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Friday, June 29, 2018

Birth defect

From Wikipedia, the free encyclopedia

Birth defect
Synonyms Congenital disorder, congenital disease, congenital deformity, congenital anomaly[1]
Drill.jpg
A boy with Down syndrome, one of the most common birth defects[2]
Specialty Medical genetics, pediatrics
Symptoms Physical disability, intellectual disability, developmental disability[3]
Usual onset Present at birth[3]
Types Structural, functional[4]
Causes Genetics, exposure to certain medications or chemicals, certain infections during pregnancy[5]
Risk factors Not enough folic acid, drinking alcohol or smoking, poorly controlled diabetes, mother over the age of 35[6][7]
Treatment Therapy, medication, surgery, assistive technology[8]
Frequency 3% of newborns (US)[2]
Deaths 628,000 (2015)[9]

A birth defect, also known as a congenital disorder, is a condition present at birth regardless of its cause.[3] Birth defects may result in disabilities that may be physical, intellectual, or developmental.[3] The disabilities can range from mild to severe.[7] Birth defects are divided into two main types: structural disorders in which there are problems with the shape of a body part and functional disorders in which there are problems with how a body part works.[4] Functional disorders include metabolic and degenerative disorders.[4] Some birth defects include both structural and functional disorders.[4]

Birth defects may result from genetic or chromosomal disorders, exposure to certain medications or chemicals, or certain infections during pregnancy.[5] Risk factors include folate deficiency, drinking alcohol or smoking during pregnancy, poorly controlled diabetes, and a mother over the age of 35 years old.[6][7] Many are believed to involve multiple factors.[7] Birth defects may be visible at birth or diagnosed by screening tests.[10] A number of defects can be detected before birth by different prenatal tests.[10]

Treatment varies depending on the defect in question.[8] This may include therapy, medication, surgery, or assistive technology.[8] Birth defects affected about 96 million people as of 2015.[11] In the United States they occur in about 3% of newborns.[2] They resulted in about 628,000 deaths in 2015 down from 751,000 in 1990.[12][9] The types with the greatest numbers of deaths are congenital heart disease (303,000), followed by neural tube defects (65,000).[9]

Classification

Much of the language used for describing congenital conditions predates genome mapping, and structural conditions are often considered separately from other congenital conditions. It is now known that many metabolic conditions may have subtle structural expression, and structural conditions often have genetic links. Still, congenital conditions are often classified in a structural basis, organized when possible by primary organ system affected.[citation needed]

Primarily structural

Several terms are used to describe congenital abnormalities. (Some of these are also used to describe noncongenital conditions, and more than one term may apply in an individual condition.)

Terminology

  • A congenital physical anomaly is an abnormality of the structure of a body part. An anomaly may or may not be perceived as a problem condition. Many, if not most, people have one or more minor physical anomalies if examined carefully. Examples of minor anomalies can include curvature of the 5th finger (clinodactyly), a third nipple, tiny indentations of the skin near the ears (preauricular pits), shortness of the 4th metacarpal or metatarsal bones, or dimples over the lower spine (sacral dimples). Some minor anomalies may be clues to more significant internal abnormalities.
  • Birth defect is a widely used term for a congenital malformation, i.e. a congenital, physical anomaly which is recognizable at birth, and which is significant enough to be considered a problem. According to the CDC, most birth defects are believed to be caused by a complex mix of factors including genetics, environment, and behaviors,[13] though many birth defects have no known cause. An example of a birth defect is cleft palate, which occurs during the fourth and seventh week of gestation.[14] Body tissue and special cells from each side of the head grow toward the center of the face. They join together to make the face.[14] A cleft means a split or separation; the "roof" of the mouth is called the palate.[15]
  • A congenital malformation is a congenital physical anomaly that is deleterious, i.e. a structural defect perceived as a problem. A typical combination of malformations affecting more than one body part is referred to as a malformation syndrome.
  • Some conditions are due to abnormal tissue development:
    • A malformation is associated with a disorder of tissue development.[16] Malformations often occur in the first trimester.
    • A dysplasia is a disorder at the organ level that is due to problems with tissue development.[16]
  • It is also possible for conditions to arise after tissue is formed:
    • A deformation is a condition arising from mechanical stress to normal tissue.[16] Deformations often occur in the second or third trimester, and can be due to oligohydramnios.
    • A disruption involves breakdown of normal tissues.[16]
  • When multiple effects occur in a specified order, it is known as a sequence. When the order is not known, it is a syndrome.

Examples of primarily structural congenital disorders

A limb anomaly is called a dysmelia. These include all forms of limbs anomalies, such as amelia, ectrodactyly, phocomelia, polymelia, polydactyly, syndactyly, polysyndactyly, oligodactyly, brachydactyly, achondroplasia, congenital aplasia or hypoplasia, amniotic band syndrome, and cleidocranial dysostosis.

Congenital anomalies of the heart include patent ductus arteriosus, atrial septal defect, ventricular septal defect, and tetralogy of fallot.

Congenital anomalies of the nervous system include neural tube defects such as spina bifida, encephalocele and anencephaly. Other congenital anomalies of the nervous system include the Arnold-Chiari malformation, the Dandy-Walker malformation, hydrocephalus, microencephaly, megalencephaly, lissencephaly, polymicrogyria, holoprosencephaly, and agenesis of the corpus callosum.

Congenital anomalies of the gastrointestinal system include numerous forms of stenosis and atresia, and perforation, such as gastroschisis.

Congenital anomalies of the kidney and urinary tract (CAKUT) include renal parenchyma, kidneys, and urinary collecting system.[17]

Defects can be bilateral or unilateral, and different defects often coexist in an individual child.

