Heightened susceptibility: A review of how pregnancy and chemical exposures influence maternal health

Pregnancy is a unique period when biological changes can increase sensitivity to chemical exposures. Pregnant women are exposed to multiple environmental chemicals via air, food, water, and consumer products, including flame retardants, plasticizers, and pesticides. Lead exposure increases risk of pregnancy-induced hypertensive disorders, although women’s health risks are poorly characterized for most chemicals. Research on prenatal exposures has focused on fetal outcomes and less on maternal outcomes. We reviewed epidemiologic literature on chemical exposures during pregnancy and three maternal outcomes: preeclampsia, gestational diabetes, and breast cancer. We found that pregnancy can heighten susceptibility to environmental chemicals and women’s health risks, although variations in study design and exposure assessment limited study comparability. Future research should include pregnancy as a critical period for women’s health. Incorporating biomarkers of exposure and effect, deliberate timing and method of measurement, and consistent adjustment of potential confounders would strengthen research on the exposome and women’s health.     

Biomonitoring of Human Fetal Exposure to Environmental Chemicals in Early Pregnancy

The first trimester of human fetal life, a period of extremely rapid development of physiological systems, represents the most rapid growth phase in human life. Interference in the establishment of organ systems may result in abnormal development that may be manifest immediately or programmed for later abnormal function. Exposure to environmental chemicals may be affecting development at these early stages, and yet there is limited knowledge of the quantities and identities of the chemicals to which the fetus is exposed during early pregnancy. Clearly, opportunities for assessing fetal chemical exposure directly are extremely limited. Hence, this review describes indirect means of assessing fetal exposure in early pregnancy to chemicals that are considered disrupters of development. Consideration is given to such matrices as maternal hair, fingernails, urine, saliva, sweat, breast milk, amniotic fluid and blood, and fetal matrices such as cord blood, cord tissue, meconium, placenta, and fetal liver. More than 150 articles that presented data from chemical analysis of human maternal and fetal tissues and fluids were reviewed. Priority was given to articles where chemical analysis was conducted in more than one matrix. Where correlations between maternal and fetal matrices were determined, these articles were included and are highlighted, as these may provide the basis for future investigations of early fetal exposure. The determination of fetal chemical exposure, at the time of rapid human growth and development, will greatly assist regulatory agencies in risk assessments and establishment of advisories for risk management concerning environmental chemicals.     

Categorizing biomarkers of the human exposome and developing metrics for assessing environmental sustainability

The concept of maintaining environmental sustainability broadly encompasses all human activities that impact the global environment, including the production of energy, use and management of finite resources such as petrochemicals, metals, food production (farmland, fresh and ocean waters), and potable water sources (rivers, lakes, aquifers), as well as preserving the diversity of the surrounding ecosystems. The ultimate concern is how one can manage Spaceship Earth in the long term to sustain the life, health, and welfare of the human species and the planet's flora and fauna. On a more intimate scale, one needs to consider the human interaction with the environment as expressed in the form of the exposome, which is defined as all exogenous and endogenous exposures from conception onward, including exposures from diet, lifestyle, and internal biology, as a quantity of critical interest to disease etiology. Current status and subsequent changes in the measurable components of the exposome, the human biomarkers, could thus conceivably be used to assess the sustainability of the environmental conditions with respect to human health. The basic theory is that a shift away from sustainability will be reflected in outlier measurements of human biomarkers. In this review, the philosophy of long-term environmental sustainability is explored in the context of human biomarker measurements and how empirical data can be collected and interpreted to assess if solutions to existing environmental problems might have unintended consequences. The first part discusses four conventions in the literature for categorizing environmental biomarkers and how different types of biomarker measurements might fit into the various grouping schemes. The second part lays out a sequence of data management strategies to establish statistics and patterns within the exposome that reflect human homeostasis and how changes or perturbations might be interpreted in light of external environmental stressors. The underlying concept is to identify probative outliers from the "unremarkable exposome" in individuals or subpopulations that could be used for discerning deviations from the healthy environment, much like current diagnostic medicine uses batteries of blood and urine tests to screen for preclinical disease conditions. Such empirically derived human in vivo data could subsequently be integrated into high-throughput in vitro and in silico testing of environmental and manufactured chemicals to support real-world toxicity evaluations.     

