Developmental toxicity

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Developmental toxicity is any developmental malformation that is caused by the toxicity of a chemical or pathogen. It is the structural or functional alteration, reversible or irreversible, which interferes with homeostasis, normal growth, differentiation, development or behavior. Developmental toxicity is caused by environmental insult, which includes drugs, alcohol, diet, toxic chemicals, and physical factors.

Contents

More factors causing developmental toxicity are radiation, infections (e.g. rubella), maternal metabolic imbalances (e.g. alcoholism, diabetes, folic acid deficiency), drugs (e.g. anticancer drugs, tetracyclines, many hormones, thalidomide), and environmental chemicals (e.g. mercury, lead, dioxins, PBDEs, HBCD, tobacco smoke).In addition, it is the study of adverse effects on the development of the organism that can result from exposure to toxic agents before conception, during fetal development, or even following birth.

The first few weeks of embryogenesis in humans. Beginning at the fertilized egg, ending with the closing of the neural tube. The embryogenesis is the most crucial time for the action of any teratogenic substances resulting in birth defects. Human embryogenesis.png
The first few weeks of embryogenesis in humans. Beginning at the fertilized egg, ending with the closing of the neural tube. The embryogenesis is the most crucial time for the action of any teratogenic substances resulting in birth defects.

Certain pathogens are also included since the toxins they secrete are known to cause adverse effects on the development of the organism when the mother or fetus is infected. The term  developmental toxicity has widely replaced the early term for the study of primarily structural congenital abnormalities, teratology, to enable inclusion of a more diverse spectrum of congenital disorders. The substances that cause developmental toxicity from embryonic stage to birth are called teratogens. The effect of the developmental toxicants depends on the type of substance, dose, duration, and time of the exposure. The first few weeks of embryogenesis in humans is more susceptible to these agents.

The embryogenesis is the most crucial time for the action of any teratogenic substances to result in birth defects. Once fertilization has taken place, the toxicants in the environment can pass through the mother to the developing embryo or fetus across the placental barrier. The fetus is at greatest risk during the first 14th to 60th day of the pregnancy when the major organs are being formed. However, depending on the type of toxicant and amount of exposure, a fetus can be exposed to toxicants at any time during pregnancy, but have different effects. For example, exposure to a particular toxicant at one time in the pregnancy may result in organ damage and at another time in the pregnancy could cause death of the fetus and miscarriage.

There are a number of chemicals, biological agents (such as bacteria and viruses), and physical agents (such as radiation) used in a variety of workplaces that are known to cause developmental disorders. Developmental disorders can include a wide range of physical abnormalities, such as bone or organ deformities, or behavioral and learning problems, such as an intellectual disability. Exposures to some chemicals during pregnancy can lead to the development of cancer later in life, called transgenerational carcinogens. Exposure to toxicants during the second and third trimesters of a pregnancy can lead to slow fetal growth and result in low birth weight.

History

Toxicology research is the study of the adverse effects of chemicals or physical agents on living organisms. The scientific study of poisons dates to Ancient Egypt, China, and Greece. Ebers Papyrus from 1500 BCE contains information on many poisons including hemlock. Shen Hung (2605 BCE, China) tested hundreds of herbs and wrote the first Pharmacopoeia. Orfila, a 19th-century Spanish physician and scientist, is a founder of modern toxicology that autopsied poison victims to evaluate target organ specific effects (liver, kidney, GI track, brain, etc.). [1]

Researchers have been able to ascertain toxicity associated with abnormal development with new breakthrough in developmental biology. Recognition of the developmental toxic effects of various molecules is recent development.

