Tran H. Tran, PharmD, BCPS

• Associate Professor, Department of Pharmacy Practice, Chicago College of Pharmacy, Midwestern University, Downers Grove
• Clinical Pharmacist, Loyola University Medical Center, Maywood, Illinois

Along with the "all-or-none" early resorptions asthma treatment tablets purchase proventil 100 mcg on-line, this led the investigators to suspect a maternally-mediated mode of action asthma bronchioles generic 100 mcg proventil. The potential role of maternal hepatotoxicity was not ruled out by these studies and remains to be determined asthma treatment image 100 mcg proventil with amex. The examples cited in this chapter constitute some of the more common profiles of maternal toxicity that might be encountered as a result of chemical toxicity asthma treatment in khewra proventil 100 mcg buy on line, and are instructive for interpreting data on the maternal toxicity­developmental toxicity relationship asthma treatment 1900 discount proventil 100 mcg buy online. Discussed below are some basic considerations that can be used in a weight of evidence evaluation of data. The type of developmental effect should be commensurate with the nature and severity of maternal toxicity. Examples General decrease in maternal food consumption and body weight gain; decreased fetal body weight. General decrease in maternal food consumption and body weight gain; fetal malformations. Maternal stomach and esophagus show microscopic evidence of hyper- and parakeratosis following dosing with a chelating agent; fetal malformations. Therefore, the timing of maternal toxicity should correspond with the estimated stage of gestation when development was affected, based on knowledge of embryo development. Examples Significantly decreased body weight during the last week of gestation (rat); decreased fetal body weight and reduced ossification of the calvarium. Plausible (see section on Maternal Weight Gain and Food Intake, and Malnutrition). Maternal body weight loss during the last five days of gestation; fetal anophthalmia. Unlikely due to the fact that the eyes form very early during organogenesis, whereas the maternal insult occurred late in the fetal period. Assessment of individual animal data is critical in these evaluations, particularly with rabbits owing to their typically greater degree of interanimal variability. The greater the correspondence between severity of maternal toxicity in individual maternal animals and effects in their litters, the greater the weight of evidence supporting the association. An example of this type of analysis can be found in a study of the herbicide triclopyr butoxyethyl ester in rats (Carney et al. The remaining 18 dams showed very little maternal toxicity and produced no evidence of developmental toxicity. Another consideration is that multiple stressors can impact upon maternal physiology to heighten the overall maternal response and exacerbate secondary developmental effects. Studies in rodents have shown that stress hormones may act as potentiators, rather than direct developmental toxicants (Goldman and Yakovac, 1964; Hartel and Hartel, 1960; Rasco and Hood, 1994). Interactions should also be considered when applying food restriction data to the interpretation of toxicity studies, as food restriction adequately models the impact of reduced maternal body weight, but not the stress or malaise associated with target organ toxicity. Thus, on an actual toxicity study, the combined impact of reduced maternal body weight gain and maternal stress on the developing fetus could be greater than suggested by food restriction data alone. For studies that match some of the common profiles of maternal and developmental effects described in this chapter, information from the literature may be sufficient to conclude that there is a plausible causal relationship between maternal toxicity and developmental toxicity. However, other cases will warrant the generation of mode of action information directed at determining human relevance (Seed et al. Whole-embryo culture can be a powerful tool in delineating between maternally mediated versus direct modes of action, as the test compound or its metabolites can be added directly to the cultures, thus removing the impact of maternal influences. Conversely, to evaluate the impact of maternal factors such as nutrient deficiencies or altered serum biochemistry, an ex vivo embryo culture approach can be used in which untreated, naive embryos are grown in serum from a separate group of treated animals (Chatot et al. These in vitro strategies can be complemented with more detailed evaluations of maternal physiology, which now include possibilities like wireless telemetry monitoring. The present assemblage of knowledge concerning the specific details of different types of maternal physiological perturbations and their impact on development should be useful in resolving at least some of these issues. There is, however, another way to deal with the vexing issue of maternal toxicity and developmental toxicity, and that is to avoid excessive maternal toxicity altogether. Alternative approaches to determining dosage ranges for developmental toxicity studies have been discussed, including those based on maternal pharmacokinetics (Carney et al. As mentioned previously, developmental toxicity studies have historically included administration of maximally tolerated doses, most commonly given as an oral bolus (gavage). Quite often gavage dosing results in very high peak blood levels that are not relevant to human exposures, which occur by different routes of exposure and which may be spread over a longer period of time, rather than incurred all at once (Carney et al. In many cases, particularly for agricultural and industrial chemicals, the dose levels tested in animals are several orders of magnitude higher than those to which people might be exposed. There is a trend in the field of toxicology to gradually move away from extremely high dose testing toward doses and routes of exposure that more accurately mimic actual human exposure levels. This trend toward lower, more realistic dose levels is being driven by several factors, namely, (1) the availability of more sensitive endpoints. The third point is particularly intriguing, as dose-dependent nonlinearities such as those related to saturation of metabolizing enzymes can result in a different spectrum of metabolites being tested at high versus low doses. Thus, a paradigm shift in dose level selection practices may be the best solution to the long-standing problem of maternal toxicity in safety studies, as it would avoid the issue altogether. Over the past 25 years there has been a growing awareness that paternal occupation, age, and chemical exposures, to social and therapeutic drugs, or to environmental factors, also contribute to adverse effects on fertility, pregnancy, and progeny outcome. Three international conferences have focused on the field of paternally mediated developmental toxicity (Olshan and Mattison, 1994; Robaire and Hales, 2003; Anderson and Brinkworth, 2007). This has recently led to an increase in recognition of the role of paternal programming in determining the susceptibility of offspring to insult later in life. Alternatively, paternal toxicant exposures may adversely affect male germ cells, decreasing germ cell numbers, and/or altering germ cell integrity. Effects on germ cell quality that are not repaired during spermatogenesis may decrease fertilizing ability or lead to postfertilization adverse effects on progeny outcome. Such effects may include pregnancy loss or spontaneous abortion and birth defects, or effects that are manifested only later in life, such as childhood cancer, behavioral effects or learning deficits, and metabolic syndrome. We now have evidence that paternally mediated adverse effects on progeny may be transmitted to subsequent generations. It has proven fairly difficult to link specific human paternal exposures to adverse effects on fertility and pregnancy outcome. There is often little information on the exposure with respect to the specific chemical or combination of chemicals involved or on the dose or timing of the exposure relative to events during sperm production and maturation. Infertility and pregnancy loss occur quite commonly in humans, even in the absence of chemical exposures, so it may be difficult to decipher the extent to which the exposure increases their incidence above background. In contrast, other developmental outcomes of concern may be rare or are observed only after a long delay, making it necessary to conduct longitudinal studies in a large exposed population. Finally, paternal and maternal exposures frequently "overlap" so it may be difficult to ascertain the relative contributions of each parent. Notwithstanding these complications, a number of epidemiological studies have reported an association between human paternal exposures and male infertility or abnormal progeny outcomes. Animal models have proven very useful in determining the impact of paternal exposures on male germ cells and progeny outcome. Using such models paternal chemical or drug exposures and lifestyle factors have been shown to have clear effects on progeny survival and development. During recent years there has been an explosion of studies demonstrating that the mechanisms by which paternal exposures trigger developmental toxicity are highly varied. Toxicant-induced disturbances in the sperm epigenome also lead to heritable alterations in progeny. Thus the exposure of male germ cells to a toxicant, or lifestyle events such as smoking or dietary factors, leaves a legacy that may have an impact not only on an individual embryo but also on future generations. Our goal in this chapter is to provide an overview of the field of male-mediated developmental toxicity