Exposure to environmental toxicants during pregnancy may have a significant impact on the developing fetus. Fetal adverse exposures are growing in importance, as our population expands and an increasing number of women enter the workforce. In 2010, women constituted 47% of the total workforce in the United States, and 66 million women were employed. Approximately two thirds worked full time.105 Sixty-six percent of women worked during their first pregnancy between 2006 and 2008; this statistic has not changed since the mid-1980s.69 Environmental exposures increase as the world’s population and economic needs expand. In 1900, there were 1.25 billion people on Earth. This number doubled by 1950, and again to 5 billion in 1987. The world population was estimated at 6.9 billion in 2010; it is projected to increase to 9 billion by 2050, and 10 billion by 2090.101 Pressures of population growth are reflected in increasing need for land, water, food, and fuel. With population expansion, economic growth, and technologic advances comes increasing interaction with chemicals in our environment that are developed to support our society. The growth of industry, commerce, and agriculture brings overuse of land, changes to the environment such as global warming, and contamination of air, water, food, and soil. It is inevitable that all humans, including developing fetuses, are exposed to environmental toxicants. This chapter describes exposures that may impact the fetus, unique pharmacokinetics of the fetus, and the spectrum of adverse outcomes associated with specific environmental toxicants (Figure 15-1). Environmental exposures that affect the fetus may occur long before conception, and possibly in an earlier generation than the parents. Commonly, the exposure impacts the ovum or sperm. In addition, there are chemicals that bioaccumulate before pregnancy and impact the fetus by enhanced elimination during pregnancy. Lipid-soluble toxins and heavy metals such as lead are stored in adipose and bone, and mobilized during pregnancy. Some chemicals such as organohalogens can affect the fetus by both nonconcurrent and concurrent exposure.2 Epigenetics is the study of phenotypic changes occurring in the absence of modification of DNA sequence. Environmental epigenetics describes the relationship between endogenous and exogenous factors (such as chemical exposure) and the epigenome.84 Changes to the epigenome are stable, heritable, and a target for environmental toxicants.37,84 The epigenome is susceptible to dysregulation at any time, but is highly vulnerable during fetal life when the rate of DNA synthesis is high. Epigenetic mechanisms include modifications in DNA methylation, alterations in histone proteins, and variable expression of noncoding RNA.37,84,117 DNA methylation is a well-described epigenetic modification involving addition of a methyl group to the nucleotide cytosine when it precedes guanine, frequently at the promoter region of DNA. Regions in which methylation occurs are more tightly coiled, hiding the promoter region and limiting gene expression. In less methylated areas, the promoter is open, allowing for DNA transcription.2,37 DNA methylation is the mechanism of X-chromosome inactivation during embryogenesis in females. Aberrant DNA methylation of the X-chromosome is implicated in fragile X syndrome.84 One of the best described epigenetic processes is genomic imprinting. Genomic imprinting occurs during early development and involves silencing of one parental allele leading to monoallelic gene expression. Dysregulation of genomic imprinting, potentially caused by aberrant methylation of DNA, leads to disorders such as Angelman syndrome, Prader-Willi syndrome, and Beckwith-Wiedemann syndrome and has been linked to autism and cancer later in life.84 Environmental toxicants can alter the epigenome during fetal life via modifications in DNA methylation. Figure 15-2 illustrates potential periods of fetal development in which environmental toxins may impact the phenotype of the developing fetus.84 Studies show associations between prenatal exposure to heavy metals such as lead and altered DNA methylation.2,37 Buccal samples from children exposed to environmental tobacco smoke in utero show hypomethylation, a finding consistent with mutation and cancer risk. Polycyclic aromatic hydrocarbons (PAHs) are chemicals found in fumes from vehicle exhaust, coal, and cigarette smoke. Prenatal exposure is associated with intrauterine growth restriction, neurodevelopmental delay, and asthma. In a cohort of 159 children, prenatal PAH exposure was associated with hypomethylation of umbilical cord WBC DNA, which persisted at 3 years of age.84 In early fetal life, oogonia are formed by meiotic division. Before birth, oogonia develop into primary oocytes and complete prophase of the first meiotic division.86 Oocytes remain in this state until puberty. As cells are highly susceptible to environmental toxicants while in active phases of division, fetal life