Teratogenic+Effects+of+Cocaine+and+Methamphetamine

Teratogenic Effects of Cocaine and Methamphetamine Developed by Jeff Alcorn, James Bahensky, and Kayla Glanz

Normal development of a human embryo begins first at fertilization of the egg by the sperm in the ampulla of the oviduct. The entry and fusion of the sperm and egg produces a diploid zygote that begins dividing, by a process known as cleavage, as the zygote travels down the fallopian tube. After multiple divisions a solid ball of cells (16-32 cells) forms what is called a morula. Two layers of cells are eventually formed, an outer layer called the trophoblast and an inner cell mass (ICM). A blastocyst is then formed by the two layers, which gives rise to a cavity inside the cell mass known as a blastocoel. Before implanting in the uterine wall the blastocyst hatches from an outer layer called the zona pellucida. Exposed adhesion proteins allow the blastocyst to attach and implant in the uterine wall. The ICM differentiates and gives rise to hypoblast and epiblast cells. Trophoblast cells give rise to the synctotrophoblast which help digest further into the uterine wall, implanting the blastocyst further. The developing embryo eventually becomes supplied with necessary nutrition and oxygen by maternal blood vessels. The chorion of the embryo interacts with the uterus epithelium to produce the placenta (Gilbert, 2010).

Further cell divisions result in the beginning of gastrulation. In gastrulation a structure called node begins coordinating epiblast movement by signaling to form the primitive streak. Three germ layers are formed from the movement of the primitive streak: the ectoderm, mesoderm, and endoderm. Migration of epiblast cells results in movement of the primitive streak from the posterior end of the embryo towards the anterior. Organogenesis, the next step in development, involves formation of structures throughout the body from the differentiation of the three germ layers. Differentiation and specialization of the cells is done in each germ layer to give rise to multiple tissues and organs throughout the body. For example, the endoderm differentiates into structures and cells such as cells of the inner digestive tract lining, the lining of the respiratory tube, and cells of the pharynx. Mesoderm cells give rise to smooth, cardiac, and skeletal muscle cells, bone tissue, and red blood cells, while the ectoderm layer develops the epidermis of the skin and the neurons of the central and peripheral nervous systems by first forming the neural tube (Gilbert, 2010).

Development of the neural tube results from the notochord’s formation of the neural plate from ectoderm cells, in a process known as neurulation. Primary neurulation in the anterior region of the notochord causes the neural plate to fold. Folding of the neural plate is facilitated by medial hinge point cells and dorsolateral hinge point cells. Secondary neurulation in the posterior caudal regions of the neural tube is achieved by the formation of a medullary cord by the mesenchymal cells condensing underneath the ectoderm surface. After condensation the medial part of the medullary cord forms multiple hollow spaces called lumens and eventually bring the spaces together to form one medial cavity. Folding and fusion of the neural plate causes the separation of two other layers besides the neural tube, including the neural crest cells and the epidermis. The epidermis is responsible for developing the integumentary structures of the body such as skin, hair, and external environment sensors of the body which help guard and protect the body from the external forces. Neural crest cells differentiate to become structures such as cartilage, bone, melanocytes, neurons, and glial cells (Gilbert, 2010). The neural tube differentiates to form the brain and spinal cord.

Structures of the brain begin formation by the emergence of three primary structures, the prosencephalon, mesencephalon and rhombencephalon. The rhombencephalon gives rise to the metencephalon and myelencephalon, while the prosencephalon further differentiates into the telencephalon and diencephalon. Adult brain structures forming from the telencephalon include the hippocampus and cerebrum, while the epithalamus, thalamus, and hypothalamus are formed by the diencephalon. The metencephalon forms the cerebellum and the pons, the myelencephalon forms the medulla, and the mesencephalon form the fiber tracts and optic lobes of the midbrain (Gilbert, 2010).

Introduction
Cocaine (C17H21NO4; molecular weight 303.3529) is a chemical compound used to stimulate the nervous system in addition to acting as a possible teratogen on the developing embryo. The drug increases levels of the neurotransmitter dopamine, which is associated with the pleasure centers of the brain. Cocaine works to prevent the reuptake of dopamine resulting in a buildup of sustained pleasure. The benefits of this “feel good” drug have led it to be a sought-after commodity of drug abusers. The user can assimilate cocaine by snorting, smoking, or injection. Cocaine is known by several street names including: Bernice, Cecil, Coke, gold dust, and happy dust (Cocaine; InfoFacts: Cocaine, 2010).