and highlight some of the recent advances. First, we will review some of the evidence for paternally mediated developmental toxicity from human studies. Since much of the human epidemiological literature pertains to the consequences of preconception paternal exposures, we will focus on the impact of exposing men after puberty. Second, we will provide examples from the wealth of animal model studies that illustrate our current understanding of the mechanisms underlying paternally mediated developmental toxicity. Animal studies have provided extensive evidence that the in utero/prenatal and prepubertal periods represent critical periods for male germ cell "programming" but here human evidence is more limited. Finally, we will discuss approaches toward ensuring that the evidence-based science necessary for risk assessment pertaining to the potential of environmental chemicals or pharmaceuticals to cause male-meditated developmental toxicity is available. However, to the best of our knowledge, human studies have not provided conclusive evidence that exposure to chemicals via the semen is associated with adverse progeny outcome. Nevertheless, concern about the possibility of embryo/fetal exposure to proven human teratogens via the seminal fluid has triggered practice guidelines. It has also been suggested that it may be a sensible precaution for men to use a condom to avoid transmission of isotretinoin to women who are pregnant, or may become pregnant, during their use of the drug. Many studies have focused on the consequences of occupational exposuresdfor example, to pesticides, heavy metals, or organic solvents. Others report on the effects of environmental and/or lifestyle exposuresdfor example, to cigarette smoke, ethanol, or phthalates. Still others have examined the effects of therapeutic exposuresdfor example, to anticancer drugs or radiotherapy. Recently, studies have also examined the impact of paternal obesity and diet on progeny outcome. They concluded that there was epidemiologic evidence that paternal exposures to pesticides and lead adversely influence male fertility. It was noted that a detailed exposure assessment strategy was important in establishing an association. Indeed, studies with lead indicated that there was a clear dose response relationship: the time to pregnancy was prolonged for 0. The evidence for effects of other chemicals on human fertility, such as other metals, organic solvents or perfluorinated compounds, was deemed to be more equivocal (Snijder et al. Difficulty in differentiating the impact of paternal versus maternal exposures may contribute to the possible lack of consistency among human studies. Using a couple-based exposure design, with preconception enrollment and quantification of exposures in both partners, Buck Louis et al. It was interesting that the chemical exposures/concentrations in the male partner were more often associated with diminished couple fecundity than the concentrations found in female partners. A number of studies have examined the fertility of men who received radiotherapy or cancer chemotherapeutic agents. Gonadal/ whole body radiation and high dose exposure to alkylating agents have been identified as risk factors for male infertility. Large cancer registry studies have shown that it is less likely for men with a history of cancer to father a child after diagnosis (Green et al. Cigarette smoking has been associated with reduced sperm count and motility (Sharma et al. A dose-dependent increase in heritable germline mutations at a minisatellite locus was observed in the children of fathers who smoke (Linschooten et al. The Överkalix study documented a negative correlation between the body mass index of sons, but not daughters, with the age of onset of smoking in their fathers (Pembrey et al. Paternal occupations that have been associated with an increased risk of having a liveborn child with a birth defect include janitor, wood worker (forestry or logging, sawmill, carpenter), fireman, electrical worker, and printer (Olshan et al. An increased risk of stillbirth, preterm delivery, cardiac malformations, or delivery of a small-for-gestational age infant was associated with paternal employment in the arts (painters), electronics, or textile industries (Sung et al. Men employed in occupations associated with solvent exposures (with painters having the highest risk) were more likely to have offspring with anencephaly (Brender and Suarez, 1990). Other studies have linked preconception paternal exposures to an increase in congenital heart anomalies. Employment in an electronics factory was associated with an increase in infant mortality, due especially to cardiac defects, among liveborn children (Sung et al. An increased risk of congenital anomalies, including heart anomalies, was reported among the offspring of male workers employed in semiconductor manufacturing for 2 months prior to conception (Lin et al. Exposure to phthalates was identified as a paternal risk condition associated with ventral septal defects in offspring (Wijnands et al. A wide range of paternal professions was also reported not to be associated with abnormal progeny outcome (McDonald et al. The sex ratio of offspring has been linked to specific paternal chemical exposures. Paternal exposure to perfluorinated compounds has also been linked to an excess of female births (Bae et al. A comparison of children who died before the age of 5 in Quebec of malignant disease from 1965 to 1970 with a control group of children revealed Paternally Mediated Developmental Toxicity 103 that there was a significant excess of fathers in hydrocarbon-related occupations among the cases, with relative odds of 2$1 (Fabia and Thuy, 1974). Cases and controls did not differ with regard to place of residence of the parents or mean paternal age. A number of studies have focused on the relationship between paternal exposures and specific types of childhood cancer. Preconception paternal pesticide exposure has been linked to an increase in the risk of childhood brain tumors. A case control study from Australia reported elevated odds ratios for an association of childhood brain tumors with pesticide exposure when the father was present during professional pest control treatments in the home in the year before the index pregnancy (Greenop et al. Paternal exposures have also been associated with an increase in childhood leukemia. Studies have also provided evidence that exposure to preconception paternal smoking, alone or in combination with postnatal passive smoking, may contribute to the risk of childhood leukemia (Chang et al. Advanced paternal age has been reported as a risk factor for schizophrenia and autism in offspring (reviewed in Paul and Robaire, 2013) but there is currently little evidence from human epidemiological studies that such outcomes are affected by occupational, environmental, or therapeutic exposures. However, paternal obesity was associated with offspring outcomes such as increased body mass and body fat and perturbed metabolic measures in male offspring (Chen et al. In the Framingham Heart Study an association was made between early-onset paternal obesity and elevated serum alanine aminotransferase levels in the offspring (Loomba et al. Furthermore, paternal exposures have a wide range of consequences on at least one, and potentially on subsequent, generations. Human studies have shown that paternal exposures may affect the genetic integrity of male germ cells.

Studies have linked pesticide exposure during pregnancy and development to a variety of neurological outcomes asthmatic bronchitis wikipedia discount proventil 100 mcg with amex. Reports show that pregnant women and children are regularly exposed to pesticides in both urban and rural environments (Berkowitz et al asthma bronchitis emphysema difference purchase generic proventil canada. Developing individuals are more susceptible to both the acute toxic effects of pesticides as well as more subtle behavioral endpoints (Sheets et al can asthmatic bronchitis be cured buy generic proventil 100 mcg on-line. While higher dose exposures are known to cause predicable outcomes asthma definition yeah purchase proventil 100 mcg visa, neurobehavioral outcomes resulting from low dose exposure to pesticides remains a topic of interest asthma symptoms diagnosis buy cheap proventil on line. The subtle effects of lower dose exposure include reduced cognitive capacity, behavioral deficits, attention deficits, and learning deficits to name a few (Shafer et al. In mutation studies changes in ion channel gene expression that alter electrical activity result in reduced action potential firing, behavioral abnormalities, chronic pain disorders, and paralysis (Catterall, 2000, Waxman, 2007). Studies showing exposure to a pesticide that is known to alter electrical activity, can change neuronal gene expression, suggests one way that early life exposures could produce effects similar to genetic mutation resulting in the cognitive and behavioral endpoints observed in humans and animals (Harrill et al. Neural proliferation is a highly regulated process that occurs on an anterior to posterior gradient. Many more neurons than required are produced at this point, leaving some to die off during the apoptosis phase of development. The divisions that occur at this time are symmetrical, with a pluripotent precursor cell producing two new precursor cells early in neurogenesis when large numbers of cells are required. Cell division may also be asymmetrical, with a single precursor cell producing one precursor cell and one differentiated neuron. The precursor cell may also give rise to two post-mitotic neurons, this typically occurs later in development when large numbers of neurons are required. These distinctions are important, as toxic insults that occur