but stimulate
cell growth which can reduce the effectiveness of DNA repair and
indirectly increase the chance of mutations, and therefore that of
cancer. One example of this would be anabolic steroids, which stimulate growth of the prostate gland and increase the risk of prostate cancer among others. Other carcinogens may cause cancer through a variety of mechanisms without producing mutations, such as tumour promotion, immunosuppression that reduces the ability to fight cancer cells or pathogens that can cause cancer, disruption of the endocrine system (e.g. in breast cancer), tissue-specific toxicity, and inflammation (e.g. in colorectal cancer).
Difference between mutagens and DNA damaging agents
A DNA damaging agent is an agent that causes a change in the structure of DNA that is not necessarily replicated when the DNA is replicated. Examples of DNA damage include a chemical addition or disruption of a nucleotide
base in DNA (generating an abnormal nucleotide or nucleotide fragment),
or a break in one or both strands in DNA. When duplex DNA containing a
damaged base is replicated, an incorrect base may be inserted in the
newly synthesized strand opposite the damaged base in the complementary
template strand, and this can become a mutation
in the next round of replication. Also a DNA double-strand break may
be repaired by an inaccurate process leading to an altered base pair, a
mutation. However, mutations and DNA damages differ in a fundamental
way: mutations can, in principle, be replicated when DNA replicates,
whereas DNA damages are not necessarily replicated. Thus DNA damaging
agents often cause mutations as a secondary consequence, but not all DNA
damages lead to mutation and not all mutations arise from a DNA damage. The term genotoxic means toxic (damaging) to DNA.
Mutagens can cause changes to the DNA and are therefore genotoxic.
They can affect the transcription and replication of the DNA, which in
severe cases can lead to cell death. The mutagen produces mutations in
the DNA, and deleterious mutation can result in aberrant, impaired or
loss of function for a particular gene, and accumulation of mutations
may lead to cancer. Mutagens may therefore be also carcinogens. However,
some mutagens exert their mutagenic effect through their metabolites,
and therefore whether such mutagens actually become carcinogenic may be
dependent on the metabolic processes of an organism, and a compound
shown to be mutagenic in one organism may not necessarily be
carcinogenic in another.
Different mutagens act on DNA differently. Powerful mutagens may result in chromosomal instability, causing chromosomal breakages and rearrangement of the chromosomes such as translocation, deletion, and inversion. Such mutagens are called clastogens.
Some mutagens can cause aneuploidy and change the number of chromosomes in the cell. They are known as aneuploidogens or aneugens.
Mutagens may also modify the DNA sequence; the changes in nucleic acid sequences by mutations include substitution of nucleotidebase-pairs and insertions and deletions
of one or more nucleotides in DNA sequences. Although some of these
mutations are lethal or cause serious disease, many have minor effects
as they do not result in residue changes that have significant effect on
the structure and function of the proteins. Many mutations are silent mutations,
causing no visible effects at all, either because they occur in
non-coding or non-functional sequences, or they do not change the amino-acid sequence due to the redundancy of codons.
In Ames test, where the varying concentrations of the chemical
are used in the test, the dose response curve obtained is nearly always
linear, suggesting that there may be no threshold for mutagenesis.
Similar results are also obtained in studies with radiations, indicating
that there may be no safe threshold for mutagens. However, the no-threshold model is disputed with some arguing for a dose rate dependent threshold for mutagenesis. Some have proposed that low level of some mutagens may stimulate the DNA repair
processes and therefore may not necessarily be harmful. More recent
approaches with sensitive analytical methods have shown that there may
be non-linear or bilinear dose-responses for genotoxic effects, and that
the activation of DNA repair pathways can prevent the occurrence of
mutation arising from a low dose of mutagen.
Types of Mutagens
Mutagens
may be of physical, chemical or biological origin. They may act
directly on the DNA, causing direct damage to the DNA, and most often
result in replication error. Some however may act on the replication
mechanism and chromosomal partition. Many mutagens are not mutagenic by
themselves, but can form mutagenic metabolites through cellular
processes, for example through the activity of the cytochrome P450 system and other oxygenases such as cyclooxygenase. Such mutagens are called promutagens.