Effects of Moderate Prenatal Alcohol Exposure during Early Gestation in Rats on Inflammation across the Maternal-Fetal-Immune Interface and Later-Life Immune Function in the Offspring

During early brain development, microglial activation can negatively impact long-term neuroimmune and cognitive outcomes. It is well-known that significant alcohol exposure during early gestation results in a number of cognitive deficits associated with fetal alcohol spectrum disorders (FASD). Additionally, microglia are activated following high levels of alcohol exposure in rodent models of FASD. We sought to examine whether moderate prenatal alcohol exposure (70 mg/dL blood alcohol concentration) activates microglia in the fetal rat brain, and whether moderate fetal alcohol exposure has long-term negative consequences for immune function and cognitive function in the rat. We also measured inflammation within the placenta and maternal serum following moderate alcohol exposure to determine whether either could be a source of cytokine production in the fetus. One week of moderate prenatal alcohol exposure produced a sex-specific increase in cytokines and chemokines within the fetal brain. Cytokines were also increased within the placenta, regardless of the sex of the fetus, and independent of the low levels of circulating cytokines within the maternal serum. Adult offspring exposed to alcohol prenatally had exaggerated cytokine production in the brain and periphery in response to lipopolysaccharide (25 μg/kg), as well as significant memory deficits precipitated by this low-level of inflammation. Thus the immune system, including microglia, may be a key link to understanding the etiology of fetal alcohol spectrum disorders and other unexplored cognitive or health risks associated with even low levels of fetal alcohol exposure.     

超声中孕期筛查胎盘脐带入口位置异常的临床价值

目的通过产前超声检查及时发现胎盘脐带入口位置异常的胎儿,特别是帆状胎盘合并血管前置胎儿,便于产中及时采取有效措施,避免因误诊治、漏诊增加围生儿的危险性,降低病死率。方法对我院1876例中孕期孕妇作常规胎儿检查后,重点观察脐带根部与胎盘连接的位置关系、脐血管走行及分支方向、数目,所有受检孕妇常规观察宫颈内口及其附近有无血管走行并用彩色多普勒检测,观察频谱特点。结果 1876例中检查出脐带入口异常99例(5.2%)。边缘性胎盘脐带入口95例(5.1%)。帆状胎盘4例(0.2%),其中1例帆状胎盘合并中央型前置胎盘;2例帆状胎盘合并血管前置;另1例双胎之一帆状胎盘。4例帆状胎盘中3例妊娠至晚期行剖宫产,婴儿存活,1例经阴道分娩一死婴。除5例流失外,所有病例均经产后确诊。结论中孕期是超声检查胎儿脐带根部与胎盘位置关系最佳时期,可提高胎儿脐带入口异常的检出率,特别是帆状盘合并血管前置,可以指导临床及时采取有效措施,避免不良妊娠结局,降低围生儿病死率。     

Understanding mixed environmental exposures using metabolomics via a hierarchical community network model in a cohort of California women in 1960’s

Even though the majority of population studies in environmental health focus on a single factor, environmental exposure in the real world is a mixture of many chemicals. The concept of “exposome” leads to an intellectual framework of measuring many exposures in humans, and the emerging metabolomics technology offers a means to read out both the biological activity and environmental impact in the same dataset. How to integrate exposome and metabolome in data analysis is still challenging. Here, we employ a hierarchical community network to investigate the global associations between the metabolome and mixed exposures including DDTs, PFASs and PCBs, in a women cohort with sera collected in California in the 1960s. Strikingly, this analysis revealed that the metabolite communities associated with the exposures were non-specific and shared among exposures. This suggests that a small number of metabolic phenotypes may account for the response to a large class of environmental chemicals.     