early and damage or kill proliferative population of neurons will likely produce a different effect than one that occurs later and kills developed neurons. The largest difference is the early exposure will not only kill off the proliferative population, but all cells it would have produced under normal circumstances. The brain regions most susceptible to these anti-proliferative effects are ones actively undergoing proliferation at the time of Developmental Neurotoxicology 253 exposure. Once the cells of a brain region are done dividing it is generally resistant to these types of insults. However some agents, such as ethanol, can produce toxic effects via other mechanisms in mature non-proliferative cells. Nowhere can this effect be seen better than in individuals exposed to radiation from the atomic bombs dropped on Hiroshima and Nagasaki Japan. Follow up studies on children born to women pregnant at the time of the bomb drops show differential effects based on gestational age at the time of exposure. The offspring of women that were exposed at approximately 8­15 weeks post ovulation, the peak of neurogenesis, displayed decreased head size and severe mental retardation (Otake et al. The ultimate position of the neuron can be quite remote from where it is produced and a complex set of physical and chemical cues are necessary to assist the cell in finding its way. Cell migration is essential for the establishment of the complex networks of neurons that gives rise to behavior. Toxins may impact neuronal migration by damaging or killing the migrating neurons, the neighboring cells that provide necessary guidance cues or by damaging the supporting structures such as the radial glia. Many of the same agents that impair proliferation also disrupt migration, including ethanol and methyl mercury (Rice and Barone, 2000). Ionizing radiation is known to result in migration defects in addition to its effects on proliferation discussed previously. Individuals exposed to ionizing radiation from the atomic bomb during 8­15 weeks post ovulation had an increased incidence of seizures in addition to mental retardation. These disruptions in migration can disrupt hippocampal development and increase seizure susceptibility in animal models (Belvindrah et al. In animal models of MeHg neurotoxicity, Purkinje and cerebellar granule cells are most susceptible to toxic insult. The mechanism of this insult is believed to arrest migration as a result of microtubule disruption in both immature neurons and the supporting glial cells (Costa et al. Similar to other examples discussed above, MeHg does not exert its toxic effects solely though disruption of migration, it can also disrupt the normal process of cell death. The synapse is a highly specialized region of the cell that on the presynaptic side releases neurotransmitters and on the postsynaptic side responds to this signal. Synaptogenesis, unlike neurogenesis, is plastic and continues throughout the life of an organism; however the underlying neural network is established early during development. As discussed previously, activity is necessary to create, maintain and strengthen synaptic connections. These results demonstrate that changes in synaptic strength in response to activity rely on complex protein-protein interactions and are not solely dependent on changing expression of a single receptor or channel. Synaptogenesis produces morphological and biochemical changes in the pre- and postsynaptic cell (Rice and Barone, 2000). Lead is toxic during all stages of neurodevelopment but it has been shown to have the greatest effects during synaptogenesis. Lead can impact the total number of synapses by interfering with both synaptogenesis and synaptic pruning. These changes in synapse number can have long lasting effects on behavior and neuronal function (Costa et al. Although many of the exposure paradigms we have discussed take place in utero or shortly after birth, synaptogenesis and the final establishment of an adult phenotype gives us an opportunity to observe effects on development into adolescence. In animal models of nicotine exposure, nicotine increased impulsive behavior and decreased attention: these effects were not observed when adult animals were exposed. While neurons are frequently discussed as a group, individual cells exhibit vast biochemical, structural, morphological, and functional attributes. The process of producing this diverse 254 Developmental Neurotoxicology array of cells from common progenitors, like all the other events in as neurotransmitter expression (ex. Pyramidal), by the brain region in which they are located, or in some cases named after the individual that first described them (ex. Early during development cell fate is programmed by the interaction between transcription factors and morphogen gradients. This fate is maintained by differential gene expression that cannot change once established. There is evidence that differential gene expression is due to epigenetic modification and, as in other epigenetic modification of neurons, there is a role for electrical activity in this differentiation. Mutations enhancing electrical activity by increasing sodium channel expression in the spinal cord of Xenopus laevis decreased the number of neurons expressing excitatory neurotransmitters while increasing the number of inhibitory neurons. The opposite occurred with the over expression of an inward rectifier potassium channel (Brorodinsky et al. Developmental cell death is a normal part of brain development and is required to prune unnecessary cells. In some brain regions, 20­80% of neurons produced are programmed to undergo cell death. Proapoptotic agents increase the number of cells that undergo apoptosis compared to individuals not exposed to these agents. This increase in cell death decreases cell number and can decrease the volume of brain regions. There are a number of agents with pro-apoptotic effects during neurodevelopment including antiepileptic agents, sedatives, drugs of abuse and anesthetics. Alcohol can exert proapoptotic effects on either neuronal progenitors or fully developed neurons depending on the time of exposure. Earlier exposures and the resulting death of progenitor cells, produces gross morphological changes in the brain in addition of severe behavioral, mental and cognitive deficits. Later exposures, once neurons are mature, often produce more subtle behavioral and cognitive effects without the gross pathological changes in the brain. This difference in cell response may explain the spectrum of deficits seen in individuals exposed to alcohol during development (Olney, 2014). However, in the developing nervous system, neurotransmitters have a wide variety of functions that do not necessarily involve neurotransmission. During development neurotransmitters may act to influence neuronal differentiation and migration (Rice and Barone, 2000). As such, exposures to agents that interfere with neurotransmitters during development can cause damage unrelated to effects that may occur in the adult animal. In animal models, antiepileptic drug exposure resulted in decreased neuronal populations because of both inhibition of proliferation and increased apoptosis. These effects were particularly apparent in the hippocampus and the cerebellum (Bath and Scharfman, 2013). During development dopamine plays a role in neuronal migration, dendritic growth, and cellular differentiation. Alterations in dopamine signaling during development can disrupt these processes leading to altered neuronal connectivity and function. Pharmacologic or genetic disruption of these processes by agents such as cocaine and other drugs of abuse have been associated with diverse neuropsychiatric disorders such as schizophrenia, emotional and learning deficits and increased risk of drug addiction (Money and Stanwood, 2013). Animal models of prenatal cocaine exposure give insight into the long-term effects of monoaminergic system disruption during development. Animals exposed to cocaine in utero have disrupted neurogenesis and migration, reduced neuron numbers and density, and differences in dopaminergic function. Behavioral changes in animal models of prenatal cocaine exposure, include deficits in attention and emotional reactivity. These findings in animals correspond with what is seen in human cases of prenatal cocaine exposure which consists of disturbances in both attention and emotion regulation in children exposed prenatally to cocaine (Ross et al. Unlike other parts of the body, the endothelial cells here are connected by tight junctions which serve to restrict the entrance of circulating toxins, drugs, and immune cells into the brain (Francis et al. However, during development this barrier is not as effective at restricting entry into the brain as it is in adults. This differential expression pattern also plays a role in increased brain permeability and susceptibility to toxic insult (Ek et al. Through epigenetic mechanisms, transient exposures during development can result in persistent changes in gene expression, and in turn neuronal function. One example of environmental toxin resulting in changes in epigenetic markers is lead. Other metals such as nickel, arsenic, chromium, methylmercury, and copper have also been shown to alter histone modifications, thereby affecting gene expression (Senut et al. The unique developmental patterning of the nervous system lends itself to complex perturbations, some of which will not become apparent until long after an exposure has ceased. The persistent nature changes to neuronal function that can occur during development of the nervous system makes it imperative that we continue to expand our knowledge in this field. The role of neural activity in synaptic development and its implications for adult brain function. Urinary