Primarily metabolic

A congenital metabolic disease is also referred to as an inborn error of metabolism. Most of these are single gene defects, usually heritable. Many affect the structure of body parts but some simply affect the function.

Other

Other well defined genetic conditions may affect the production of hormones, receptors, structural proteins, and ion channels.

Causes

Fetal alcohol exposure

The mother's consumption of alcohol during pregnancy can cause a continuum of various permanent birth defects : cranofacial abnormalities,[18] brain damage,[19] intellectual disability,[20] heart disease, kidney abnormality, skeletal anomalies, ocular abnormalities.[21]

The prevalence of children affected is estimated at least 1 percent in U.S.[22] as well in Canada.

Very few studies have investigated the links between paternal alcohol use and offspring health.[23]

However, recent animal research has shown a correlation between paternal alcohol exposure and decreased offspring birth weight. Behavioral and cognitive disorders, including difficulties with learning and memory, hyperactivity, and lowered stress tolerance have been linked to paternal alcohol ingestion. The compromised stress management skills of animals whose male parent was exposed to alcohol are similar to the exaggerated responses to stress that children with fetal alcohol syndrome display because of maternal alcohol use. These birth defects and behavioral disorders were found in cases of both long- and short-term paternal alcohol ingestion.[24][25] In the same animal study, paternal alcohol exposure was correlated with a significant difference in organ size and the increased risk of the offspring displaying ventricular septal defects at birth.[25]

Toxic substances

Substances whose toxicity can cause congenital disorders are called teratogens, and include certain pharmaceutical and recreational drugs in pregnancy as well as many environmental toxins in pregnancy.

A review published in 2010 identified 6 main teratogenic mechanisms associated with medication use: folate antagonism, neural crest cell disruption, endocrine disruption, oxidative stress, vascular disruption and specific receptor- or enzyme-mediated teratogenesis.[26]

It is estimated that 10% of all birth defects are caused by prenatal exposure to a teratogenic agent.[27] These exposures include, but are not limited to, medication or drug exposures, maternal infections and diseases, and environmental and occupational exposures. Paternal smoking use has also been linked to an increased risk of birth defects and childhood cancer for the offspring, where the paternal germline undergoes oxidative damage due to cigarette use.[28][29] Teratogen-caused birth defects are potentially preventable. Studies have shown that nearly 50% of pregnant women have been exposed to at least one medication during gestation.[30] During pregnancy, a female can also be exposed to teratogens from the contaminated clothing or toxins within the seminal fluid of a partner.[31][24][32] An additional study found that of 200 individuals referred for genetic counseling for a teratogenic exposure, 52% were exposed to more than one potential teratogen.[33]

Medications and supplements

Probably, the most well-known teratogenic drug is thalidomide. It was developed near the end of the 1950s by Chemie Grünenthal as a sleep inducing aid and antiemetic. Because of its ability to prevent nausea it was prescribed for pregnant women in almost 50 countries worldwide between 1956–1962. Until William McBride published the study leading to its withdrawal from the market at 1961, about 8- 10 000 severely malformed children were born. The most typical disorder induced by thalidomide were reductional deformities of the long bones of the extremities. Phocomelia otherwise a rare deformity, which therefore helped to recognise the teratogenic effect of the new drug. Among other malformations caused by thalidomide were those of ears, eyes, brain, kidney, heart, digestive and respiratory tract. 40% of the prenatally affected children died soon after birth.[34] As thalidomide is used today as a treatment for multiple myeloma and leprosy, several births of affected children were described in spite of the strictly required use of contraception among female patients treated by it.

Vitamin A, is the sole vitamin which is embryotoxic even in a therapeutic dose, for example in multivitamins, because its metabolite retinoic acid, plays an important role as a signal molecule in the development of several tisues and organs. Its natural precursor, β-carotene, is considered safe, whereas the consumption of animal liver can lead to malformation, as the liver stores lipophile vitamins, including retinol.[34] Isotretinoin (13-cis-retinoic-acid; brand name Roaccutane), vitamine A analog, which is often used to treat severe acne, is such a strong teratogen that just a single dose taken by a pregnant woman (even transdermally) may result in serious birth defects. Because of this effect, most countries have systems in place to ensure that it is not given to pregnant women, and that the patient is aware of how important it is to prevent pregnancy during and at least one month after treatment. Medical guidelines also suggest that pregnant women should limit vitamin A intake to about 700 μg/day, as it has teratogenic potential when consumed in excess.[35][36] Vitamine A and similar substances can induce spontaneous abortions, premature births, defects of eyes (microphthalmia), ears, thymus, face deformities, neurological (hydrocephalus, microcephalia) and cardiovascular defects, as well as mental retardation.[34]

Tetracycline, an antibiotic, should never be prescribed to women of reproductive age or to children, because of its negative impact on bone mineralization and teeth mineralization. The "tetracycline teeth" have brown or grey colour as a result of a defective development of both the dentine and the enamel of teeth.[34]

Several anticonvulsants are known to be highly teratogenic. Phenytoin, also known as diphenylhydantoin, along with carbamazepine is responsible for the fetal hydantoin syndrome, which may typically include broad nose base, cleft lip and/or palate, microcephalia, nails and fingers hypoplasia, intrauterine growth restriction and mental retardation. Trimethadione taken during pregnancy is responsible for the fetal trimethadione syndrome, characterized by craniofacial, cardiovascular, renal and spine malformations, along with a delay in mental and physical development. Valproate has antifolate effects, leading to neural tube closure-related defects such as spina bifida. Lower IQ and autism have recently also been reported as a result of intrauterine valproate exposure.[34]

Hormonal contraception is considered as harmless for the embryo. Peterka and Novotná[34] do however state that syntethic progestines used to prevent miscarriage in the past frequently caused masculinization of the outer reproductive organs of female newborns due to their androgenic activity.