Terato means monster in Greek. Until the 18th century, the preformism theory was accepted by which abnormal growth was considered as deformations. The 19th century saw developmental in descriptive embryology where abnormalities were now considered as malformations or errors during a developmental process giving rise to the concept of teratogenesis. By the 20th century, the concept of epigenesis the interaction between a genetic program and environment was established and in the second half of the 20th century researchers had evidence that environmental factors can cause malformations and even trans-generational effects. [2]

This type of specific research that looks for malformations in fetal development is called Developmental and Reproductive Toxicology (DART)

Testing and risk assessment

Testing for developmental toxicant is done in different stages:

DART (Developmental and Reproductive Toxicology)

DART is the specific research of looking for malformations from the toxicity of chemicals, medications, pesticides, dietary supplements, etc. The National Toxicology Program (NTP) has been conducting DART research for chemicals that have not been FDA approved or undergone the appropriate research for human offspring. [3]

The research is conducted by using pregnant animals and exposing them to a certain chemical, medication, drug, pesticide, etc. throughout their pregnancy and then complete teratology on the fetuses to look for malformations. These malformations can be anything from a tissue malformation to a skeletal malformation. They can also allow the animal to deliver the offspring to look for malformations in growing animals. These malformations can be anything from behaviors, intellect, sexual maturity such as testicular development, vaginal opening, and the ability to reproduce.

Because of the complexity of the embryo-fetal development, including the maternal-fetal interactions during gestation, it is important to understand the mechanism of toxicity and test the toxic effect in more than two species before confirming the substance to be a developmental toxicant. Embryo have different critical periods for the organ formation from day 15 to day 60 and hence the susceptibility to toxicant injury is directly related to the period of development.

Toxicity effects

Developmental toxicity is the alterations of the developmental processes (organogenesis, morphogenesis) rather than functional alterations of already developed organs. The effects of the toxicants depends on the dose, threshold and duration. The effects of toxicity are:

  1. Minor structural deformities - e.g. Anticonvulsant drugs, Warfarin, Retinoic Acid derivatives
  2. Major structural deformities - e.g. DES (diethylstilbestrol), cigarette smoking
  3. Growth Retardation - e.g. Alcohol, Polychlorinated Biphenyls
  4. Functional alterations - e.g. Retinoic Acid derivatives, Polychlorinated Biphenyls, Phenobarbitol, Lead
  5. Death- e.g. Rubella, ACE inhibitors

Examples

Maternal irradiation and congenital malformations

One of the first environmentally induced congenital malformations in humans were recognized as a result of maternal irradiation. Hiroshima (1953) and Nagasaki (1955) had ascertained this fact for the first time based on the records of births occurring before May 31, 1946, but after the atomic bombing (August 6, 1945, in Hiroshima; August 9, 1945, in Nagasaki). A 20% increase in microcephaly frequency was seen in children with in-utero radiation exposure during the first trimester of the pregnancy (Miller 1956, 1968). Sensitivity to these radiations was seen to be predominantly high during the 7–15th week of gestation.

Two pertinent points were observed during this study:

  1. The severity and frequency of the congenital abnormalities seen increased with dose of radiation which depended on the closeness to the source or explosion.
  2. It was determined that there were critical periods of pregnancy when these exposures had the maximum effect on the fetal development.
Cataracts in a child's eyes due to congenital rubella syndrome (CRS) Cataracts due to Congenital Rubella Syndrome (CRS) PHIL 4284 lores.jpg
Cataracts in a child's eyes due to congenital rubella syndrome (CRS)

Congenital rubella syndrome (CRS)

Rubella was the first recognized human epidemic of malformations. Following a widespread epidemic of rubella infection in 1940, Norman Gregg, an Australian ophthalmologist, reported in 1941 the occurrence of congenital cataracts among 78 infants born following maternal rubella infection in early pregnancy. This indicated that the virus had to cross the placental barrier to reach the fetus and cause malformations. The time of exposure to the virus also had a direct impact on the incidence of congenital malformations with exposure during week 4, 5–8 and 9–12 weeks of pregnancy caused 61%, 26% and 8% of congenital malformations. This was the first published recognition of congenital rubella syndrome (CRS). The progeny had congenital eye, heart and ear defects as well as intellectual disability. [4]

Prescription Thalidomide Pack of Thalidomide tablets.jpg
Prescription Thalidomide