concentrations of metabolites of pyrethroid insecticides in the general U. Impact of early life exposure to antiepileptic drugs on neurobehavioral outcomes based on laboratory animal and clinical research. Activity-dependent homeostatic specification of transmitter expression in embryonic neurons. From ionic currents to molecular mechanisms: the structure and function of voltage-gated sodium channels. Development of the motivational system during adolescence, and its sensitivity to disruption by nicotine. Down-regulation of voltage-dependent sodium channels initiated by sodium influx in developing neurons. Proceedings of the National Academy of Sciences of the United States of America, 87, 5907­5911. Internalization of voltage-dependent sodium channels in fetal rat brain neurons: A study of the regulation of endocytosis. Organophosphate pesticide exposure and neurodevelopment in young Shanghai children. Transcriptional response of rat frontal cortex following acute in vivo exposure to the pyrethroid insecticides permethrin and deltamethrin. Current internal exposure to pesticides in children and adolescents in Germany: Urinary levels of metabolites of pyrethroid and organophosphorus insecticides. Persistent epigenetic differences associated with prenatal exposure to famine in humans. Proceedings of the National Academy of Sciences of the United States of America, 105(44), 17046­17059. Prenatal nutrition, epigenetics and schizophrenia risk: can we test causal effects Changes in the pattern of growth in stature related to prenatal exposure to ionizing radiation. Role of calcium and calpain in the downregulation of voltage-gated sodium channel expression by the pyrethroid pesticide deltamethrin. Focus on apoptosis to decipher how alcohol and many other drugs disrupt brain development. A review of forty-five years study of Hiroshima and Nagasaki atomic bomb survivors. Activity-induced internalization and rapid degradation of sodium channels in cultured fetal neurons. Critical periods of vulnerability for the developing nervous system: Evidence from humans and animal models. At what age is the developing cerebral cortex of the rat comparable to that of the full-term newborn human baby

Regions subtending a persistent subventricular zone are particularly susceptible to chemical or viral agents asthma symptoms 3 yr old order proventil 100 mcg amex, which induce glial tumors in experimental animals (Grove et al asthma obesity discount generic proventil uk. In adults asthma 80 proventil 100 mcg mastercard, the ependyma consist of a single layer of ciliated cuboidal hedis asthma definition proventil 100 mcg without a prescription, columnar asthma treatment theophylline order proventil 100 mcg otc, or squamous cells, depending on their anatomical location. The cilia are arranged in a central configuration on the free or ventricular surface of the cell and are attached to basilar bodies located in the apical cytoplasm of the ependymal cell (Westergaard, 1970). The lateral surfaces of ependymal cells interdigitate and possess two types of junction, namely, gap junctions and zonulae adherentia (Brightman and Palay, 1963; Klinkerfuss, 1964). Gap junctions, which were initially mistaken for zonulae adherentes, are usually found between pairs of adherent junctions and provide intracellular communication between 2 and 70 adjacent ependymal cells (Jarvis and Andrew, 1988). However, since no tight junctions exist between apposed lateral membranes of ependymal cells, transit of macromolecules from ventricles to the parenchyma is possible (Brightman and Reese, 1969). These fascicles are part of an extensive cytoskeleton, which coordinate the considerable mechanical work carried out by the ependyma. As such, the ependyma are likely an important component of any neurotoxicological condition that arises from exposure to agents that interfere with either energy metabolism or components of the cytoskeleton. Although probably not of primary consequence in mechanisms of neurotoxicity, perturbations of ependymal function may contribute to the overall picture of neurological damage. Induction of choline acetyl transferase in cholinergic neurons by physical contact is mediated by a membrane-derived factor and other soluble factors (Lee et al. Concomitant with expression and release of growth and other factors in the brain is the transient expression of neuronspecific receptors in developing cerebellar Purkinje cells, suggesting local delivery of neurotrophins (Cohen-Cory et al. If the terminal projections of neurons express the appropriate receptor, cell bodies distal from the primary site of glial secretion may benefit from binding to neurotrophins (Lu et al. Mature astrocytes derived from the hippocampus retain the ability to induce neurogenesis and neuronal differentiation in adult stem cells, whereas mature astrocytes from the spinal cord do not induce neurogenesis and induce a marginal amount of neuronal differentiation in comparison to hippocampal astrocytes (Song et al. Thus, it is reasonable to suggest that glial mechanisms of neurotrophin-mediated repair might be critical to the reestablishment of neuronal function following neurotoxic insult. Investigation of interactions of neurotrophins and their receptors with neurotoxicants is crucial to a complete understanding of recovery processes invoked following neural damage, and much remains to be elucidated in this regard. This guidance is achieved both by the formation of physical astrocytic boundaries and by the secretion of a variety of glycoproteins, glycolipids, and glycosaminoglycans by fibrous astrocytes into the extracellular space (Cooper and Steindler, 1986; Imai et al. Components of the extracellular matrix that inhibit neuronal migration include J1/tenascin and 473 proteoglycan; both are transiently expressed at various times throughout development (Steindler and Cooper, 1987). J1/tenascin and the associated chondroitin sulfate-containing 473 proteoglycan are developmentally regulated and appear surrounding the whisker barrels, neostratal striosomes, and nuclear boundaries before and during neuronal migration (Steindler et al. However, these inhibitory boundaries disappear only after regional synaptic contacts are established (Steindler and Cooper, 1987). The association of neuroblasts with radial arms of fibrous astrocytes in the developing nervous system was postulated by Golgi (1903). Later studies by Rakic (1981) and Rakic and Black (1984) largely confirmed astrocytic roles in the guidance of migrating neurons to their ultimate destination. Experiments in vitro provide strong evidence for the participation of astrocytes and other neural cell types in determining the kind and rate of neurite extension (Baird et al. The most rapid rates of cerebellar granule cell neurite extension have been observed on either astrocyte monolayers or the extracellular matrix derived from astrocytes (Baptista et al. The processes of migration and neurite extension are likely mediated by adhesion molecules on apposed astrocyte surfaces. Binding to astrocytes is also mediated by astrotactin 1, a 100 kDa glycoprotein expressed on the neuronal cell surface (Edmondson et al. Astrotactin 1 expression on the neuronal surface is regulated by direct binding of astrotactin 2, which is highly expressed in cerebellar granule neurons during migration (Wilson et al. Following physical or chemical neural injury resulting in the loss of synaptic contacts, many of the transient guidance/adhesion events observed during development are repeated during the process of reestablishment of neuron­neuron contact. However, the specific cellular locus of secretion of many chemotaxic or inhibitory extracellular molecules remains to be elucidated (Edmondson et al. Reactive gliosis, a potentially damaging process, is a common astrocytic response to axonal damage. Thus, the specific expression and/or induction of intra- and extra-cellular signaling cascades involving neurotrophins is important for the role of astrocytes in regeneration of neurons following injury. This advantage/disadvantage concept of reactive gliosis in axonal regeneration has recently been reviewed (Sofroniew, 2009; Toy and Namgung, 2013). There is much interest in the exogenous application of glial-derived neurotrophins for the clinical management of a variety of degenerative central and peripheral nervous system diseases. However, with the possible exception of lead, relatively little is known about the role of neurotoxicants in the inhibition or stimulation of expression of these maintenance and regenerative factors. This is achieved by transporter-/receptor-mediated movement of ions, amino acids, and neurotransmitters (Kimelberg et al. Protein kinase C-linked proton pumps in astrocyte membranes aid in the regulation of extracellular pH ([pH]o). Astrocytes secrete Hþ ions into the extracellular space (Chesler and Kraig, 1989) and are thought to participate in postexcitotoxic compensation by mildly acidifying the perineuronal space, and thereby ameliorating the neurotoxic effects of glutamate receptor agonists (Giffard et al. Other buffering systems described in the membranes of astrocytes in culture include Ca2 þ (Tsien et al. Many of these ion-regulatory proteins are expressed in oligodendrocytes, Schwann cells, and their precursor cells (Hortnagl et al. It is also important to note that the distribution of ion channels is heterogeneous with respect to region, cell type, and cellular contact with neuronal subtype (Barres et al. Astrocytes, which as mentioned earlier form extensive contacts with both synapses and cerebral blood vessels, have also been implicated in assuring increases in flow evoked by synaptic activity. The cellular bases of this mechanism have yet to be fully understood, but a recent review (Iadecola and Nedergaard, 