Diethylstilbestrol is a synthetic estrogen used from the 1940s to 1971 when the prenatal exposition has been linked to the clear-cell adenocarcinoma of the vagina. Following studies showed elevated risks for other tumors and congenital malformations of the sex organs for both sexes.

All cytostatics are strong teratogens, abortion is usually recommended when pregnancy is discovered during or before chemotherapy. Aminopterin, a cytostatic drug with anti-folate effect, was used during the 1950s and 1960s to induce therapeutic abortions. In some cases the abortion didn´t happen, but the newborns suffered a fetal aminopterin syndrome consisting of growth retardation, craniosynostosis, hydrocephalus, facial dismorphities, mental retardation and/or leg defomities[34][37]

Toxic substances

Drinking water is often a medium through which harmful toxins travel. Studies have shown that heavy metals, elements, nitrates, nitrites, fluoride can be carried through water and cause congenital disorders.

Nitrate, which is found mostly in drinking water from ground sources, is a powerful teratogen. A case-control study in rural Australia that was conducted following frequent reports of prenatal mortality and congenital malformations found that those who drank the nitrate-infected groundwater, as opposed to rain water, ran the risk of giving birth to children with central nervous system disorders, muscoskeletal defects, and cardiac defects.[38]

Chlorinated and aromatic solvents such as benzene and trichloroethylene sometimes enter the water supply due to oversights in waste disposal. A case-control study on the area found that by 1986, leukemia was occurring in the children of Woburn, Massachusetts at a rate that was four times the expected rate of incidence. Further investigation revealed a connection between the high occurrence of leukemia and an error in water distribution that delivered water to the town with significant contamination manufacturing waste containing trichloroethylene.[39] As an endocrine disruptor, the DDT was shown to induce miscarriages, interfere with the development of the female reproductive system, cause the congenital hypothyroidism and suspectibly childhood obesity.[34]

Fluoride, when transmitted through water at high levels, can also act as a teratogen. Two reports on fluoride exposure from China, which were controlled to account for the education level of parents, found that children born to parents who were exposed to 4.12 PPM fluoride grew to have IQs that were, on average, seven points lower than their counterparts whose parents consumed water that contained 0.91 PPM fluoride. In studies conducted on rats, higher PPM fluoride in drinking water lead to increased acetylcholinesterase levels, which can alter prenatal brain development. The most significant effects were noted at a level of 5 PPM.[40]

The fetus is even more susceptible to damage from carbon monoxide intake, which can be harmful when inhaled during pregnancy, usually through first or second-hand tobacco smoke. The concentration of carbon monoxide in the infant born to a non-smoking mother is around 2%, and this concentration drastically increases to a range of 6%–9% if the mother smokes tobacco. Other possible sources of prenatal carbon monoxide intoxication are exhaust gas from combustion motors, use of dichloromethane (paint thinner, varnish removers) in enclosed areas, defective gas hot water heaters, indoor barbeques, open flames in poorly-ventilated areas, atmospheric exposure in highly polluted areas. Exposure to carbon monoxide at toxic levels during the first two trimesters of pregnancy can lead to intrauterine growth restriction, leading to a baby that has stunted growth and is born smaller than 90% of other babies at the same gestational age. The effect of chronic exposure to carbon monoxide can depend on the stage of pregnancy in which the mother is exposed. Exposure during the embryonic stage can have neurological consequences, such as telencephalic dysgenesis, behavioral difficulties during infancy, and reduction of cerebellum volume. There are also possible skeletal defects that could result from exposure to carbon monoxide during the embryonic stage, such as hand and foot malformations, hip dysplasia, hip subluxation, agenisis of a limb, and inferior maxillary atresia with glossoptosis. Also, carbon monoxide exposure between days 35 and 40 of embryonic development can lead to an increased risk of the child developing a cleft palate. Exposure to carbon monoxide or polluted ozone exposure can also lead to cardiac defects of the ventrical septal, pulmonary artery and heart valves.[41] The effects of carbon monoxide exposure are decreased later in fetal development during the fetal stage, but they may still lead to anoxic encephalopathy.[42]

Industrial pollution can also lead to congenital defects. Over a period of 37 years, the Chisso Corporation, a petrochemical and plastics company, contaminated the waters of Minamata Bay with an estimated 27 tons of methylmercury, contaminating the local water supply. This led to many people in the area developing what became known as the “Minamata Disease.” Because methylmercury is a teratogen, the mercury poisoning of those residing by the bay resulted in neurological defects in the offspring. Infants exposed to mercury poisoning in utero showed predispositions to cerebral palsy, ataxia, inhibited psychomotor development, and mental retardation.[43]

Landfill sites have been shown to have adverse effects on fetal development. Extensive research has been shown that landfills have several negative effects on babies born to mothers living near landfill sites: low birth weight, birth defects, spontaneous abortion, and fetal and infant mortality. Studies done around the Love Canal site near Niagara Falls and the Lipari Landfill in New Jersey have shown a higher proportion of low birth babies than communities farther away from landfills. A study done in California showed a positive correlation between time and quantity of dumping and low birth weights and neonatal deaths. A study in the United Kingdom showed a correspondence between pregnant women living near landfill sites and an increased risk of congenital disorders, such as neural tube defects, hypospadias, epispadia, and abdominal wall defects, such as gastroschisis and exomphalos. A study conducted on a Welsh community also showed an increase incidence of gastroschisis. Another study was done on twenty-one European hazardous waste sites and showed that those living within three kilometers had an increased risk of giving birth to infants with birth defects and that as distance from the land increased, the risk decreased. These birth defects included neural tube defects, malformations of the cardiac septa, anomalies of arteries and veins, and chromosomal anomalies.[44] Looking at communities that live near landfill sites brings up environmental justice. A vast majority of sites are located near poor, mostly black, communities. For example, between the early 1920s and 1978, about 25% of Houston’s population was black. However, over 80% of landfills and incinerators during this time were located in these black communities.[45]