represents a critical period of vulnerability. This hypothesis is supported by the increasing incidence of nondisjunctional events with advancing maternal age and prolonged environmental exposures. Exposures impacting regulatory and endocrine functions of the ovum can influence ovarian competence throughout life. Figure 15-3 represents critical windows of exposures that may affect the male and female reproductive system.86 Developmental exposure to environmental toxicants can have an impact on fertility that may be transmitted to future generations. Active smoking during pregnancy is associated with loss of ova in the fetus, which may reduce fertility in women born to mothers who smoke. In animal models, fetal exposure to nicotine results in granulosa cell proliferation, impaired ovarian steroidogenesis and angiogenesis, increased ovarian cell apoptosis, and reduced fertility.13 Endocrine disrupting chemicals (EDCs) are compounds that act as agonists or antagonists to the endocrine system. Epidemiologic studies demonstrate an association between developmental exposure to EDCs and infertility. Bisphenol A (BPA) is an EDC found in plastic products. An inverse relationship has been found between the number of eggs recovered during in vitro fertilization and urinary BPA levels. The EDC diethylstilbestrol (DES) was prescribed from the 1940s to the 1970s to prevent miscarriage. Daughters of women exposed to DES during pregnancy developed vaginal clear cell carcinoma and infertility.117 Transgenerational effects of DES exposure (progeny whose grandmothers took DES during pregnancy) have been reported. Effects include hypospadias in grandsons and premature birth of DES grandchildren.63 Evidence suggests that effects of DES may be transmitted transgenerationally via both epigenetic (hypomethylation) and genetic processes.37,117 Spermatogonia are highly sensitive to apoptosis after exposure to cytotoxic agents. Toxicants may impact male fertility by limiting sperm production. Mutations in the male germ cell line can be transmitted to the next generation. Unlike the female, cell divisions in the male that produce mature spermatozoa occur after puberty. However, mature spermatozoa have no DNA repair mechanisms and are vulnerable to the effects of mutagens. Transient aneuploidy of autosomal and sex chromosomes has been reported in sperm of men treated for Hodgkin disease with chemotherapy in the preceding 3 months.86 Environmental toxicants that impact spermatogenesis have been identified. Chronic occupational exposure to the pesticide 1,2-dibromo-3-chloropropane (DBCP) is associated with cessation or reduction in spermatogenesis. In the rat model, exposure of the pregnant female to two EDCs (vinclozolin, a fungicide used in the wine industry, and the pesticide methoxychlor) led to impaired spermatogenesis and infertility in males in four subsequent generations. Epigenetic mechanisms are postulated.86 The relationship between paternal occupation and cancer in offspring has been extensively studied.44,71,89 One study reported increased risk of central nervous system (CNS) tumors with paternal occupational exposure to pesticides (relative risk [RR] 2.36; 95% CI 1.27-4.39) and work as a painter (RR 2.18; 95% CI 1.26-3.78). There was increased risk of leukemia associated with paternal woodworking (RR 2.18, 95% CI 1.26-3.78).44 A case control study evaluating paternal exposure to pesticides reported increased risk of astrocytoma in offspring; combining occupational and home exposures significantly elevated this risk (OR = 1.8, 95% CI 1.1-3.1).89 There is evidence linking paternal exposure to motor vehicles in the periconceptual period (driving, exhaust fumes, inhaled particulate hydrocarbons) and childhood leukemia. It is postulated that these exposures may directly affect spermatogenesis.71 Approximately 60% of congenital malformations of unknown etiology are estimated to be secondary to environmental toxicants.39 Studies report increased prevalence of birth defects in offspring of fathers employed as janitors, painters, printers, agricultural workers, groundskeepers, welders, electrical industry workers, and firefighters.22,34,39 In addition, paternal exposure to organic solvents and pesticides was a significant risk factor for congenital anomalies in offspring.22 Male fertility diminishes and sperm DNA mutations increase with advancing paternal age. Advanced paternal age is associated with pregnancy loss, birth defects, and autosomal dominant genetic disorders such as Marfan syndrome and achondroplasia. Congenital malformations seen more frequently include cleft lip and palate, hydrocephalus, neural tube defects, limb reduction defects, tracheoesophageal fistula, congenital cataracts, and congenital heart disease.53 A possible mechanism for paternally mediated effects is the impairment of a paternal gene necessary for the normal growth and development of the fetus. Replacement of the father’s genetic material with a second copy of the mother’s genetic