2007) posits that astrocytes, due to their organization in non-overlapping spatial domains, may be uniquely positioned to shape the spatial distribution of the vascular responses that are evoked by neural activity. Iadecola and Nedergaard (2007) in an elegant review address the role of astrocytic calcium transient as an important determinant of microvascular function, suggesting that astrocytes may regulate blood flow even independently of synaptic activity. Cortical astrocyte processes have since been shown to form continuous contact with blood vessels throughout the somatosensory cortex in vivo (McCaslin et al. However, recent work has shown that propagation of high-amplitude calcium waves in astrocytic endfeet is a precipitating event in the inversion of neurovascular coupling from vasodilation to vasoconstriction following subarachnoid hemorrhage (Pappas et al. This dual role of astrocytic signaling as a major component of local vasoconstriction and vasodilation is reviewed by Filosa et al. From an early developmental period, glia and neurons establish a highly dynamic and reciprocal relationship, which is maintained throughout life, influencing nervous system growth, morphology, behavior, repair, and aging. Considering the diversity and complexity of this relationship, it is reasonable to postulate 148 Glial Cells that the glial­neuronal interdependency represents at least one of the functional units of nervous tissue (vis-a-vis neuron­neuron interactions, glial­glial interactions, endothelial­glial interactions, and so on). Perturbation of homeostatic functions in glial or neuronal cell types is likely, therefore, to render the unit dysfunctional. A neurotoxic event might disrupt adhesion molecule interactions and ultimately glial­neuronal contact; intercellular communication or exchange of macromolecules might be altered, leading to both structural and functional consequences for each cell type. Glial uptake of a pro-neurotoxicant could result in its metabolic conversion to an active toxicant, its release and ensuing neuronal toxicity, while initially sparing glial function (Edmondson et al. Microglia constitute approximately 10% of the total glial cell population and are considered to be the macrophages of the brain. Microglia are the immunocompetent cells, which form the main brain defense system; they are activated upon various kinds of injuries and diseases (Kreutzberg, 1996). Cellular processes of resting microglia are never in contact with each other (Nimmerjahn et al. However, upon injury, microglia are activated, undergoing a series of biochemical and morphological changes. Analogous to their counterparts, the astrocytes, activated microglia possess numerous mechanisms that are simultaneously neuroprotective and neurodestructive, depending on the severity of brain insult (for additional discussion see below). Given their primary functions in phagocytosis and remodeling, it is believed that if microglia were readily activated then juxtaposed neurons would be at a constant risk of microglialmediated damage. It is almost certain, therefore, that in vivo microglial responses are held under strict regulatory control. Stimulated by in vitro observations on the ability of microglial cultures to release a number of neurotoxic substances, renewed interest has focused on their potential to mediate secondary neurodegenerative processes through the elaboration and release of neurotoxic substances during ischemic or traumatic brain injury. Resident microglia (rather than blood circulating) were implicated in this response and as the source of the quinolinic acid. However, since it is also well established that microglial cells in culture release a number of neuron-survival promoting compounds (Chamak et al. In addition to their role in mediating neurotoxicity, recent studies (reviewed in Block et al. In addition, in the mature brain, these cells can regulate and facilitate repair of injury through guided migration of stem cells to the site of inflammation and injury, and potentially, they may also be involved in neurogenesis. Microglial overactivation and dysregulation may result from environmental toxins, such as the pesticide rotenone, to neuronal death or damage. The mechanisms and homeostatic changes associated with microglial activation and their detrimental or beneficial effects have yet to be fully deciphered. However, it appears that although microglial activation is necessary and crucial for host defense and neuron survival, the overactivation of microglia results in neurotoxic sequelae. These reviews suggest that microglial cells themselves may be subject to cellular senescence in the sense that they no longer function efficiently as they age (Conde and Streit, 2006). It has been suggested that as the microglia age their ability to respond to neuronal injury may become compromised as exemplified in aged rat retinas, where the retinas express greater lectin reactivity for microglia compared with young rats, and transient retinal ischemia produces a greater increase in the reactive microgliosis (Kim et al. Aged rats also exhibited a significantly greater loss of retinal ganglion neurons after ischemia. Consistent with reports on degenerating microglial cells in aged humans and humans with neurodegenerative diseases (Streit et al. The amphibian glial cells were found to have a normal high intracellular Kþ and, in fact, to be characterized by a membrane potential that was essentially the same as the Nernst potential for Kþ (À 80 to À 90 mV). These had the same characteristic, namely, a nonexcitable cell with large negative membrane potential, apparently sensitive only to changes in [Kþ]o. This led to one of the earliest functions proposed for glial cells, and specifically astrocytes, namely, the control of extracellular Kþ (Kuffler et al. Work since the 1970s has shown this narrow interpretation to be totally incorrect. Table 1 represents some of the roles and functions that are attributed to astrocytes, both in normal brain physiology and development and in the etiology of pervasive brain dysfunction. Major progress in the modern experimental period of astrocyte research commenced in the early 1970s with the availability of primary cultures prepared from neonatal or late-stage fetal rodent brains. These cultures were found to contain predominately, and with appropriate manipulations, almost exclusively, monolayers of astrocytes (Block et al. Classically conceived neurotoxic mechanisms have generally proposed a neuron-specific action for chemicals or neuropathic diseases. However, it has been shown that a direct insult of neurotoxic compounds on astrocytes leading to their compromised function may represent the primary biochemical trigger for the ensuing neurotoxicity. Functional consequences have only been studied in vitro, and several of those will be summarized below. There appears to be a sizable body of work to suggest that these cells, when adversely affected by neurotoxins or physical trauma. Other data suggest that astrocytes actively metabolize proneurotoxicants, leading to the formation and release of toxic intermediates, which can directly compromise neuronal activity while sparing the astrocytes themselves. Chronic exposure of astrocytes to ammonia in vivo leads to diminished glutamine metabolism and impairment of astrocytic energy metabolism. Furthermore, the reduced astrocytic capacity to metabolize ammonia leads to ammonia-induced cytotoxicity in juxtaposed neurons, and promotes accumulation of glutamine, which, in turn, leads to decreased cerebral glucose consumption and amino acid imbalances (Hawkins and Jessy, 1991; Hawkins et al. Apparently normal neuronal somata (arrows) are partially denuded by the retraction of astrocytic end feet. Rarely, perforation of the capillary wall with transient erythrocytes can be observed (arrow). Electron microscopic examination reveals significantly swollen astrocytic cell bodies and nuclei (C; large arrow) and mildly edematous oligodendrocytes (small arrow). A second example of the role of astrocytes in mediating neurotoxicity is illustrated by the intracellular conversion of a proneurotoxicant to an active metabolite capable of inflicting selective neuronal damage. It has yet to be determined whether this pathway may also prominently function in other chemical-induced neurotoxicities. At high doses, particularly after intrahippocampal injections, quinolinic acid causes convulsions and neurodegenerative changes that are remarkably similar to those observed in human temporal lobe epilepsy (Dam, 1980; Schwarcz et al. Evidence also suggests that activated microglia/macrophages may also produce quinolinic acid under immunocompromised conditions. Analogous findings have also been reported in the R6/2 transgenic mouse, which expresses an N-terminal fragment of mutant huntingtin. Sagittal and parasagittal sections (A) through a control (left side) and treated rat (right side) reveal well-defined hemorrhagic astrocytic tumors in treated rats. Oligodendrogliomas are frequently formed in the lumber region of the spinal cord (B, arrow). For an excellent review on astrocytes in neurodegenerative disease, the reader is directed to Maragakis and Rothstein (2006). Neurotoxic mechanisms may also involve an effect on astrocyte physiology that either exacerbates coincidental neuron injury or initiates secondary neurotoxicity. For example, astrocytic swelling and the ensuing release of glutamate may have important implications for neuronal homeostasis (Kimelberg et al. Astrocytic swelling occurs rapidly, within 1 h of injury (in vivo), but may reverse slowly with time. Persistent astrocytic swelling can be viewed as a pathological extension of more limited and controlled volume changes, which are part of the normal homeostatic function of astrocytes.