Thalidomide Tragedy (1950)

Thalidomide was used as treatment for cancers, leprosy and HIV, however, the drug was extensively used for the treatment of nausea in pregnant women in the late 1950s and early 1960s until it became apparent in the 1960s that it resulted in severe birth defects. Fetus that were exposed to thalidomide while in the womb experienced limb malformation by which the limb was not developed or appeared as stumps. Other effects also seen with thalidomide exposure included deformed eyes and hearts, deformed alimentary and urinary tracts, blindness and deafness. [5] The thalidomide tragedy marked a turning point in toxicity testing, as it prompted United States and international regulatory agencies to develop systematic toxicity testing protocol. The effects of thalidomide led to important discoveries in the biochemical pathways of limb development. [6] Many thalidomide victims and their families are still seeking justice for the struggles that they had to endure. The most notable way that survivors are fighting for justice is by forming Thalidomide survivor societies. These societies provide a safe space for Thalidomide survivors to freely share their stories and rally together to fight for social change as well as enforce strict laws on drug testing and control. The most notable society in the United States is the US Thalidomide Survivors Society. This society focuses on the survivors within the United States, while also promoting other international societies. [7]

Effects on neurulation

Neurulation is one of the most important stages in the development of vertebrates. It is the process of formation of a flat neural plate which then convolutes to form the hollow neural tube. [8] It is considered to be one of the main targets of developmental toxicity and defects in neurulation is a common consequence of toxicant exposure and results in large proportion of human defects. [9] Neurulation exposure to developmental toxicity is caused by the increased rate of cell proliferation and the ventral to dorsal migration of neuroepithelial cells. Epigenetic factors disrupt the normal process of the formation of the neural tube causing Neural Tube Defects (NTD). This leads to spina bifida, a common human defect. [10]

Facial characteristics that suggest the diagnosis of FAS Photo of baby with FAS.jpg
Facial characteristics that suggest the diagnosis of FAS

Fetal alcohol syndrome (FAS)

Fetal alcohol spectrum disorders (FASD) is a term that constitutes the set of conditions that can occur in a person whose mother drank alcohol during the course of pregnancy. These effects can include physical and cognitive problems. FASD patient usually has a combination of these problems. [11] Extent of effect depends on exposure frequency, dose and rate of ethanol elimination from amniotic fluid. FAS disrupts normal development of the fetus, which may cause certain developmental stages to be delayed, skipped, or immaturely developed. [12] Since alcohol elimination is slow in a fetus than in an adult and the fact that they do not have a developed liver to metabolize the alcohol, alcohol levels tend to remain high and stay in the fetus longer. Birth defects associated with prenatal exposure to alcohol can occur in the first three to eight weeks of pregnancy before a woman even knows that she is pregnant. [13]

Diethylstilbestrol (DES) cervix. The cockscomb, collar, and pseudopolyp of cervix. Cockscomb (hoods) are markedly enlarged folds of cervical stroma and epithelium . Low, broad folds are collars (rims). A pseudopoly is that portion of the cervix which is medial to a constricting band (sulcus) and has on superficial examination the appearance of a polyp. Diethylstilbestrol (des) cervix (5).jpg
Diethylstilbestrol (DES) cervix. The cockscomb, collar, and pseudopolyp of cervix. Cockscomb (hoods) are markedly enlarged folds of cervical stroma and epithelium . Low, broad folds are collars (rims). A pseudopoly is that portion of the cervix which is medial to a constricting band (sulcus) and has on superficial examination the appearance of a polyp.