Recent studies have shown that cocaine may act as a possible teratogen capable of disrupting normal embryo development. It has been cited to impair both cognitive and motor functioning in humans; however, no authorized human experimentation has been demonstrated. To further study teratogenic effects of cocaine, animal models must be used to avoid possible ethical dilemmas. The animal model allows for the study of mechanism of action, the localization of defects, and research concerning possible treatment options (Dow-Edwards, 2011; Ismail & Bedi, 2007).

Teratogen Impaired Development
Maternal use of cocaine during pregnancy has not been consistently associated with malformations of the fetus, making the teratogenic effects of prenatal cocaine use controversial. Women who use cocaine during pregnancy are usually using other drugs in conjunction with cocaine (alcohol, cannabis, cannabis, etc.), have a low socioeconomic status, and fail to provide adequate prenatal care, all of which combined can cause poor pregnancy and infant health (Gouin, Murphy, & Shah, 2011).Studies have suggested that polydrug use, poor prenatal care, and low socioeconomic status have been shown to intensify the effects of cocaine use during pregnancy. In a study comparing the use of cocaine in conjunction with other narcotics versus the use of narcotics alone, results showed that maternal cocaine consumption in conjunction with other narcotics increases the risk for spontaneous abortion; however, only polydrug users were evaluated, suggesting that other narcotics may play a role in spontaneous abortions. Placenta abruptio, a condition in which the placenta separates from the fetus before delivery, has an increased incidence of occurring while women use cocaine in conjunction with other narcotics when compared to other narcotics alone as well (Simi, Ormond, & Pergament, 1998). In addition to pregnancy complications, birth defects have also been reported from maternal cocaine use. Abnormalities in the nervous system, skeletal system, urogenital system, and digestive system have been associated with maternal cocaine use; however, the these birth defects were reported by polydrug users (Organization of Teratology Information Specialties, 2010).

Recently, studies have indicated that the use of cocaine (exclusively) by women during fetal development has been significantly associated with low birthweight, preterm birth, and small-for-gestational age neonates. Results of these studies have shown that the infants of cocaine users versus non-users typically weighed an average of 492 grams less than infants who were not exposed to cocaine during development. Similarly, prenatal cocaine consumption is strongly associated with small-for-gestational age infants at birth when compared to non-cocaine users, suggesting that infants who have been exposed to cocaine during development have a lower gestational age at birth than do infants of non-users. Results also showed that the use of cocaine during pregnancy was significantly associated with delivery before 37 weeks, or preterm birth (Gouin, Murphy, & Shah, 2011).

Mechanism
Cocaine is not consistently associated with birth defects and abnormalaties and, consequently, little research has been conducted on the mechanism in which cocaine does, or does not, cause teratogenic effects on fetal development. Research has proven, however, that cocaine is capable of crossing the maternal-placental blood barrier. Because of this ability, cocaine can be found in the urine, feces, hair, and umbilical cord of a newborn baby. Once across the maternal-placental barrier, cocaine acts as a reactive oxygen species (ROS) family member and caused oxidative damage to fetal blood vessels, causing them to constrict. Constriction of fetal blood vessels results in poor oxygen and poor nutrient supply to the fetus, consequently resulting in retarded fetal growth that causes low birthweight and small-for-gestation age (Simi, Ormond, & Pergament, 1998; Organization of Teratology Information Specialties, 2010).

In addition to oxidative damage, cocaine stimulates the central nervous but cocaine also inhibits the neurotransmitter dopamine. Cocaine binds to the site of synapses and blocks the dopamine receptor, blocking the dopamine transmitter from binding at the synapse. Without the synapse, dopamine is not reabsorped as it normally is, causing an accumulation of dopamine in synaptic clefts. Dopamine accumulation has profound cognitive effects on the fetal brain such as addiction and separation from the mother (Kubrusly & Bhide, 2010. Prenatal dopamine disruption has been shown to cause more irritable, jittery, and visual and sensory disturbances in cocaine-exposed newborns than in non-cocaine-exposed newborns. School-age children exposed to cocaine during pregnancy have been reported to have delays in learning and growth and life-long effects of prenatal exposure include attention deficit disorders, increased aggression (Organization of Teratology Information Specialties, 2010).