For tissue-specific blood perfusion rates peep 0 asthma proventil 100 mcg order visa, less data are available to calculate agedependent changes from birth to 18 years of age except for brain asthma symptoms body aches discount 100 mcg proventil. Rather than fitting a polynomial function to the growth curves asthma symptoms xylene proventil 100 mcg fast delivery, Mirfazaelian et al asthma symptoms explained order proventil with amex. Age-dependent changes in physiology asthmatic bronchitis length generic proventil 100 mcg on line, such as cardiac output and tissue perfusion rates, are more limited, primarily due to the difficulty in obtaining such data (tissue weights are relatively simple to obtain while microsphere infusion studies to determine localized blood flows are far more difficult and expensive). The maturation of hepatic and renal clearances, in particular, has historically received significant attention in pediatric drug development (Anderson and Holford, 2008; Besunder et al. Journal of Toxicology and Environmental Health, Part A 70, 1027­1037 McCarver and Hines, 2002). While many metabolic enzymes begin to develop before birth, many others develop and mature during the first year of life in humans and throughout lactation in rats and mice (Alcorn and McNamara, 2002a,b; Chengelis, 1988a,b; Rane and Tomson, 1980; Rich and Boobis, 1997). Renal clearance mechanisms are relatively immature in humans at birth and can take 6­12 months to mature. Some of these models relied upon extrapolation of adult data to neonates, infants, children, and adolescents because there are either limited data available or it is not possible or ethical to obtain such data. For certain pharmaceuticals, however, there are data available in both adults and postnatal youths that can be used to validate the models or adjust key pharmacokinetic processes such as hepatic or renal clearances. Both drugs can be cleared in the urine, although metabolism is the dominant process. Neonates were of particular interest in this model since the pharmacokinetics of these drugs at this age differed the most significantly from adults. Interestingly, a secondary metabolic pathway was proposed for back conversion of the caffeine metabolite, theophylline, to caffeine, via methylation, and this metabolic pathway was present in neonates and not adults. Selected Laboratory and Mobile Examination Center Data, Version 1, 1995; Price K, Haddad S, Krishnan K: Physiological modeling of age-specific changes in the pharmacokinetics of organic chemicals in children. Journal of Toxicology and Environmental Health, Part A 66:417­433, 2003 and Haddad S, Restieri C, Krishnan K: Characterization of age-related changes in body weight and organ weights from birth to adolescence in humans. In this case, simple scaling of adult metabolic rate would not predict the kinetics of caffeine and theophylline in the neonate. Model simulations were reasonably consistent with published values, although published data are highly variable. One challenging aspect for using drug pharmacokinetic data collected in the young is that these neonates, infants, children, and adolescents are being treated for a disease, which may confound interpretation of the drug pharmacokinetics. Monte Carlo simulations of a pediatric population predicted a high degree of variability in plasma concentrations of methadone and clearance kinetics. However, to use this theoretical modeling assessment for solvent risk assessment purposes, an updated solvent model, using current information on infants, is needed to compare infants with adults. The remaining age-dependent tissue volumes, blood flows, and ventilation rates were computed for each age based on the equations of Price et al. Body weights, tissue weights, and physiology parameters were taken from Delp et al. In each case, the volume of the liver at each age (as a fraction of body weight) made the most important contribution for calculating in vivo Vmax values. That is, enzyme activity and microsomal protein content were less important that liver weight. If the parent chemical is responsible for toxicity, then the younger rats are likely to be more sensitive than adults; the converse is true if the toxicity is based on the formation of toxic metabolites. The enhanced sensitivity of neonates to organophosphate insecticides compared to adult rats is well established (Timchalk et al. Adult human pharmacokinetic studies were conducted, in which volunteers were orally administered 0. Ontogeny of metabolic model parameters (a- and b-esterases) was described using logistic equations. Hepatic chlorpyrifos and chlorpyrifos-oxon metabolism were measured using human microsomes from donors aged 13 days to 75 years. Chlorpyrifos-oxon metabolism in human plasma (age 3 days to 43 years) was measured, and maximal velocities for metabolism were scaled using a logistic model. Hepatic in vitro Vmax values were scaled using microsomal protein content (33 mg/g hepatic tissue), and in vitro Km was scaled based on predictions of the unbound concentration. For environmental levels of chlorpyrifos, chlorpyrifos-oxon plasma levels and cholinesterase inhibition were predicted to be slightly greater in adults than in 6-monthold infants. At much higher doses of chlorpyrifos, the reverse was predicted, where the infant internal exposure to chlorpyrifosoxon and resulting cholinesterase inhibition would be greater than in adults. Using the 95th percentile of the population predictions, data-driven adjustment factors were calculated for toxicokinetic variability. Valcke and Krishnan (2014) also evaluated adjustment factors for inhaled solvents in children. The 95th percentile adjustment factors for benzene, chloroform, bromoform, trichloroethylene, and tetrachloroethylene were less than 2. This in silico research provided predictions of pediatric populations exposed to solvents and determined that the use of an uncertainty factor of 3. Due to the difficulties associated with conducting clinical trials for drugs in infants and children, pediatric pharmacometrics has been extensively applied for pediatric populations. Pediatric pharmacometrics is the development of quantitative models, accounting for maturation of biochemical and physiological aspects of development to predict efficacy and the likelihood of adverse reactions. More specifically, pharmacokinetics, pharmacodynamics, and disease are evaluated in different subpopulations using probabilistic methodologies. Many pediatric pharmacometric examples are for drugs already on the market but used off-label in children. Required information on labels includes age-appropriate dose, efficacy, and safety. The model contained pre- and postoperative organ function for adults and pediatric patients. The goal was to make better-informed decisions for drug dosage in these pediatric populations because of a failure of conventional methods to predict dosage. Goodness-of-fit plots were shown (model predicted concentration of drug on x-axis and observed drug concentration on Y-axis) for adults with and without open heart surgery, pediatric patients with open heart surgery, and adults and pediatric patients with and without low cardiac output syndrome. The author stated that current milrinone doses for cardiac output syndrome were not optimal for the therapeutic-targeted peak and trough range; thus, modeling can assist in dosage selection. Using a commercial software program, the authors reduced hepatic and renal blood flows, scaled model parameters to children, and simulated pediatric clinical trials with carvedilol. Since there is no information on optimal dosing of children, therapeutic dose monitoring is utilized, with targeted voriconazole concentrations of 1­5. The authors proposed intestinal first-pass metabolism of voriconazole in children but not in adults. In this case, the authors propose intestinal metabolism as an age-dependent feature for children to describe the available data. One of the existing data gaps is the lack of information on laboratory animal-specific blood flows to the placenta and growing fetus. While it is relatively easy to measure tissue volumes either by dissection or imaging, it is significantly more difficult to measure blood flows to each tissue, although there are experimental techniques available that could be used to derived estimates in each species, strain, or sex. It is less than desirable to continue to use estimates of placental blood perfusion rates derived from sheep as surrogates for rats and mice when it is possible to obtain such data. The establishment of species-, strain-, and sex- specific enzyme ontogeny has received much attention in the past decade; however, basic anatomy and physiology remain seriously underfunded areas of research. Commercial software companies have incorporated this information into their software programs. Currently, there are several approaches for developing algorithms to calculate species- and age-dependent changes in anatomy and physiology during development. For example, polynomial regressions for body weight growth in humans developed by Haddad et al. For older adults, the polynomial expression fails, while the Gompertz equation, which was developed for all ages, remains applicable. Likewise, algorithms developed for the growth and development of one strain of rat may not apply to other strains. Authors with interests in specific ages should evaluate the equations for their intended use. Considerable progress has also been made for using pharmacokinetic information with pharmaceuticals in adults and in children at various ages to identify key processes that can be extrapolated from adults and at what stage of development such extrapolations will fail. Not surprising, neonates or premature infants show the greatest differences compared to adults for disposition of drugs and their metabolites. These differences can either enhance or reduce susceptibility to adverse consequences of chemicals and drugs. In the field of chemical toxicology, the use of computational tools to extrapolate dose or exposure from animal and human in vitro high-through-put systems to in vivo (human) will be necessary. Acknowledgement the authors thank Fred Beland, Luísa Camacho, and Marie-Emilie Willemin for reviewing this manuscript. Very special thanks to Richard (Rick) Corley, who wrote the previous version of this article. Anatomical, physiological and metabolic changes with gestational age during normal pregnancy: A database for parameters required in physiologically based pharmacokinetic modelling. Development of physiologically based pharmacokinetic/pharmacodynamic model for indomethacin disposition in pregnancy. Physiologically based pharmacokinetic model of midazolam disposition during pregnancy. Effect of physical exercise on uptake, distribution and elimination of vapors in man. Modeling of inhalation exposures to vapors: Uptake, distribution, and elimination (pp. The development of a stochastic physiologically-based pharmacokinetic model for lead. A simple estimate of glomerular filtration rate in low birth weight infants during the first year of life: Noninvasive assessment of body composition and growth. A computer program linking physiologically based pharmacokinetic model with cancer risk assessment for breast-fed infants. Physiologically based pharmacokinetic modeling of the lactational transfer of methylmercury. Computer simulation of the lactational transfer of tetrachloroethylene in rats using a physiologically based model. Ornithine decarboxylase activity, nucleic acids and cell turnover in the livers of pregnant rats. Age- and sex-related changes in the components of the hepatic microsomal mixed function oxidase system in Sprague­Dawley rats. Correlation of unbound plasma clearances of fifteen extensively metabolized drugs between humans and rats. Pharmacokinetics of 2-methoxyethanol and 2-methoxyacetic acid in the pregnant mouse: A physiologically based mathematical model. A physiologically based pharmacokinetic model for retinoic acid and its metabolites. Evaluation of the uncertainty in an oral reference dose for methylmercury due to interindividual variability in pharmacokinetics. The use of physiologically based models to integrate diverse data sets and reduce uncertainty in the prediction of perchlorate and iodide kinetics across life stages and species. Review and evaluation of the potential impact of age- and gender-specific pharmacokinetic differences on tissue dosimetry. Predicting neonatal perchlorate dose and inhibition of iodide uptake in the rat during lactation using physiologically-based pharmacokinetic modeling. Predicting fetal perchlorate dose and inhibition of iodide kinetics during gestation: A physiologically-based pharmacokinetic analysis of perchlorate and iodide kinetics in the rat. Evaluation of the potential impact of age- and gender-specific pharmacokinetic differences on tissue dosimetry. Physiologically based modelling of darunavir/ritonavir pharmacokinetics during pregnancy. Use of physiologically based pharmacokinetic models coupled with pharmacodynamic models to assess the clinical relevance of current bioequivalence criteria for generic drug products containing ibuprofen. Physiologically-based pharmacokinetic modeling of renally excreted antiretroviral drugs in pregnant women. Effects of aging on cardiac output, regional blood flow, and body composition in fischer-344 rats. Predictive performance of a physiologically based pharmacokinetic model of busulfan in children. Predicting plasma concentrations of bisphenol a in children younger than 2 years of age after typical feeding schedules, using a physiologically based toxicokinetic model. Development and evaluation of a generic physiologically based pharmacokinetic model for children. A physiologically based pharmacokinetic model for developmental exposure to bde-47 in rats. Development of a pediatric physiologically based pharmacokinetic model for sirolimus: Applying principles of growth and maturation in neonates and infants. Biologically based dose­response models for developmental toxicants: Lessons from methylmercury. Physiologically based pharmacokinetic modeling of the pregnant rat: A multiroute exposure model for trichloroethylene and its metabolite, trichloroacetic acid. Physiologically based pharmacokinetic modeling of the lactating rat and nursing pup: A multiroute exposure model for trichloroethylene and its metabolite, trichloroacetic acid. Pharmacokinetic modeling: Prediction and evaluation of route dependent dosimetry of bisphenol A in monkeys with extrapolation to humans. Evaluation of iodide deficiency in the lactating rat and pup using a biologically based dose­response model.