Another issue regarding environmental justice is lead poisoning. If the fetus is exposed to lead during the pregnancy, this can result in learning difficulties and slowed growth. A lot of paints (before 1978) and pipes contain lead. Therefore, pregnant women who live in homes with lead paint will inhale the dust containing lead, leading to lead exposure in the fetus. When lead pipes are used for drinking water and cooking water, this water is ingested, along with the lead, exposing the fetus to this toxin. This issue is more prevalent in poorer communities. This is because more well off families are able to afford to have their homes repainted and pipes renovated.[46]

Smoking

Paternal smoking prior to conception has been linked with the increased risk of congenital abnormalities in offspring.[23]

Smoking causes DNA mutations in the germline of the father, which can be inherited by the offspring. Cigarette smoke acts as a chemical mutagen on germ cell DNA. The germ cells suffer oxidative damage, and the effects can be seen in altered mRNA production, infertility issues, and side effects in the embryonic and fetal stages of development. This oxidative damage may result in epigenetic or genetic modifications of the father's germline. Research has shown that fetal lymphocytes have been damaged as a result of a father's smoking habits prior to conception.[31][29]

Correlations between paternal smoking and the increased risk of offspring developing childhood cancers (including acute leukemia, brain tumors, and lymphoma) before age five have been established. However, further research is needed to confirm these findings. Little is currently known about how paternal smoking damages the fetus, and what window of time in which the father smokes is most harmful to offspring.[29]

Infections

A vertically transmitted infection is an infection caused by bacteria, viruses or, in rare cases, parasites transmitted directly from the mother to an embryo, fetus or baby during pregnancy or childbirth. It can occur when the mother gets an infection as an intercurrent disease in pregnancy.

Congenital disorders were initially believed to be the result of only hereditary factors. However, in the early 1940s, Australian pediatric ophthalmologist Norman Gregg began recognizing a pattern in which the infants arriving at his surgery were developing congenital cataracts at a higher rate than those who developed it from hereditary factors. On October 15, 1941, Gregg delivered a paper which explained his findings-68 out of the 78 children who were afflicted with congenital cataracts had been exposed in utero to rubella due to an outbreak in Australian army camps. These findings confirmed, to Gregg, that there could, in fact, be environmental causes for congenital disorders.

Rubella is known to cause abnormalities of the eye, internal ear, heart, and sometimes the teeth. More specifically, fetal exposure to rubella during weeks five to ten of development (the sixth week particularly) can cause cataracts and microphthalmia in the eyes. If the mother is infected with rubella during the ninth week, a crucial week for internal ear development, there can be destruction of the organ of Corti, causing deafness. In the heart the ductus arteriosus can remain after birth, leading to hypertension. Rubella can also lead to atrial and ventricular septal defects in the heart. If exposed to rubella in the second trimester, the fetus can develop central nervous system malformations. However, because infections of rubella may remain undetected, misdiagnosed, or unrecognized in the mother, and/or some abnormalities are not evident until later in the child’s life, precise incidence of birth defects due to rubella are not entirely known. The timing of the mother’s infection during fetal development determines the risk and type of birth defect. As the embryo develops, the risk of abnormalities decreases. If exposed to the rubella virus during the first four weeks, the risk of malformations is 47 percent. Exposure during weeks five through eight creates a 22 percent chance, while weeks nine to twelve a seven percent chance exists, followed by a percentage of six if the exposure is during the thirteenth to sixteenth weeks. Exposure during the first eight weeks of development can also lead to prematurity and fetal death. These numbers are calculated from immediate inspection of the infant after birth. Therefore, mental defects are not accounted for in the percentages because they are not evident until later in the child’s life. If they were to be included, these numbers would be much higher.[47]

Other infectious agents include cytomegalovirus, the herpes simplex virus, hyperthermia, toxoplasmosis, and syphilis. Mother exposure to cytomegalovirus can cause microcephaly, cerebral calcifications, blindness, chorioretinitis (which can cause blindness), hepatosplenomegaly, and meningoencephalitis in fetuses.[47] Microcephaly is a disorder in which the fetus has an atypically small head,[48] cerebral calcifications means certain areas of the brain have atypical calcium deposits,[49] and meningoencephalitis is the enlargement of the brain. All three disorders cause abnormal brain function or mental retardation. Hepatosplenomegaly is the enlargement of the liver and spleen which causes digestive problems.[50] It can also cause some kernicterus and petechiae. Kernicterus causes yellow pigmentation of the skin, brain damage, and deafness.[51] Petechaie is when the capillaries bleed resulting in red/purple spots on the skin.[52] However, cytomegalovirus is often fatal in the embryo.

The herpes simplex virus can cause microcephaly, microphthalmus (abnormally small eyeballs),[53] retinal dysplasia, hepatosplenomegaly, and mental retardation.[47] Both microphthalmus and retinal dysplasia can cause blindness. However, the most common symptom in infants is an inflammatory response that develops during the first three weeks of life.[47] Hyperthermia causes anencephaly, which is when part of the brain and skull are absent in the infant.[47][54] Mother exposure to toxoplasmosis can cause cerebral calcification, hydrocephalus (causes mental disabilities),[55] and mental retardation in infants. Other birth abnormalities have been reported as well, such as chorioretinitis, microphthalmus, and ocular defects. Syphilis causes congenital deafness, mental retardation, and diffuse fibrosis in organs, such as the liver and lungs, if the embryo is exposed.[47]

Lack of nutrients

For example, a lack of folic acid, a vitamin B, in the diet of a mother can cause cellular neural tube deformities that result in spina bifida. Congenital disorders such as a neural tube deformity (NTD) can be prevented by 72% if the mother consumes 4 milligrams of folic acid before the conception and after 12 weeks of pregnancy.[56] Folic acid, or vitamin B9, aids the development of the foetal nervous system.[56]

Studies with mice have found that food deprivation of the male mouse prior to conception leads to the offspring displaying significantly lower blood glucose levels.[57]

Physical restraint

External physical shocks or constrainment due to growth in a restricted space, may result in unintended deformation or separation of cellular structures resulting in an abnormal final shape or damaged structures unable to function as expected. An example is Potter syndrome due to oligohydramnios. This finding is important for future understandings of how genetics may predispose individuals for diseases like obesity, diabetes, and cancer.