Ultraviolet radiations with wavelength above 260 nm are absorbed strongly by bases, producing pyrimidine dimers, which can cause error in replication if left uncorrected.
Chemical mutagens either directly or indirectly damage DNA. On this basis, they are of 2 types:
Directly acting chemical mutagens
They
directly damage DNA, but may or may not undergo metabolism to produce
promutagens (metabolites that can have higher mutagenic potential than
their substrates).
Reactive oxygen species (ROS) – These may be superoxide, hydroxyl radicals and hydrogen peroxide,
and large number of these highly reactive species are generated by
normal cellular processes, for example as a by-products of mitochondrial
electron transport, or lipid peroxidation.
As an example of the latter, 15-hydroperoxyeicosatetraenoic acid, a
natural product of cellular cyclooxygenases and lipoxygenases, breaks
down to form 4-hydroxy-2(E)-nonenal, 4-hydroperoxy-2(E)-nonenal, 4-oxo-2(E)-nonenal, and cis-4,5-epoxy-2(E)-decanal;
these bifunctional electophils are mutagenic in mammalian cells and may
contribute to the development and/or progression of human cancers (see 15-Hydroxyicosatetraenoic acid). A number of mutagens may also generate these ROS. These ROS may result
in the production of many base adducts, as well as DNA strand breaks and
crosslinks.
Alkylating agents such as ethylnitrosourea.
The compounds transfer methyl or ethyl group to bases or the backbone
phosphate groups. Guanine when alkylated may be mispaired with thymine.
Some may cause DNA crosslinking and breakages. Nitrosamines
are an important group of mutagens found in tobacco, and may also be
formed in smoked meats and fish via the interaction of amines in food
with nitrites added as preservatives. Other alkylating agents include mustard gas and vinyl chloride.
Aromatic amines and amides have been associated with carcinogenesis since 1895 when German physician Ludwig Rehn observed high incidence of bladder cancer among workers in German synthetic aromatic amine dye industry. 2-Acetylaminofluorene,
originally used as a pesticide but may also be found in cooked meat,
may cause cancer of the bladder, liver, ear, intestine, thyroid and
breast.
Alkaloid from plants, such as those from Vinca species, may be converted by metabolic processes into the active mutagen or carcinogen.
Bromine and some compounds that contain bromine in their chemical structure.
Sodium azide, an azide salt that is a common reagent in organic synthesis and a component in many car airbag systems
Psoralen combined with ultraviolet radiation causes DNA cross-linking and hence chromosome breakage.
Benzene, an industrial solvent and precursor in the production of drugs, plastics, synthetic rubber and dyes.
Chromium trioxide, a highly toxic and oxidizing substance used in electroplating.
Indirectly acting chemical mutagens
They
are not necessarily mutagenic by themselves, but they produce
promutagens mutagenic compounds through metabolic processes in cells.
Some chemical mutagens additionally require UV or visible light activation for their mutagenic effect. These are the photomutagens, which include furocoumarins and limettin.
Base analogs
Base analog, which can substitute for DNA bases during replication and cause transition mutations. Some examples are 5-bromouracil and 2-aminopurine.
Many metals, such as arsenic, cadmium, chromium, nickel and their compounds may be mutagenic, but they may act, however, via a number of different mechanisms. Arsenic, chromium, iron, and nickel may be associated with the
production of ROS, and some of these may also alter the fidelity of DNA
replication. Nickel may also be linked to DNA hypermethylation and histone deacetylation, while some metals such as cobalt, arsenic, nickel and cadmium may also affect DNA repair processes such as DNA mismatch repair, and base and nucleotide excision repair.
Biological agents
Transposons,
a section of DNA that undergoes autonomous fragment
relocation/multiplication. Its insertion into chromosomal DNA disrupts
functional elements of the genes.