They are not covalently bound to plastics and carriers and can freely leach into the environment asthma and allergy associates cheap proventil 100 mcg buy on-line. Mono-2-ethylhexyl phthalate asthma treatment doctors proventil 100 mcg buy without a prescription, a major metabolite of phthalates asthmatic bronchitis emedicine discount 100 mcg proventil amex, has been observed in higher concentration in the urine of women diagnosed with leiomyomas or adenomyoma (Huang et al asthmatic bronchitis foods to avoid purchase 100 mcg proventil. Several in vitro studies implicate phthalates in altered activities of endometrial cells (Kim et al asthmatic bronchitis 8 month order proventil in india. The incidence of adenocarcinoma was Female Reproductive C: Uterine Tumors and the Environment 443 highest (50%) in the 10 mg/day treatment group. The common sources of genistein in the human diet are soy-based foods, infant formulas, and dietary supplements. While several studies suggest a protective effect of genistein against cancers (Lamartiniere et al. For example, neonatal mice injected with a dose of genistein similar to the levels to which human infants are exposed in soy-based formulas developed benign and malignant lesions of the reproductive tract such as uterine adenocarcinomas (Newbold et al. Since uterine leiomyomas are also highly responsive to ovarian steroid hormones, the effects of plant phytoestrogens on these tumors are now also being investigated. The animals were then euthanized at 16 months of age and uteri harvested for analysis of number and size of leiomyoma tumors. The levels of oxidative stress biomarkers as well as cell cycle regulatory proteins were also lower in the leiomyomas from birds fed the genistein diet. Clearly additional studies are warranted to determine more specifically how the timing of exposure to genistein influences its effects in the female reproductive tract. The naturally occurring bromoethane, which is used in industrial and pharmaceutical applications, is a highly lipophilic chemical and can pass through the blood­brain barrier (Klassen, 1996). Uterine carcinomas showed the highest incidence in mice treated with chloroethane, whereas bromoethane induced a variety of uterine neoplasms such as adenocarcinomas as well as adenoma and squamous cell carcinoma of the uterine endometrial epithelium. The mechanism by which bromoethane, chloroethane, and ethylene oxide induce uterine tumors is not understood (Picut et al. Mechanistic studies with chloroethane suggest that the tumorigenesis of this chemical depends on its species-specific metabolism, which can lead to hormonal effects and subsequent uterine tumor development (Fedtke et al. Another possible mechanism might be due to the direct genotoxic effect of chloroethane through metabolic formation of acetaldehyde (Fedtke et al. However, female B6C3F1 mice exposed to bromoethane for 2 years did not show such a correlation (Bucher et al. It is primarily used not only in batteries but also in metal coatings, platings, pigments, and as a stabilizer for plastics. Diet is a main source of human exposure to cadmium in the nonoccupationally exposed population. Smoking is also a major source of cadmium exposure, as cadmium levels accumulate in the tobacco plant, and cadmium in tobacco smoke is effectively absorbed through the lungs. While the average cadmium intake from food has been calculated to range from 8 to 25 mg/day for humans (van Wijngaarden et al. However, recent studies have determined that cadmium has estrogenic effects and may contribute to the development of hormone-related cancers (Johnson et al. In vitro studies have shown that cadmium acts as an estrogen mimic, stimulating proliferation of breast cancer cells (Brama et al. Both the inorganic and organic forms of As are toxic with the organic form being a stronger toxicant (Watson and Yager, 2007). Human exposure to As, which occurs primarily through drinking water, is considered a major environmental health concern in both the United States and worldwide (Watson and Yager, 2007). This problem is more serious in rural areas where people use private wells, giving rise to estimates that 25 million people in the United States are being exposed to excess As in their drinking water (Davey et al. In epidemiological studies As exposure has been linked to increased risk of numerous cancers, such as skin, lung, bladder, and liver, as well as diabetes, cardiovascular diseases, reproductive, developmental, and neurological problems (Smith et al. However, similar findings have not been easy to establish in animal models due to the relative insensitivity of most animal models to As when compared to humans (Waalkes et al. Using this system, Waalkes and coworkers were able to demonstrate the induction of uterine and oviductal preneoplastic hyperplasia along with ovarian tumors and lung adenocarcinomas in adult offspring (Waalkes et al. Investigations on the mechanism of As toxicity indicate genetic damage, alterations of cell signaling pathways, as well as endocrine disruption (Watson and Yager, 2007) as potential mechanisms. In vitro studies in mammalian cancer cells have shown that As can induce gene expression through a variety of nuclear receptors including glucocorticoid, mineralocorticoid, progestin, and androgen receptors as well as retinoic acid and thyroid hormone receptors (Bodwell et al. Arsenic appears to Female Reproductive C: Uterine Tumors and the Environment 445 interact with nuclear receptors in a biphasic dose­response manner showing stimulatory effects at low concentrations and inhibitory effects at higher concentrations through disruption of gene transcription (Bodwell et al. For example, treatment with As at higher concentrations ranging from 2 to 5 mM inhibited estradiol-induced gene expression both in vivo in a chick embryo model and in cultured cells by blocking ongoing gene transcription (Davey et al. Other factors such as tissue specificity, timing of exposure, gene environment, and coexposure also play a role in As toxicity (Davey et al. This chemical, which is formed during the manufacture or degradation of some chlorinated hydrocarbons, finds its way into the environment from municipal incinerators, sewage sludge, discharge from paper mills, forest fires, automobile exhaust, and even cigarettes (Whysner and Williams, 1996). This industrial chemical is widely used in automotive and antifreeze products, solvents, nonionic surfactants, and polyester resins (National Institute for Occupational Safety and Health, 1983). Arsenic: Extension of its endocrine disruption potential to interference with estrogen receptor-mediated signaling. The papillary features of these tumor cells resemble human endometrial adenocarcinomas and are associated with estrogen-related obesity, diabetes, and hypertension. In general, exposure during the early gestational period has no effect, whereas later intrauterine exposure increases the susceptibility of tumor development. Uma Devi and Hossain (2000) reported that fetal mice exposed to irradiation on day 17 of gestation had a higher incidence of uterine tumors as compared to those exposed on day 14. Strain specificity appears to be an important factor impacting studies of the effects of radiation on uterine tumorigenesis in animal models. Tumors that occur spontaneously in a specific strain of mouse may increase in occurrence when compared to the induction of other types of tumors that are not known to occur in that strain of mouse. In contrast, a similar study by Uma Devi and Hossain (2000) using strain I Swiss mice exposed to irradiation on day 17 postconception resulted in an increase in both ovarian and uterine tumors. The interpretation of these findings is important considering that the Swiss strain I mouse has a high natural susceptibility to ovarian tumors, but not to mammary tumors, while the C3H strain has a high susceptibility to mammary tumors but not to ovarian cancer (Valentin, 2003). While this represented a decrease in incidence in the offspring, it was still a significant percentage of tumors in these mice. Studies on the endocrine disrupting chemical vinclozolin, a fungicide with antiandrogenic activity, demonstrated that treatment of F0 females from days E8 to E14 of gestation resulted in a significant increase in F1­F3 females with pregnancy problems including uterine hemorrhage and regenerative anemia (Nilsson et al. There was also an increased incidence in mammary and pituitary tumors in the F1­F3 offspring. Since imprinted genes require epigenetic reprogramming of the germ line in association with the somatic cells in the gonad, endocrine disruptors can influence subsequent generations through these epigenetic processes (Anway and Skinner, 2006; Stel and Legler, 2015; Casati et al. Such findings showing a direct link between exposure to specific environmental factors and epigenetic modifications (Jirtle and Skinner, 2007; Skinner et al. Consequently, detailed, long-term studies are necessary as the transgenerational effects of environmental factors require the observation of potential effects on at least three