Treatments
Most cocaine-exposed infants do not require treatment for cocaine addiction; however, the cocaine exposure does cause increased irritability. Phenobarbital, an anti-anxiety medication, may help reduce the irritability of the infant and help recover from the addiction. However, Phenobarbital may only benefit for a short period of time. Cocaine-exposed infants are typically placed under intense nursery care in order to ensure decreased aggression due to irritable stimuli as well as to ensure adequate nutrition to the underdeveloped newborn (Cheous, 2011).

First and foremost, prevention is the only and most effective way to treat cocaine-exposed infants.

Introduction
Methamphetamine (C10H15N; molecular weight 149.2328) is white powder used to stimulate the central nervous system in addition to acting as a possible teratogen on the developing embryo. The drug acts in a similar manner to cocaine by increasing levels of the neurotransmitter dopamine to sustain pleasure; however, unlike cocaine it is transported into the cell (Methamphetamine; Roussotte, Soderberg & Sowell, 2010). Although a doctor can prescribe methamphetamine, it is highly controlled and has few medical uses. Due to the controlled nature of this drug and its ability to stimulate euphoria, many users abuse the drug and obtain it illegally. Illegal methamphetamine producing operations (a.k.a. meth labs) usually obtain some ingredients from medications containing ephedrine; however, legislation moving these drugs behind the counter at pharmacies in Tennessee has reduced the number of “lab” seizures from 1,500 in 2004 to 955 in 2005 (DEA: Methamphetamine).

Methamphetamine can be introduced in the body dissolved in a liquid, by snorting, smoking, or injection. Methamphetamine is known by numerous street names including: speed, ice, crank, poor man's cocaine, and chicken feed (Methamphetamine; DEA: Methamphetamine).

Recent studies have shown that methamphetamine may act as a possible teratogen capable of disrupting normal patterns of functional activation and interrupting functional connectivity within the developing brain (Roussotte et al., 2011). It has been cited to cause vasoconstriction, disrupting developing axis formation, altering gene expression, recruitment of support networks for verbal memory, and structural brain abnormalities such as reduced brain volume (Roussotte, Soderberg & Sowell, 2010).

Teratogen Impaired Development
Affects of Methamphetamine use by mothers during prenatal development usually include smaller head circumference compared to normal groups. Infants exposed prenatally to methamphetamine also have been shown in studies to be up to 3.5 times likelier to be small for their gestational age (SGA) which increases the risk of mortality and developing conditions such as type 2 diabetes later in life. Gestational age at birth has been found to be lower in groups of rats and infants which are exposed to methamphetamine during prenatal development (Melo et al., 2006; Noailles et al., 2003; Smith et al., 2006). Infants exposed to prenatal stimulants such as methamphetamine or cocaine have been shown to have even more decreased birth weight and head circumference than those exposed to narcotics. Lower growth rates in weight, height, and head circumference after birth have been seen in these groups compared to unexposed infant peers (Smith et al., 2006).

Other implications of maternal methamphetamine use during pregnancy may include defects in cardiac function, cleft lip, and increased likelihood of biliary atresia, which is a blockage of ducts which carry bile from the liver to the gallbladder (Biliary atresia, 2011; Smith et al., 2006). Use of Methamphetamine prenatally is believed to increase blood pressure in the infant as well as affect development of the baby's brain, spinal cord, heart, and kidneys, and causes constriction in blood vessels in the fetus. Constriction of blood vessels from methamphetamine exposure causes poor blood supply, causing poor oxygen and nutrient supply. Each of these affects of methamphetamine exposure likely act to inhibit growth and impair functional and cognitive processes. Prenatal Methamphetamine exposure may also cause fetal brain hemorrhage and has been suspected to increase apoptosis in cells in the infant brain especially in areas of the hippocampus during rat development (Melo et al., 2006; Noailles et al., 2003). Long-term problems with motor coordination and other neurological abnormalities have also been suspected to have been from methamphetamine exposure during development in mice (University of Toronto, 2005).