Oncoviruses
– Virus DNA may be inserted into the genome and disrupts genetic
function. Infectious agents have been suggested to cause cancer as early
as 1908 by Vilhelm Ellermann and Oluf Bang, and 1911 by Peyton Rous who discovered the Rous sarcoma virus.
Bacteria – some bacteria such as Helicobacter pylori
cause inflammation during which oxidative species are produced, causing
DNA damage and reducing efficiency of DNA repair systems, thereby
increasing mutation.
Antioxidants are an important group of anticarcinogenic compounds that may help remove ROS or potentially harmful chemicals. These may be found naturally in fruits and vegetables. Examples of antioxidants are vitamin A and its carotenoid precursors, vitamin C, vitamin E, polyphenols, and various other compounds. β-Carotene is the red-orange colored compounds found in vegetables like carrots and tomatoes. Vitamin C may prevent some cancers by inhibiting the formation of mutagenic N-nitroso compounds (nitrosamine). Flavonoids, such as EGCG in green tea,
have also been shown to be effective antioxidants and may have
anti-cancer properties. Epidemiological studies indicate that a diet
rich in fruits and vegetables is associated with lower incidence of some
cancers and longer life expectancy, however, the effectiveness of antioxidant supplements in cancer prevention in general is still the subject of some debate.
Other chemicals may reduce mutagenesis or prevent cancer via
other mechanisms, although for some the precise mechanism for their
protective property may not be certain. Selenium,
which is present as a micronutrient in vegetables, is a component of
important antioxidant enzymes such as gluthathione peroxidase. Many
phytonutrients may counter the effect of mutagens; for example, sulforaphane in vegetables such as broccoli has been shown to be protective against prostate cancer. Others that may be effective against cancer include indole-3-carbinol from cruciferous vegetables and resveratrol from red wine.
An effective precautionary measure an individual can undertake to
protect themselves is by limiting exposure to mutagens such as UV
radiations and tobacco smoke. In Australia, where people with pale skin
are often exposed to strong sunlight, melanoma is the most common cancer diagnosed in people aged 15–44 years.
In 1981, human epidemiological analysis by Richard Doll and Richard Peto indicated that smoking caused 30% of cancers in the US. Diet is also thought to cause a significant number of cancer
fatalities, and it has been estimated that around 32% of cancer deaths
may be avoidable by modification to the diet. Mutagens identified in food include mycotoxins from food contaminated with fungal growths, such as aflatoxins which may be present in contaminated peanuts and corn; heterocyclic amines
generated in meat when cooked at high temperature; PAHs in charred meat
and smoked fish, as well as in oils, fats, bread, and cereal; and nitrosamines generated from nitrites used as food preservatives in cured meat such as bacon (ascorbate, which is added to cured meat, however, reduces nitrosamine formation). Overly-browned starchy food such as bread, biscuits and potatoes can generate acrylamide, a chemical shown to cause cancer in animal studies. Excessive alcohol consumption has also been linked to cancer; the possible mechanisms for its carcinogenicity include formation of the possible mutagen acetaldehyde, and the induction of the cytochrome P450 system which is known to produce mutagenic compounds from promutagens.
For certain mutagens, such as dangerous chemicals and radioactive
materials, as well as infectious agents known to cause cancer,
government legislations and regulatory bodies are necessary for their
control.
Test systems
Many different systems for detecting mutagen have been developed. Animal systems may more accurately reflect the metabolism of human,
however, they are expensive and time-consuming (may take around three
years to complete), they are therefore not used as a first screen for
mutagenicity or carcinogenicity.
Ames test – This is the most commonly used test, and Salmonella typhimurium strains deficient in histidine
biosynthesis are used in this test. The test checks for mutants that
can revert to wild-type. It is an easy, inexpensive and convenient
initial screen for mutagens.
Resistance to 8-azaguanine in S. typhimurium – Similar to Ames test, but instead of reverse mutation, it checks for forward mutation that confer resistance to 8-Azaguanine in a histidine revertant strain.