generations of offspring (Anway and Skinner, 2006; Skinner et al. These tumors can be classified according to their spatial localization within the uterine wall as intramural (within the myometrium), submucosal (lying just beneath or within the endometrium), or subserosal (located just beneath the outer serosa) (Benda, 2001). The monoclonal origin hypothesis was also confirmed by experiments testing the inactivation of X-linked phosphoglycerol-kinase (Hashimoto et al. Uterine fibroids are the most common tumors of the female reproductive tract, occurring in up to 70­80% of reproductive aged women (Walker and Stewart, 2005; Segars et al. It is estimated that nearly half of women with fibroids have clinically significant symptoms including menorrhagia, anemia, infertility, pain, and pressure. Recent survey studies have reported that over 600,000 hysterectomies are performed in the United States every year, and that uterine leiomyomas represent 30­40% of the hysterectomies carried out in women ages 18­64 (Merrill, 2008; Cardozo et al. Epidemiological studies have shown that 7 out of every 10 Caucasian women and 8 out of every 10 African-American women eventually develop uterine leiomyomas (Day Baird et al. In addition, while 25­30% of Caucasian women present with symptoms including abnormal uterine bleeding, 60% of AfricanAmerican women show clinical symptoms (Faerstein et al. The bleeding pattern in women with leiomyomas is characterized by menorrhagia or hypermenorrhea and can often lead to anemia as well as loss of work productivity and a sense of social stigmatization (Stewart, 2001). The reasons for the higher incidence and severity of uterine leiomyomas among African-American women are unclear but may be related to other risk factors such as obesity, diabetes, and hypertension. Investigators have also found an increased risk for developing leiomyomas in patients with diabetes or hypertension (Faerstein et al. Epidemiological studies focusing on the incidence of other benign fibrotic conditions such as glomerulonephritis and renal fibrosis have also reported a similar increased incidence associated with obesity, diabetes, and hypertension (Collins and Winkleby, 2002; Sowers et al. These health problems have been reported to occur at a higher frequency in African-Americans and may account for the increased incidence of progressive renal fibrosis in the African-American population as compared to whites. It is possible that increased rates of hypertension, obesity, and diabetes among African-American women may play a role in the increased incidence of symptomatic leiomyomas among these women. Other factors such as early menarche (<10 years old) and chlamydial infection are also positively correlated with a higher risk of symptomatic uterine leiomyomas, whereas use of oral contraceptives or increasing parity have been shown to have a protective effect (Faerstein et al. However, these results may be biased, as a relative of a patient with leiomyomas might be more likely to seek diagnosis (Flake et al. Further evidence supporting a role for genetic factors in the development of symptomatic leiomyomas has come from karyotypic analysis of leiomyoma tumors. Approximately 40% of leiomyomas have nonrandom chromosomal abnormalities, and a number of specific cytogenetic rearrangements have been associated with leiomyomas (Townsend et al. Common chromosomal abnormalities identified in these tumors include a translocation between chromosomes 12 and 14, deletion of chromosome 7, trisomy of chromosome 12, and rearrangements of 6p10q and 13q. The genotypes for the latter two genes that have been shown to be associated with a higher risk of developing these tumors show a higher frequency in African-American women (Amant et al. These mutations are predicted to result in absent or truncated protein, or substitutions or deletions of highly conserved amino acids. Targeted deletion of Tsc2 in the myometrium of mice also leads to the development of uterine fibroids (Prizant et al. In contrast to other areas of tumor biology, the number of published studies reporting whole-genome or whole-exome deep sequencing of leiomyomas is relatively few. The diversity of genetic mechanisms potentially affecting leiomyoma development suggests that these benign tumors are composed of various distinct subtypes of neoplasms, just as cancers are divided into numerous specific subsets of disorders (Stewart and Morton, 2006). The identification of steroid receptor expression in leiomyoma cells suggests possible direct effects of these hormones on tumor growth. The cell proliferation rate is higher in leiomyoma than in normal myometrium regardless of the phase of the cycle but, when looking at the two different phases of the menstrual cycle, leiomyomas show a higher proliferative rate during the secretory phase during which progesterone is the dominant hormone (Maruo et al. This characteristic increase in collagen deposition in leiomyoma tumors was also observed by Leppert et al. Thus, leiomyomas are an example of a benign fibrotic disease that is hormonally responsive and may be susceptible to the effects of endocrine disrupting chemicals. These include (a) the assumption that chronic, low-level exposure to estrogenic agents affects the reproductive system and development based upon the known effects of more acute, high-level exposures to such agents in humans or animals; (b) documented adverse effects on reproduction or development in wild-life species exposed to increased pesticide use or industrial activity; and (c) historical trends showing decreased semen quality and increased incidence of genito-urinary defects, testicular cancer, and breast cancer over time in humans (Daston, 1997). Based upon this type of evidence, the estrogenic activity of several environmental toxicants, as well as reports of intentional or accidental exposure to them, has lead to epidemiological or direct investigation of the involvement of several endocrine disruptors in numerous disorders including uterine leiomyomas. These blood samples were used to study the relationship between blood dioxin levels and the risk of developing uterine leiomyomas. Interestingly, higher levels of dioxin in the blood samples seemed to have a protective effect, as these women had a lower incidence of leiomyomas (Eskenazi et al. Using the same population, another study found that exposure to high levels of dioxins was associated with double the risk of developing breast cancer (Warner et al. Phytoestrogens such as isoflavones and lignans have also been the focus of investigation because of their potential health benefits. They are known to have weak estrogenic activity with some evidence of antiestrogenic activity as well (Setchell and Cassidy, 1999; Setchell, 2001; Tang and Adams, 1980; Orcheson et al. In a study involving Japanese women living in Takayama, the authors evaluated the association between soy product intake and premenopausal hysterectomy. Their results showed that an intermediate level of intake of total isoflavone (32. In a more recent case-controlled study the excretion of isoflavones and lignans in urine was used as a quantitative measure of phytoestrogen intake. Two groups of women, those diagnosed with uterine leiomyomas by ultrasound or surgery between Sep. The authors observed a reduced incidence of leiomyoma tumors in patients with increased excretion of lignans in the urine. However, isoflavone excretion in the urine was not different between cases and controls (Atkinson et al. They found that the median levels of urinary genistein, daidzein, and equol; total isoflavones; and total phytoestrogens were similar in both groups of women. Only the levels of urinary enterolactone were significantly higher in women with leiomyomas. Furthermore, high exposure indices, based on the presumed contaminant burden experienced during the entire lifespan of a specific seal, were correlated with a higher prevalence of leiomyomas in Baltic gray seals examined between 1973 and 2007 (Bredhult et al. Several studies have investigated potential associations between cadmium exposure and risk of uterine leiomyomas. They observed a dose­response association between cadmium and endometriosis but no association for uterine leiomyomas. Their results showed that tissue cadmium concentrations were lower in leiomyomas than in autologous myometrium. This was a cohort of 473 women aged 18­44 who underwent surgery to determine whether they had uterine leiomyomas. Multivariate regression analysis showed that the odds of a uterine fibroid diagnosis were higher in women with increased whole blood cadmium levels and increased urinary cobalt. They hypothesized that increased exposure to cadmium may contribute to uterine fibroid growth or that fibroids may serve as a reservoir for these trace elements. Urinary concentrations were measured in 495 women who later underwent laparoscopy or laparotomy for diagnosis of uterine leiomyomas. However, none of the exposures were associated with a significant odds ratio even when adjusting for relevant covariates.

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