material (uniparental disomy), or vice versa, results in a nonviable conceptus.55 In Prader-Willi syndrome, there is a functional mutation in paternal 15q, resulting in inactivation of the genes in that region of the chromosome. Environmental factors may play a role in uniparental disomy and lead to paternally mediated effects on the fetus. Studies have shown association between paternal exposure to hydrocarbons and Prader-Willi syndrome. In one study, approximately 50% of fathers of patients with Prader-Willi syndrome were occupationally exposed to hydrocarbons.18 Organohalogens are stable lipophilic chemicals that bioaccumulate in the environment, enter the food chain, and are stored in adipose tissue. Polychlorinated biphenyls (PCBs) are organohalogens that were used as liquid insulators for transformers and capacitors in the 1970s. Many countries banned or limited their use, but exposure remains a public health concern because of resistance to chemical and biologic breakdown. Exposure occurs primarily through ingestion of dairy products, animal fat, and fish. Polychlorinated biphenyls are endocrine disruptors that are mobilized from adipose tissue during pregnancy and can cross the placenta. Maternal occupational exposure is linked to low birth weight and prematurity.28,40 Human poisonings have occurred through dietary consumption of PCBs. In 1979, an epidemic of PCB poisoning from contaminated rice oil, termed yu-cheng disease, occurred in Taiwan. Adults developed hyperpigmentation, acne, and peripheral neuropathy. Of the first 39 hyperpigmented children born to poisoned women, eight died. Children born up to 6 years after the outbreak of yu-cheng disease had ectodermal defects and developmental delay. Children born 6 years after maternal exposure were as developmentally delayed as those born within 1 year of the epidemic; indicating significant maternal body burden.20 Cognitive defects seen in Taiwanese children with yu-cheng disease are comparable to those observed in American children prenatally exposed to PCBs. Studies in Michigan and North Carolina showed cognitive and gross motor delays in children prenatally exposed to PCBs through maternal body burden.28,48 In Michigan, cognitive deficits were seen in children who had elevated cord blood levels of PCBs and whose mothers had regularly consumed contaminated sport fish.28 Lead readily crosses the placenta, and is a known neurotoxin. Developmental exposure is linked to learning disability, cognitive and language deficits, and ADHD.49 The major repository for lead is bone, and chronic exposure results in significant accumulation of lead in the skeleton. Lead stores are mobilized from bone during pregnancy, potentially exposing the fetus during critical stages of brain development. It is postulated that enhanced calcium turnover during pregnancy increases lead mobilization. Maternal tibial and patellar bone lead levels are correlated with low birth weight and decreased head circumference. One study established maternal trabecular bone lead level as an independent risk factor for cognitive delay at 24 months of age.49 Significant fetal exposure secondary to maternal body burden is described in case reports of congenitally lead-poisoned children whose mothers were inadequately treated for childhood plumbism.92 Methylmercury is a neurotoxin found in fish and seafood. The safe limit of mercury ingestion for pregnant women is the subject of ongoing research.110 The US Environmental Protection Agency (EPA) has set a reference dose of mercury at 0.1 mg/kg per day. Approximately 8% of women have body burdens exceeding the reference dose. Prenatal exposure is associated with neurodevelopmental delay.27 In Minamata Bay, Japan, methylmercury from an acetaldehyde-producing plant contaminated the food chain, and pregnant women from a local fishing village gave birth to severely neurologically damaged infants.68 Biologic markers of fetal exposure have been developed using cord blood and meconium.27,79,113 In 2007, The Environmental Working Group measured cord blood levels of 413 chemicals from 10 US newborns. They found 287 toxicants, with an average of 200 chemicals in cord blood of each infant. Chemicals included pesticides, PCBs, and heavy metals such as mercury.27 Meconium analysis is a sensitive tool used to determine antenatal exposure to environmental toxicants. In a study of 426 infants born in the Philippines, exposure rate was 26.5% for lead, 83.9% for mercury, and 53% for the organophosphate pesticide malthion.79 The strongest associations between maternal exposure and adverse pregnancy outcome (spontaneous abortion, miscarriage, and birth defects) have been found for lead, mercury, pesticides, organic solvents, and ionizing radiation. Occupations linked with adverse pregnancy outcome secondary to exposures include anesthesiologists, hair dressers, laboratory technicians, dry cleaners, agricultural workers, and those working in the chemical, electronic, or shoe factories.45 In a Finnish population-based study, offspring of women working in factories, mining, and construction were at greater risk of low birth weight. Children whose mothers worked in farming and forestry were more likely to be born prematurely.81 Table 15-1 lists agents that are suspected to cause adverse pregnancy outcomes.111 TABLE 15-1 Agents Associated with Adverse Female Reproductive Capacity or Developmental Effects in Human and Animal Studies* *Major studies (Birnbaum LS, Tuomisto J. Non-carcinogenic effects of TCDD in animals, Food Addit Contam. 