For multicellular organisms that develop in a womb, the physical interference or presence of other similarly developing organisms such as twins can result in the two cellular masses being integrated into a larger whole, with the combined cells attempting to continue to develop in a manner that satisfies the intended growth patterns of both cell masses. The two cellular masses can compete with each other, and may either duplicate or merge various structures. This results in conditions such as conjoined twins, and the resulting merged organism may die at birth when it must leave the life-sustaining environment of the womb and must attempt to sustain its biological processes independently.

Genetic causes

Genetic causes of congenital anomalies include inheritance of abnormal genes from the mother or the father, as well as new mutations in one of the germ cells that gave rise to the fetus. Male germ cells mutate at a much faster rate than female germ cells, and as the father ages, the DNA of the germ cells mutates quickly.[58][28] If an egg is fertilized with sperm that has damaged DNA, there is a possibility that the fetus could develop abnormally.[58][59]

Genetic disorders or diseases are all congenital, though they may not be expressed or recognized until later in life. Genetic diseases may be divided into single-gene defects, multiple-gene disorders, or chromosomal defects. Single-gene defects may arise from abnormalities of both copies of an autosomal gene (a recessive disorder) or of only one of the two copies (a dominant disorder). Some conditions result from deletions or abnormalities of a few genes located contiguously on a chromosome. Chromosomal disorders involve the loss or duplication of larger portions of a chromosome (or an entire chromosome) containing hundreds of genes. Large chromosomal abnormalities always produce effects on many different body parts and organ systems.

Socioeconomic status

A low socioeconomic status in a deprived neighborhood may include exposure to “environmental stressors and risk factors.”[60] Socioeconomic inequalities are commonly measured by the Cartairs-Morris score, Index of Multiple Deprivation, Townsend deprivation index, and the Jarman score.[61] The Jarman score, for example, considers “unemployment, overcrowding, single parents, under-fives, elderly living alone, ethnicity, low social class and residential mobility.”[61] In Vos’ meta-analysis these indices are used to view the effect of low SES neighborhoods on maternal health. In the meta-analysis, data from individual studies were collected from 1985 up until 2008.[61] Vos concludes that a correlation exists between prenatal adversities and deprived neighborhoods.[61] Other studies have shown that low SES is closely associated with the development of the fetus in utero and growth retardation.[62] Studies also suggest that children born in low SES families are “likely to be born prematurely, at low birth weight, or with asphyxia, a birth defect, a disability, fetal alcohol syndrome, or AIDS.”[62] Bradley and Corwyn also suggest that congenital disorders arise from the mother’s lack of nutrition, a poor lifestyle, maternal substance abuse and “living in a neighborhood that contains hazards affecting fetal development (toxic waste dumps).”[62] In a meta-analysis that viewed how inequalities influenced maternal health, it was suggested that deprived neighborhoods often promoted behaviors such as smoking, drug and alcohol use.[60] After controlling for socioeconomic factors and ethnicity, several individual studies demonstrated an association with outcomes such as perinatal mortality and preterm birth.[60]

Radiation

For the survivors of the atomic bombing of Hiroshima and Nagasaki, who are known as the Hibakusha, no statistically demonstrable increase of birth defects/congenital malformations was found among their later conceived children, or found in the later conceived children of cancer survivors who had previously received radiotherapy.[63][64][65] [66] The surviving women of Hiroshima and Nagasaki who were able to conceive, though exposed to substantial amounts of radiation, later had children with no higher incidence of abnormalities/birth defects than in the Japanese population as a whole.[67][68]

Relatively few studies have researched the effects of paternal radiation exposure on offspring. Following the Chernobyl disaster, it was assumed in the 1990s that the germ line of irradiated fathers suffered minisatellite mutations in the DNA, which was inherited by descendants.[24][69] more recently however, the World Health Organization states, "children conceived before or after their father's exposure showed no statistically significant differences in mutation frequencies".[70] This statistically insignificant increase was also seen by independent researchers analyzing the children of the liquidators.[71] Animal studies have shown that incomparably massive doses of X-ray irradiation of male mice resulted in birth defects of the offspring.[31]

In the 1980s, a relatively high prevalence of pediatric leukemia cases in children living near a nuclear processing plant in West Cumbria, UK, led researchers to investigate whether the cancer was a result of paternal radiation exposure. A significant association between paternal irradiation and offspring cancer was found, but further research areas close to other nuclear processing plants did not produce the same results.[31][24] Later this was determined to be the Seascale cluster in which the leading hypothesis is the influx of foreign workers, who have a different rate of leukemia within their race than the British average, resulted in the observed cluster of 6 children more than expected around Cumbria.[72]

Parent's age

Certain birth complications can occur more often in advanced maternal age (greater than 35 years). Complications include fetal growth restriction, preeclampsia, placental abruption, pre-mature births, and stillbirth. These complications not only may put the child at risk, but also the mother.[73] The effects of the fathers age on offspring are not yet well understood and are studied far less extensively than the effects of the mother's age.[74] Fathers contribute proportionally more DNA mutations to their offspring via their germ cells than the mother, with the paternal age governing how many mutations are passed on. This is because, as humans age, male germ cells acquire mutations at a much faster rate than female germ cells.[58][31][28]