DES (diethylstilbestrol)

DES (diethylstilbestrol) is a drug that mimics estrogen, a female hormone. From 1938 until 1971, doctors prescribed this drug to help some pregnant women who had had miscarriages or premature deliveries on the theory that miscarriages and premature births occurred because some pregnant women did not produce enough estrogen naturally to sustain the pregnancy for full term. An estimated 5–10 million pregnant women and the children born during this period were exposed to DES. Currently, DES is known to increase the risk of breast cancer, and cause a variety of birth-related adverse outcomes exposed female offsprings such as spontaneous abortion, second-trimester pregnancy loss, preterm delivery, stillbirth, neonatal death, sub/infertility and cancer of reproductive tissues. DES is an important developmental toxicant which links the fetal basis of adult disease. [14]

Methylmercury

Methylmercury and inorganic mercury is excreted in human breast milk and infants are particularly susceptible to toxicity due to this compound. [15] The fetus and infant are especially vulnerable to mercury exposures with special interest in the development of the CNS since it can easily cross across the placental barrier, accumulate within the placenta and fetus as the fetus cannot eliminate mercury and have a negative effect on the fetus even if the mother does not show symptoms. [16] Mercury causes damage to the nervous system resulting from prenatal or early postnatal exposure and is very likely to be permanent. [17]

Chlorpyrifos

It is an organophosphate insecticide that acts on the nervous system of insects by inhibiting acetylcholinesterase but are moderately toxic to humans. But it is known have developmental effects appear in fetuses and children even at very small doses. It has been shown to cause abnormal reflexes in neonates, poorer mental development in 2 and 3 year olds, poorer verbal IQ in 3+1⁄2 and 5 year old and pervasive developmental disorder in 2, 3 and 3+1⁄2 year olds. [18]

Environmental endocrine disruptors

Endocrine disruptors are molecules that alter the structure or function of the endocrine system. These chemicals can act as a part of developmental toxicity because they can alter hormonal pathways in the endocrine system, leading to negative health effects. One of the most common endocrine disruptor is Bisphenol A (BPA). BPA is often found in human waste material, specifically plastics. This means that BPA is also used in water bottles, which can be dangerous when the chemicals from the plastics leach into the purified drinking water for human consumption.  More endocrine disrupting chemicals include forms of phthalic acid esters that are used as plasticizers. Both BPA and phthalic acid esters are found in waterways. [19] Prenatal BPA exposure is associated with aggression and neurobehaviour changes. [20] Another common toxin is pyrifluquinazon, which is an insecticide used to control pests. Vinclozolin is also an endocrine disrupting chemical; it is a fungicide used on produce to help them have a longer shelf life . [21] Endocrine disruptors may have different effects depending on the extent of the exposure. [22] Many endocrine disrupting chemicals are not only found in plastic, but also found in many hygiene products, cosmetics, cleaners, food, and much more. These toxins can have a lead role in human health as they can lead to metabolic diseases, infertility issues, and even neurodevelopmental disorders. [23]

Dietary Supplements

Many dietary supplements are approved without FDA approval due to them being listed as "food" instead of drugs. However, many of them contain chemicals that have not been tested and approved for use of pregnant women. It is important to investigate and research any type of dietary supplement before taking it during pregnancy. Some dietary supplements that have been found to have harmful effects are listed below.

Major developmental toxicants

Some of the known developmental toxicants can be grouped under the following categories:

Reproductive toxins:

Anti-convulsants:

Chemicals:

Biological agents:

Lifestyle:

Maternal metabolic imbalances:

Related Research Articles

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. 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. 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, the genetic makeup of the embryo, and the transfer rate of the teratogen.

<span class="mw-page-title-main">Birth defect</span> Condition present at birth regardless of cause

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

<span class="mw-page-title-main">Fetal alcohol spectrum disorder</span> Group of conditions resulting from maternal alcohol consumption during pregnancy

Fetal alcohol spectrum disorders (FASDs) are a group of conditions that can occur in a person who is exposed to alcohol during gestation, as a result of their mother drinking alcohol during pregnancy. The several forms of the condition are: fetal alcohol syndrome (FAS), partial fetal alcohol syndrome (pFAS), alcohol-related neurodevelopmental disorder (ARND), and neurobehavioral disorder associated with prenatal alcohol exposure (ND-PAE). Other terms used are fetal alcohol effects (FAE), partial fetal alcohol effects (PFAE), alcohol-related birth defects (ARBD), and static encephalopathy, but these terms have fallen out of favor and are no longer considered part of the spectrum.