2000;17:275) of the reproductive health effects of exposure to dioxin have shown that dioxin should be added to this list. †1 = limited positive data; 2 = strong positive data; 3 = limited negative data; 4 = strong negative data. ‡Agent may have male-mediated effects. From Welch LS, et al, eds. Case studies in environmental medicine: reproductive and developmental hazards. Washington, DC: Agency for Toxic Substances and Disease Registry, US Department of Health and Human Services; 1993. Paraoccupational exposures occur when occupational chemicals are tracked into the home or industrial chemicals are used at home. Paraoccupational exposure occurred when a janitor in New Mexico used grain treated with fungicide containing organic mercury to feed his hogs. After consumption of contaminated meat, family members became severely ill with organic mercury poisoning. The mother was in the second trimester of her pregnancy and remained symptom-free. Urine from mother and her newborn had elevated levels of mercury, indicating placental transfer. The newborn developed seizures, severe neurodevelopmental delay, and blindness.31 Prenatal exposure to environmental tobacco smoke is associated with low birth weight, sudden infant death syndrome, and neurodevelopmental delays. Exposure during pregnancy decreases uterine blood flow, and carbon monoxide in environmental tobacco smoke can result in production of carboxyhemoglobin, further affecting fetal oxygen delivery.36 Studies suggest a relationship between air pollution and low birth weight, preterm delivery, and intrauterine mortality. Motor vehicle emissions contribute significantly to air pollution, and with urban sprawl comes increasing needs for automobile travel. Padula and colleagues demonstrated higher probability of low birth weight associated with increased traffic density areas in Southern California.80 Term infants born near the World Trade Center within the month after September 11, 2001 were also growth restricted.66 Because fetal development occurs through multiple short critical periods, the quality of water consumed by pregnant women is important. Studies of the relationship between drinking water contaminants and adverse pregnancy outcomes show associations with spontaneous abortion and intrauterine growth restriction. Congenital anomalies such as neural tube defects, oral clefts, cardiac defects, and choanal atresia were found in studies evaluating trichloroethylene-contaminated drinking water.7 Maternal diet during pregnancy may impact the epigenome. The agouti mouse contains a coat color gene controlled by DNA methylation. If pregnant mice are fed normal rat chow, offspring have either a yellow coat or brown coat. Those with a brown coat have normal weight, whereas those with a yellow coat are prone to obesity, diabetes, and cancer. Mice fed a diet supplemented with methyl donors such as folic acid, tend to develop brown color coat and are not obese.84 Maternal exposure to bisphenol A (BPA), an endocrine disruptor, shifts distribution of offspring’s coat color to yellow. This effect can be reversed by dietary supplementation with choline, folate, or other methyl donors.37 Similarly, pregnant sheep exposed to diets restricted in vitamin B12, folate, and the amino acid methionine deliver offspring with altered DNA methylation. Offspring have increased body mass, impaired immune function, insulin resistance, and hypertension as adults.95 Properties enabling chemicals to cross the placenta are low molecular weight, lipid solubility, and resemblance to nutrients with specific transport mechanisms. An example of a low-molecular-weight compound is carbon monoxide, a constituent of environmental tobacco smoke. Carbon monoxide has a very high affinity for hemoglobin, and displaces oxygen. Accumulation of carboxyhemoglobin leads to hypoxia and impaired cellular metabolism.36 Examples of lipid-soluble chemicals that readily cross the placenta are PCBs, organic solvents, and polycyclic hydrocarbons such as benzo(a)pyrene, a carcinogen in environmental tobacco smoke. Both the organic solvent ethanol and PCBs have been measured in equal concentration in fetal and maternal blood.14,24 Lead is actively transported across the placenta via calcium channels. Studies have shown that calcium supplementation may reduce the transfer of lead to the fetus.49 Ionizing radiation is a well-characterized teratogen.2,43 It is postulated that ionizing radiation is most teratogenic