Around a 5% increase in the incidence of ventricular septal defects, atrial septal defects, and patent ductus arteriosus in offspring has been found to be correlated with advanced paternal age. Advanced paternal age has also been linked to increased risk of achondroplasia and Apert syndrome. Offspring born to fathers under the age of 20 show increased risk of being affected by patent ductus arteriosus, ventricular septal defects, and the tetralogy of Fallot. It is hypothesized that this may be due to environmental exposures or lifestyle choices.[74]

Research has found that there is a correlation between advanced paternal age and risk of birth defects such as limb anomalies, syndromes involving multiple systems, and Down's syndrome. Recent studies have concluded that 5-9% of Down's syndrome cases are due to paternal effects, but these findings are controversial.

There is concrete evidence that advanced paternal age is associated with the increased likelihood that a mother will have a miscarriage or that fetal death will occur.[58]

Unknown

Although significant progress has been made in identifying the etiology of some birth defects, approximately 65% have no known or identifiable cause.[27] These are referred to as sporadic, a term that implies an unknown cause, random occurrence regardless of maternal living conditions,[77] and a low recurrence risk for future children. For 20-25% of anomalies there seems to be a "multifactorial" cause, meaning a complex interaction of multiple minor genetic anomalies with environmental risk factors. Another 10–13% of anomalies have a purely environmental cause (e.g. infections, illness, or drug abuse in the mother). Only 12–25% of anomalies have a purely genetic cause. Of these, the majority are chromosomal anomalies.[78]

Screening

Newborn screening tests were introduced in the early 1960s and initially dealt with just two disorders. Since then tandem mass spectrometry, gas chromatography–mass spectrometry , and DNA analysis has made it possible for a much larger range of disorders to be screened. Newborn screening mostly measures metabolite and enzyme activity using a dried blood spot sample.[79] Screening tests are carried out in order to detect serious disorders that may be treatable to some extent.[80] Early diagnosis makes possible the readiness of therapeutic dietary information, enzyme replacement therapy and organ transplants.[81] Different countries support the screening for a number of metabolic disorders (inborn errors of metabolism (IEM)), and genetic disorders including cystic fibrosis and Duchenne muscular dystrophy.[80][82] Tandem mass spectroscopy can also be used for IEM, and investigation of sudden infant death, and shaken baby syndrome.[80]

Screening can also be carried out prenatally and can include obstetric ultrasonography to give scans such as the nuchal scan. 3D ultrasound scans can give detailed information of structural anomalies.

Epidemiology


Congenital anomalies deaths per million persons in 2012 
  0–26
  27–34
  35–46
  47–72
  73–91
  92–111
  112–134
  135–155
  156–176
  177–396

Disability-adjusted life year for congenital anomalies per 100,000 inhabitants in 2004.[83]
 
  no data
  less than 160
  160–240
  240–320
  320–400
  400–480
  480–560
  560–640
  640–720
  720–800
  800–900
  900–950
  more than 950

Congenital anomalies resulted in about 632,000 deaths per year in 2013 down from 751,000 in 1990.[12] The types with the greatest death are congenital heart defects (323,000), followed by neural tube defects (69,000).[12]

Many studies have found that the frequency of occurrence of certain congenital malformations depends on the sex of the child (table).[84][85][86][87][88] For example, pyloric stenosis occurs more often in males while congenital hip dislocation is four to five times more likely to occur in females. Among children with one kidney, there are approximately twice as many males, whereas among children with three kidneys there are approximately 2.5 times more females. The same pattern is observed among infants with excessive number of ribs, vertebrae, teeth and other organs which in a process of evolution have undergone reduction—among them there are more females. Contrarily, among the infants with their scarcity, there are more males. Anencephaly is shown to occur approximately twice as frequently in females.[89] The number of boys born with 6 fingers is two times higher than the number of girls.[90] Now various techniques are available to detect congenital anomalies in fetus before birth.[citation needed]

About 3% of newborns have a "major physical anomaly", meaning a physical anomaly that has cosmetic or functional significance.[91] Physical congenital abnormalities are the leading cause of infant mortality in the United States, accounting for more than 20% of all infant deaths. Seven to ten percent of all children[clarification needed] will require extensive medical care to diagnose or treat a birth defect.[92]
The sex ratio of patients with congenital malformations
Congenital anomaly Sex ratio, ♂♂:♀♀
Defects with female predominance
Congenital hip dislocation 1 : 5.2;[93] 1 : 5;[94] 1 : 8;[88] 1 : 3.7[95]
Cleft palate 1 : 3[94]
Anencephaly 1 : 1.9;[93] 1 : 2[89]
Craniocele 1 : 1.8[93]
Aplasia of lung 1 : 1.51[93]
Spinal herniation 1 : 1.4[93]
Diverticulum of the esophagus 1 : 1.4[93]
Stomach 1 : 1.4[93]
Neutral defects
Hypoplasia of the tibia and femur 1 : 1.2[93]
Spina bifida 1 : 1.2[95]
Atresia of small intestine 1 : 1[93]
Microcephaly 1.2 : 1[95]
Esophageal atresia 1.3 : 1;[93] 1.5 : 1[95]
Hydrocephalus 1.3 : 1[95]
Defects with male predominance
Diverticula of the colon 1.5 : 1[93]
Atresia of the rectum 1.5 : 1;[93] 2 : 1[95]
Unilateral renal agenesis 2 : 1;[93] 2.1 : 1[95]
Schistocystis 2 : 1[93]
Cleft lip and palate 2 : 1;[94] 1.47 : 1[95]
Bilateral renal agenesis 2.6 : 1[93]
Congenital anomalies of the genitourinary system 2.7 : 1[88]
Pyloric stenosis, congenital 5 : 1;[94] 5.4 : 1[88]
Meckel's diverticulum More common in boys[93]
Congenital megacolon More common in boys[93]
All defects 1.22 : 1;[96] 1.29 : 1[88]
  • Data[88] obtained on opposite-sex twins. ** — Data[95] were obtained in the period 1983–1994.
P. M. Rajewski and A. L. Sherman (1976) have analyzed the frequency of congenital anomalies in relation to the system of the organism. Prevalence of men was recorded for the anomalies of phylogenetically younger organs and systems.[93]