Findings of the effects of prenatal Methamphetamine exposure need to be further studied and researched in order to understand its effects on development completely. Problems or inconclusiveness of experiments arise from the obvious ethical problems that would arise from testing human subjects with methamphetamine during prenatal development. Small sample sizes in human testing have made results of studies inconclusive, along with the presence of other drug use in those mothers that use meth during pregnancy. Along with other drugs, Alcohol, nicotine, and marijuana exposure, which are most commonly used by methamphetamine users, could also play a role in variable development. Rats have consistently been used as models to test methamphetamine's effect on prenatal development, but continued research is needed for conclusive findings on the subject.

Mechanism
Mechanisms for which methamphetamine causes some of its effects are still being studied. However, we know methamphetamine stimulates the cardiovascular and central nervous systems by elevating the release of neurotransmitters such as dopamine, serotonin, and norepinephrine and preventing the re-uptake of the same neurotransmitters. Effects of this increased presence of neurotransmitters causes a response similar to that of stimulation to the sympathetic nervous system. Methamphetamine causes dilation of bronchioles and pupils, increases the heart rate, and constricts the blood vessels, causing higher blood pressure (Melo et al., 2006, Smith et al., 2006). Methamphetamine's effect of increasing blood pressure in the mother by blood vessel vasoconstriction is believed to affect the fetus by restricting and decreasing blood flow into the placenta and fetus. Less blood flow, meaning less oxygen and nutrients, to the fetus usually results in less growth in babies during gestation. This can be seen by the fact that infants exposed to methamphetamine before birth usually are smaller than their peers that are not exposed to methamphetamine (Smith et al., 2006).

Ingestion or exposure to a teratogen by a mother likely result in the exposure of the same teratogen to an infant, and may cause varying results in the infants development, depending on the level of exposure. Mechanisms for other teratogenic effects methamphetamine produces, besides small birth-weights, have not been conclusively proven. However, there are some mechanisms which likely cause some some of the results and damage seen in the developing fetus. Inhibition of the blood brain barrier, oxidative stress, and the production of reactive oxygen species (ROS) may contribute to some of the neural damage and cognitive and motor deficits seen as a side effect in some children who are exposed prenatally to methamphetamine. Exposure of methamphetamine has been implicated in increasing the permeability of the blood brain barrier (BBB) by decreasing the tightness of brain microvascular endothelial cells (BMEC), a group of cells that make up an important portion of the blood brain barrier. Methamphetamine has this effect on the BMEC cells and the BBB because methamphetamine decreases the expression of tight junctions in the cell membrane (Ramirez et al., 2009). Along with diminishing the blood brain barrier, methamphetamine has been shown to produce reactive oxygen species and oxidative stress (Jayanthi et al., 2004, Ramirez et al., 2009, Yamomoto & Zhu 1998). This oxidative stress in neurons has been shown in various instances such as disease to cause neurodegeneration. Depending on the level of oxidative stress produced by methamphetamine, neuronal cell death may result from the oxidative stress's activation of apoptotic pathways in the cell. This will result in programmed cell death, loss of tissue, and less growth in the neurons and infant brain.

Timing of drug use during pregnancy must further be investigated. However, there does not seem to be a certain time in which methamphetamine affects the fetus most. Methamphetamine exposure looks to affect the fetus negatively throughout development, usually affecting their size and gestational age at birth (Smith et al., 2006; University of Toronto, 2005). The duration and amount of exposure of methamphetamine prenatally to an infant is likely to play a larger role than the timing of methamphetamine use. The amount of deficit in the brain matter of an embryo exposed to methamphetamine must be quantified and further studied. However, the amount of damage is likely proportional to the amount of methamphetamine exposure and duration of exposure during gestation.

Treatments
As methamphetamine may cause some cognitive defects and memory impairment, treatment of the newborn may be associated with cognitive rehabilitation to increase mental capacities such as memory retention.

Similar to cocaine the most important form of treatment is the prevention of exposure to harmful teratogens. Expecting and new mothers must take great care to avoid exposing their infants to these harmful compounds.