Escherichia coli systems – Both forward and reverse mutation detection system have been modified for use in E. coli. Tryptophan-deficient
mutant is used for the reverse mutation, while galactose utility or
resistance to 5-methyltryptophan may be used for forward mutation.
DNA repair – E. coli and Bacillus subtilis strains deficient in DNA repair may be used to detect mutagens by their effect on the growth of these cells through DNA damage.
Yeast
Systems similar to Ames test have been developed in yeast. Saccharomyces cerevisiae is generally used. These systems can check for forward and reverse mutations, as well as recombinant events.
Drosophila
Sex-Linked Recessive Lethal Test
– Males from a strain with yellow bodies are used in this test. The
gene for the yellow body lies on the X-chromosome. The fruit flies are
fed on a diet of test chemical, and progenies are separated by sex. The
surviving males are crossed with the females of the same generation, and
if no males with yellow bodies are detected in the second generation,
it would indicate a lethal mutation on the X-chromosome has occurred.
Mammalian cell lines such as Chinese hamster V79 cells, Chinese hamster ovary (CHO) cells or mouse lymphoma cells may be used to test for mutagenesis. Such systems include the HPRT assay for resistance to 8-azaguanine or 6-thioguanine, and ouabain-resistance (OUA) assay.
Rat primary hepatocytes may also be used to measure DNA repair
following DNA damage. Mutagens may stimulate unscheduled DNA synthesis
that results in more stained nuclear material in cells following
exposure to mutagens.
Chromosome check systems
These
systems check for large scale changes to the chromosomes and may be
used with cell culture or in animal test. The chromosomes are stained
and observed for any changes. Sister chromatid exchange is a
symmetrical exchange of chromosome material between sister chromatids
and may be correlated to the mutagenic or carcinogenic potential of a
chemical. In micronucleus Test, cells are examined for
micronuclei, which are fragments or chromosomes left behind at anaphase,
and is therefore a test for clastogenic agents that cause chromosome
breakages. Other tests may check for various chromosomal aberrations
such as chromatid and chromosomal gaps and deletions, translocations,
and ploidy.
Animal test systems
Rodents are usually used in animal test. The chemicals under
test are usually administered in the food and in the drinking water, but sometimes by dermal application, by gavage,
or by inhalation, and carried out over the major part of the life span
for rodents. In tests that check for carcinogens, maximum tolerated
dosage is first determined, then a range of doses are given to around 50
animals throughout the notional lifespan of the animal of two years.
After death the animals are examined for sign of tumours. Differences in
metabolism between rat and human however means that human may not
respond in exactly the same way to mutagen, and dosages that produce
tumours on the animal test may also be unreasonably high for a human,
i.e. the equivalent amount required to produce tumours in human may far
exceed what a person might encounter in real life.
Mice with recessive mutations for a visible phenotype may also be
used to check for mutagens. Females with recessive mutation crossed
with wild-type males would yield the same phenotype as the wild-type,
and any observable change to the phenotype would indicate that a
mutation induced by the mutagen has occurred.
Mice may also be used for dominant lethal assays where
early embryonic deaths are monitored. Male mice are treated with
chemicals under test, mated with females, and the females are then
sacrificed before parturition and early fetal deaths are counted in the uterine horns.
Transgenic mouse assay using a mouse strain infected with a viral shuttle vector
is another method for testing mutagens. Animals are first treated with
suspected mutagen, the mouse DNA is then isolated and the phage segment
recovered and used to infect E. coli. Using similar method as the blue-white screen, the plaque formed with DNA containing mutation are white, while those without are blue.
In anti-cancer therapy
Many
mutagens are highly toxic to proliferating cells, and they are often
used to destroy cancer cells. Alkylating agents such as cyclophosphamide and cisplatin, as well as intercalating agent such as daunorubicin and doxorubicin may be used in chemotherapy.
However, due to their effect on other cells which are also rapidly
dividing, they may have side effects such as hair loss and nausea.
Research on better targeted therapies may reduce such side-effects.
Ionizing radiations are used in radiation therapy.