<span class="mw-page-title-main">Persistent organic pollutant</span> Organic compounds that are resistant to environmental degradation

Persistent organic pollutants (POPs) are organic compounds that are resistant to degradation through chemical, biological, and photolytic processes. They are toxic and adversely affect human health and the environment around the world. Because they can be transported by wind and water, most POPs generated in one country can and do affect people and wildlife far from where they are used and released.

Environmental toxicants and fetal development is the impact of different toxic substances from the environment on the development of the fetus. This article deals with potential adverse effects of environmental toxicants on the prenatal development of both the embryo or fetus, as well as pregnancy complications. The human embryo or fetus is relatively susceptible to impact from adverse conditions within the mother's environment. Substandard fetal conditions often cause various degrees of developmental delays, both physical and mental, for the growing baby. Although some variables do occur as a result of genetic conditions pertaining to the father, a great many are directly brought about from environmental toxins that the mother is exposed to.

Prenatal development includes the development of the embryo and of the fetus during a viviparous animal's gestation. Prenatal development starts with fertilization, in the germinal stage of embryonic development, and continues in fetal development until birth.

Maternal use of androgens or high doses of certain weakly androgenic synthetic progestogens (progestins) structurally related to testosterone can masculinize (virilize) the vulva of a female fetus during susceptible times in pregnancy.

<span class="mw-page-title-main">Benzyl butyl phthalate</span> Chemical compound

Benzyl butyl phthalate (BBP) is an organic compound historically used a plasticizer, but which has now been largely phased out due to health concerns. It is a phthalate ester of containing benzyl alcohol, and n-butanol tail groups. Like most phthalates, BBP is non-volatile and remains liquid over a wide range of temperatures. It was mostly used as a plasticizer for PVC, but was also a common plasticizer for PVCA and PVB.

Congenital amputation is birth without a limb or limbs, or without a part of a limb or limbs.

<span class="mw-page-title-main">Bisphenol S</span> Chemical compound

Bisphenol S (BPS) is an organic compound with the formula (HOC6H4)2SO2. It has two phenol functional groups on either side of a sulfonyl group. It is commonly used in curing fast-drying epoxy resin adhesives. It is classified as a bisphenol, and a close molecular analog of bisphenol A (BPA). BPS differentiates from BPA by possessing a sulfone group (SO2) as the central linker of the molecule instead of a dimethylmethylene group (C 2), which is the case of bisphenol A.

Women should speak to their doctor or healthcare professional before starting or stopping any medications while pregnant. Non-essential drugs and medications should be avoided while pregnant. Tobacco, alcohol, marijuana, and illicit drug use while pregnant may be dangerous for the unborn baby and may lead to severe health problems and/or birth defects. Even small amounts of alcohol, tobacco, and marijuana have not been proven to be safe when taken while pregnant. In some cases, for example, if the mother has epilepsy or diabetes, the risk of stopping a medication may be worse than risks associated with taking the medication while pregnant. The mother's healthcare professional will help make these decisions about the safest way to protect the health of both the mother and unborn child. In addition to medications and substances, some dietary supplements are important for a healthy pregnancy, however, others may cause harm to the unborn child.

<span class="mw-page-title-main">Reproductive toxicity</span> A hazard associated with chemical substances

Reproductive toxicity refers to the potential risk from a given chemical, physical or biologic agent to adversely affect both male and female fertility as well as offspring development. Reproductive toxicants may adversely affect sexual function, ovarian failure, fertility as well as causing developmental toxicity in the offspring. Lowered effective fertility related to reproductive toxicity relates to both male and female effects alike and is reflected in decreased sperm counts, semen quality and ovarian failure.