In respect of an etiology, sexual distinctions can be divided on appearing before and after differentiation of male's gonads in during embryonic development, which begins from eighteenth week. The testosterone level in male embryos thus raises considerably.[97] The subsequent hormonal and physiological distinctions of male and female embryos can explain some sexual differences in frequency of congenital defects. It is difficult to explain the observed differences in the frequency of birth defects between the sexes by the details of the reproductive functions or the influence of environmental and social factors.

United States

The CDC and National Birth Defect Project studied the incidence of birth defects in the US. Key findings include:
  • Down syndrome was the most common condition with an estimated prevalence of 14.47 per 10,000 live births, implying about 6,000 diagnoses each year.
  • About 7,000 babies are born with a cleft palate, cleft lip or both.
Adjusted National Prevalence Estimates and Estimated Number of Cases in the United States, 2004–2006[98]
Birth Defects Cases per Births Estimated Annual Number of Cases Estimated National Prevalence per 10,000 Live Births (Adjusted for maternal race/ethnicity)
Central nervous system defects
Anencephaly 1 in 4,859 859 2.06
Spina bifida without anencephaly 1 in 2,858 1460 3.50
Encephalocele 1 in 12,235 341 0.82
Eye defects
Anophthalmia/ microphthalmia 1 in 5,349 780 1.87
Cardiovascular defects
Common truncus 1 in 13,876 301 0.72
Transposition of great arteries 1 in 3,333 1252 3.00
Tetralogy of Fallot 1 in 2,518 1657 3.97
Atrioventricular septal defect 1 in 2,122 1966 4.71
Hypoplastic left heart syndrome 1 in 4,344 960 2.30
Orofacial defects
Cleft palate without cleft lip 1 in 1,574 2651 6.35
Cleft lip with and without cleft palate 1 in 940 4437 10.63
Gastrointestinal defects
Esophageal atresia/tracheoeophageal fistula 1 in 4,608 905 2.17
Rectal and large intestinalatresia/stenosis 1 in 2,138 1952 4.68
Musculoskeletal defects
Reduction deformity, upper limbs 1 in 2,869 1454 3.49
Reduction deformity, lower limbs 1 in 5,949 701 1.68
Gastroschisis 1 in 2,229 1871 4.49
Omphalocele 1 in 5,386 775 1.86
Diaphragmatic hernia 1 in 3,836 1088 2.61
Chromosomal anomalies
Trisomy 13 1 in 7,906 528 1.26
Trisomy 21 (Down syndrome) 1 in 691 6037 14.47
Trisomy 18 1 in 3,762 1109 2.66

Teratology

From Wikipedia, the free encyclopedia
 
Teratology is the study of abnormalities of physiological development. It is often thought of as the study of human congenital abnormalities, but it is broader than that, taking into account other non-birth developmental stages, including puberty; and other organisms, including plants. The related term developmental toxicity includes all manifestations of abnormal development that are caused by environmental insult. These may include growth retardation, delayed mental development or other congenital disorders without any structural malformations.

Teratogens are substances that may cause birth defects via a toxic effect on an embryo or fetus.[2]

Etymology

The term teratology stems from the Greek τέρας teras (genitive τέρατος teratos), meaning "monster" or "marvel", and λόγος logos, meaning "the word" or, more loosely, "the study of".[3]

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[4]), 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.[by whom?][5]

Mammalia

Teratogenesis

Along with this new awareness of the in utero vulnerability of the developing mammalian embryo came the development and refinement of The Six Principles of Teratology which are still applied today. These principles of teratology were put forth by Jim Wilson in 1959 and in his monograph Environment and Birth Defects.[6] These principles guide the study and understanding of teratogenic agents and their effects on developing organisms:
  1. Susceptibility to teratogenesis depends on the genotype of the conceptus and the manner in which this interacts with adverse environmental factors.
  2. 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.
  3. Teratogenic agents act in specific ways on developing cells and tissues to initiate sequences of abnormal developmental events.
  4. 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.
  5. There are four manifestations of deviant development (Death, Malformation, Growth Retardation and Functional Defect).
  6. 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).
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. 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.

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.

Humans

In humans, congenital disorders resulted in about 510,000 deaths globally in 2010.[7]
About 3% of newborns have a "major physical anomaly", meaning a physical anomaly that has cosmetic or functional significance.[8]

Vaccinating while pregnant

In humans, vaccination has become readily available, and is important to the prevention of some diseases like polio, rubella, and smallpox, among others. There has been no association between congenital malformations and vaccination, as shown in Finland in which expecting mothers received the oral polio vaccine and saw no difference in infant outcomes than mothers who had not received the vaccine.[9] However, it is still not recommended to vaccinate for polio while pregnant unless there is risk of infection [10]. Another important implication of this includes the ability to get the influenza vaccine while pregnant. During the 1918 and 1957 influenza pandemics, mortality in pregnant women was 45%. However, even with prevention through vaccination, influenza vaccination in pregnant women remains low at 12%. Munoz et al. demonstrated that there was no adverse outcomes observed in the new infants or mothers.[11]

Causes

Causes of teratogenesis can broadly be classified as:

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 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.[12] Another notably deformed fossil was a specimen of the choristodere Hyphalosaurus, which had two heads- the oldest known example of polycephaly.[13]

Plantae

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.