during organogenesis in the first trimester.43 Prenatal exposure is associated with infertility, microcephaly, and increased incidence of childhood cancer in offspring.2 Children of survivors of the atomic bombs in Hiroshima and Nagasaki exposed in utero at less than 18 weeks’ gestation developed microcephaly, with the lowest observable effect at a dose of 1 to 9 rad (Figure 15-4).5 The brain of a neonate undergoing cranial computed tomography (CT) with settings of 400 mA, 125 kV (peak), and a standard slice thickness of 4 mm receives a dose of 10.5 rad.114 Therefore, it has been recommended that CT be used sparingly for infants, particularly when other imaging techniques are available. An excess of cancer among Japanese individuals exposed in utero has also been reported (Figure 15-5).116 Not all forms of radiation are hazardous to the fetus. Ultraviolet light does not penetrate to the fetus and does not constitute a future cancer risk.2 Heat may directly penetrate to the fetus and cause birth defects. Animal studies demonstrate that both maternal core temperature 2° C above baseline and duration of hyperthermia are important risk factors. One study showed an association between hot tub use after conception and twofold increased risk of miscarriage. In a study of the effects of heat on the outcome of pregnancy, 22,491 women undergoing α-fetoprotein screening were asked about their use of hot tubs, saunas, and electric blankets, and whether they had experienced a fever during the first trimester. The adjusted relative risk for neural tube defects with hot tub use was 2.8 (95% CI 1.2-6.5). With exposure to two of these heat sources, the relative risk increased to 6.5.19 Noise has a waveform that may be transmitted to the fetus. At 23 to 25 weeks, sound may produce physiologic changes, and the auditory system is functional between 25 and 29 weeks’ gestation.51,52 A 27-week fetus can hear low frequency sounds below 500 Hz. Excessive noise is associated with birth defects, prematurity, and low birth weight.51 In addition, noise-induced hearing loss may be evident after in utero exposure. The cochlear hair cells are sensitive to low-frequency sound. Animal studies show that intense low-frequency sound can damage the cochlear hair cells; effects are determined by gestational age and by the intensity and duration of sound exposure.58 The Sound Study Group recommends that pregnant women should avoid extended exposure to low-frequency sound levels (<250 Hz) greater than 65 db and that sources of sound applied directly to the mother’s abdomen (headphones) should be avoided, because of no clear benefit and potential risks to fetal hearing.52
Adverse Exposures to the Fetus
Exposures Not Concurrent with Pregnancy
Preconceptional Effects
Exposures Affecting the Epigenome
Exposures Affecting the Ovum
Paternal Effects
Secondary Fetal Exposure: Maternal Body Burden
Polychlorinated Biphenyls
Lead.
Mercury.
Maternal Exposures Concurrent with Pregnancy
Occupation and Paraoccupation
Agent
Human Outcomes
Strength of Association in Humans†
Animal Outcomes
Strength of Association in Animals†
Anesthetic gases‡
Reduced fertility, spontaneous abortion
1, 3
Birth defects
1, 3
Arsenic
Spontaneous abortion, low birth weight
1
Birth defects, fetal loss
2
Benzo[a]pyrene
None
NA
Birth defects
1
Cadmium
None
NA
Fetal loss, birth defects
2
Carbon disulfide
Menstrual disorders, spontaneous abortion
1
Birth defects
1
Carbon monoxide
Low birth weight, fetal death (high doses)
1
Birth defects, neonatal death
2
Chlordecone
None
NA
Fetal loss
2, 3
Chloroform
None
NA
Fetal loss
1
Chloroprene
None
NA
Birth defects
2, 3
Ethylene glycol ethers
Spontaneous abortion
1
Birth defects
2
Ethylene oxide
Spontaneous abortion
1
Fetal loss
1
Formamides
None
NA
Fetal loss, birth defects
2
Inorganic mercury‡
Menstrual disorders, spontaneous abortion
1
Fetal loss, birth defects
1
Lead‡
Spontaneous abortion, prematurity, neurologic dysfunction in child
2
Birth defects, fetal loss
2
Organic mercury
CNS malformation, cerebral palsy
2
Birth defects, fetal loss
2
Physical stress
Prematurity
2
None
NA
PBBs
None
NA
Fetal loss
2
PCBs
Neonatal PCB syndrome (low birth weight, hyperpigmentation, eye abnormalities)
2
Low birth weight, fetal loss
2
Radiation, ionizing
Menstrual disorders, CNS defects, skeletal and eye anomalies, mental retardation, childhood cancer
2
Fetal loss, birth defects
2
Selenium
Spontaneous abortion
3
Low birth weight, birth defects
2
Tellurium
None
NA
Birth defects
2
2,4-Dichlorophenoxyacetic acid
Skeletal defects
4
Birth defects
1
2,4,5-Trichlorophenoxyacetic acid
Skeletal defects
4
Birth defects
1
Video display terminals
Spontaneous abortion
4
Birth defects
1
Vinyl chloride‡
CNS defects
1
Birth defects
1, 4
Xylene
Menstrual disorders, fetal loss
1
Fetal loss, birth defects
1
Air
Water
Diet
Pathways of Fetal Exposure
Placenta-Dependent Pathways
Placenta-Independent Pathways
Radiation
Heat
Noise
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Adverse Exposures to the Fetus