<span class="mw-page-title-main">Thalidomide scandal</span> Medical condition

In the late 1950s and early 1960s, the use of thalidomide in 46 countries by women who were pregnant or who subsequently became pregnant resulted in the "biggest anthropogenic medical disaster ever," with more than 10,000 children born with a range of severe deformities, such as phocomelia, as well as thousands of miscarriages.

Birth injury refers to damage or injury to the child before, during, or just after the birthing process. "Birth trauma" refers specifically to mechanical damage sustained during delivery.

Prenatal cocaine exposure (PCE), theorized in the 1970s, occurs when a pregnant woman uses cocaine and thereby exposes her fetus to the drug. Babies whose mothers used cocaine while pregnant supposedly have increased risk of several different health issues during growth and development.

<span class="mw-page-title-main">Health effects of pesticides</span> How pesticides affect human health

Health effects of pesticides may be acute or delayed in those who are exposed. Acute effects can include pesticide poisoning, which may be a medical emergency. Strong evidence exists for other, long-term negative health outcomes from pesticide exposure including birth defects, fetal death, neurodevelopmental disorder, cancer, and neurologic illness including Parkinson's disease. Toxicity of pesticides depend on the type of chemical, route of exposure, dosage, and timing of exposure.

Prenatal memory, also called fetal memory, is important for the development of memory in humans. Many factors can impair fetal memory and its functions, primarily maternal actions. There are multiple techniques available not only to demonstrate the existence of fetal memory but to measure it. Fetal memory is vulnerable to certain diseases so much so that exposure can permanently damage the development of the fetus and even terminate the pregnancy by aborting the fetus. Maternal nutrition and the avoidance of drugs, alcohol and other substances during all nine months of pregnancy is important to the development of the fetus and its memory systems. The use of certain substances can entail long-term permanent effects on the fetus that can carry on throughout their lifespan.

Testicular dysgenesis syndrome is a male reproduction-related condition characterized by the presence of symptoms and disorders such as hypospadias, cryptorchidism, poor semen quality, and testicular cancer. The concept was first introduced by N.E. Skakkaebaek in a research paper along with the department of Growth and Reproduction in Copenhagen University. The paper suggests the origin and underlying cause of TDS can be detected as early as in fetal life, where environmental and genomic factors could affect the development of the male reproductive system.

Antiandrogens in the environment have become a topic of concern. Many industrial chemicals, including phthalates and pesticides, exhibit antiandrogen activity in animal experiments. Certain plant species have also been found to produce antiandrogens. In animal studies, environmental antiandrogens can harm reproductive organ development in fetuses exposed in utero as well as their offspring.

Fetal programming, also known as prenatal programming, is the theory that environmental cues experienced during fetal development play a seminal role in determining health trajectories across the lifespan.

References

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  2. ↑ Sander K (1997). Landmarks in Developmental Biology 1883–1924. Springer. doi:10.1007/978-3-642-60492-8. ISBN   978-3-642-64428-3. S2CID   11288064.
  3. ↑ National Toxicology Program. "Developmental & Reproductive Toxicity (DART) Reports". National Toxicology Program - DART. Archived from the original on 20 April 2023. Retrieved 19 Apr 2023.{{cite web}}: CS1 maint: bot: original URL status unknown (link)
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  19. ↑ Gani, Khalid Muzamil; Kazmi, Absar Ahmad (2020-03-01). "Ecotoxicological risk evaluation and regulatory compliance of endocrine disruptor phthalates in a sustainable wastewater treatment scheme". Environmental Science and Pollution Research. 27 (8): 7785–7794. doi:10.1007/s11356-019-07418-7. ISSN   1614-7499. PMID   31889277. S2CID   209509980.
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  21. ↑ Feijó, Mariana; Martins, Roberta V L; Socorro, Sílvia; Pereira, Luísa; Correia, Sara (2021-05-07). "Effects of the endocrine disruptor vinclozolin in male reproduction: a systematic review and meta-analysis†". Biology of Reproduction. 104 (5): 962–975. doi:10.1093/biolre/ioab018. ISSN   0006-3363. PMID   33524106.
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