Mutagen

From Wikipedia, the free encyclopedia

The international pictogram for chemicals that are sensitising, mutagenic, carcinogenic or toxic to reproduction.

In genetics, a mutagen is a physical or chemical agent that changes the genetic material, usually DNA, of an organism and thus increases the frequency of mutations above the natural background level. As many mutations can cause cancer, mutagens are therefore also likely to be carcinogens, although not always necessarily so. Some chemicals only become mutagenic through cellular processes. 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 physician Hippocrates named tumors resembling a crab karkinos (from which the word "cancer" is derived via Latin), meaning crab.[1] 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,[2] 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.[3] 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.[4] In 1915, Yamagawa and Ichikawa showed that repeated application of coal tar to rabbit's ears produced malignant cancer.[5] Subsequently, in the 1930s the carcinogen component in coal tar was identified as a polyaromatic hydrocarbon (PAH), benzo[a]pyrene.[2][6] 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 radioactivy by Henri Becquerel.[7] Georgii Nadson and German Filippov were the first who created fungi mutants under ionizing radiation in 1925.[8][9] 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,[10][11] visible due to presence of enlarged 'polytene' chromosomes in fruit fly salivary glands.[12] His collaborator Edgar Altenburg also demonstrated the mutational effect of UV radiation in 1928.[13] Muller went on to use x-rays to create Drosophila mutants that he used in his studies of genetics.[14] He also found that X-rays not only mutate genes in fruit flies,[10] 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,[16] and ultraviolet (UV) radiation on maize in 1936.[17] 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.[18]

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.[19] 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.[20][21] Early studies by Ames showed around 90% of known carcinogens can be identified in Ames test as mutagenic (later studies however gave lower figures),[22][23][24] and ~80% of the mutagens identified through Ames test may also be 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.[26]

Effects

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.[27]
Different mutagens act on the DNA differently. Powerful mutagens may result in chromosomal instability,[28] causing chromosomal breakages and rearrangement of the chromosomes such as translocation, deletion, and inversion. Such mutagens are called clastogens.

Mutagens may also modify the DNA sequence; the changes in nucleic acid sequences by mutations include substitution of nucleotide base-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.

Some mutagens can cause aneuploidy and change the number of chromosomes in the cell. They are known as aneuploidogens.[29]

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.[30] [10] 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.[31]

Types

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.[32] Such mutagens are called promutagens.

Physical mutagens

DNA reactive chemicals

A DNA adduct (at center) of the mutagenic metabolite of benzo[a]pyrene from tobacco smoke.

A large number of chemicals may interact directly with DNA. However, many such as PAHs, aromatic amines, benzene are not necessarily mutagenic by themselves, but through metabolic processes in cells they produce mutagenic compounds.
  • 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-hydroperoxyicosatetraenocic 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).[33] 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.
  • Deaminating agents, for example nitrous acid which can cause transition mutations by converting cytosine to uracil.
  • Polycyclic aromatic hydrocarbon (PAH), when activated to diol-epoxides can bind to DNA and form adducts.
  • 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,[citation needed] 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.

Base analogs

  • Base analog, which can substitute for DNA bases during replication and cause transition mutations.

Intercalating agents

Metals

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.[34] 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.[35]

Biological agents

  • Transposon, a section of DNA that undergoes autonomous fragment relocation/multiplication. Its insertion into chromosomal DNA disrupts functional elements of the genes.
  • Virus – 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,[36] 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.

Protection

Fruits and vegetables are rich in antioxidants.

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.[38] 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,[39] however, the effectiveness of antioxidant supplements in cancer prevention in general is still the subject of some debate.[39][40]

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.[41] Others that may be effective against cancer include indole-3-carbinol from cruciferous vegetables and resveratrol from red wine.[42]

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.[43][44]

In 1981, human epidemiological analysis by Richard Doll and Richard Peto indicated that smoking caused 30% of cancers in the US.[45] Diet is also thought to cause a significant number of cancer, and it has been estimated that around 32% of cancer deaths may be avoidable by modification to the diet.[46] 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;[47] and nitrosamines generated from nitrites used as food preservatives in cured meat such as bacon (ascobate, which is added to cured meat, however, reduces nitrosamine formation).[38] Overly-browned starchy food such as bread, biscuits and potatoes can generate acrylamide, a chemical shown to cause cancer in animal studies.[48][49] 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.[50]

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.[51]

Test systems

Many different systems for detecting mutagen have been developed.[52][53] 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.

Bacterial

  • 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 repairE. 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.

Plant assays

Plants such as Zea mays, Arabidopsis thaliana and Tradescantia have been used in various test assays for mutagenecity of chemicals.

Cell culture assay

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.

In fiction

In science fiction, mutagens are often represented as substances that are capable of completely changing the form of the recipient or gaining them superpower. Powerful radiations are the agents of mutation for the superheroes in Marvel Comics's Fantastic Four, Daredevil, and Hulk, while in the Teenage Mutant Ninja Turtles franchise the mutagen is chemical agent also called "ooze", and for Inhumans the mutagen is the Terrigen Mist. Mutagens are also featured in television series, computer and video games, such as the Cyberia, The Witcher, Metroid Prime: Trilogy, Resistance: Fall of Man, Resident Evil, Infamous, Command & Conquer, Gears of War 3, BioShock, and Fallout.

Energy

From Wikipedia, the free encyclopedia https://en.wikipedia.org/wiki/Energy Energy A plasma globe , using el...