Categorizing Biomarkers of the Human Exposome and Developing Metrics for Assessing Environmental Sustainability

The concept of maintaining environmental sustainability broadly encompasses all human activities that impact the global environment, including the production of energy, use and management of finite resources such as petrochemicals, metals, food production (farmland, fresh and ocean waters), and potable water sources (rivers, lakes, aquifers), as well as preserving the diversity of the surrounding ecosystems. The ultimate concern is how one can manage Spaceship Earth in the long term to sustain the life, health, and welfare of the human species and the planet's flora and fauna. On a more intimate scale, one needs to consider the human interaction with the environment as expressed in the form of the exposome, which is defined as all exogenous and endogenous exposures from conception onward, including exposures from diet, lifestyle, and internal biology, as a quantity of critical interest to disease etiology. Current status and subsequent changes in the measurable components of the exposome, the human biomarkers, could thus conceivably be used to assess the sustainability of the environmental conditions with respect to human health. The basic theory is that a shift away from sustainability will be reflected in outlier measurements of human biomarkers. In this review, the philosophy of long-term environmental sustainability is explored in the context of human biomarker measurements and how empirical data can be collected and interpreted to assess if solutions to existing environmental problems might have unintended consequences. The first part discusses four conventions in the literature for categorizing environmental biomarkers and how different types of biomarker measurements might fit into the various grouping schemes. The second part lays out a sequence of data management strategies to establish statistics and patterns within the exposome that reflect human homeostasis and how changes or perturbations might be interpreted in light of external environmental stressors. The underlying concept is to identify probative outliers from the “unremarkable exposome” in individuals or subpopulations that could be used for discerning deviations from the healthy environment, much like current diagnostic medicine uses batteries of blood and urine tests to screen for preclinical disease conditions. Such empirically derived human in vivo data could subsequently be integrated into high-throughput in vitro and in silico testing of environmental and manufactured chemicals to support real-world toxicity evaluations.     

Blood-borne biomarkers and bioindicators for linking exposure to health effects in environmental health science

Environmental health science aims to link environmental pollution sources to adverse health outcomes to develop effective exposure intervention strategies that reduce long-term disease risks. Over the past few decades, the public health community recognized that health risk is driven by interaction between the human genome and external environment. Now that the human genetic code has been sequenced, establishing this “G × E” (gene–environment) interaction requires a similar effort to decode the human exposome, which is the accumulation of an individual’s environmental exposures and metabolic responses throughout the person’s lifetime. The exposome is composed of endogenous and exogenous chemicals, many of which are measurable as biomarkers in blood, breath, and urine. Exposure to pollutants is assessed by analyzing biofluids for the pollutant itself or its metabolic products. New methods are being developed to use a subset of biomarkers, termed bioindicators, to demonstrate biological changes indicative of future adverse health effects. Typically, environmental biomarkers are assessed using noninvasive (excreted) media, such as breath and urine. Blood is often avoided for biomonitoring due to practical reasons such as medical personnel, infectious waste, or clinical setting, despite the fact that blood represents the central compartment that interacts with every living cell and is the most relevant biofluid for certain applications and analyses. The aims of this study were to (1) review the current use of blood samples in environmental health research, (2) briefly contrast blood with other biological media, and (3) propose additional applications for blood analysis in human exposure research.     

SEROTONIN IN TOXAEMIA OF PREGNANCY

Serotonin (5-hydroxytryptamine) contents of maternal blood, fetal cord blood, and placenta from thirty-five patients with toxaemia of pregnancy and forty normal pregnant subjects were estimated. Placental monoamine oxidase activity from ten normal and ten toxaemic cases were also estimated. An increased content and uptake of serotonin by platelets in maternal blood from toxaemic patients were observed and there was a concomitant reduction in platelet count. Raised levels of serotonin and a decrease in monoamine oxidase levels were observed in placentas of the toxaemic group. The levels of serotonin in fetal cord blood were significantly higher than those in normal maternal blood. It is suggested that the fetus could be the source of increased serotonin in this syndrome, due to the decrease in monoamine oxidase activity in the toxaemic placenta. An abnormality in indole amine metabolism may contribute to the pathology associated with toxaemia of pregnancy.     

Bioanalysis for cocaine,opiates, methadone,and amphetamines exposure detection during pregnancy

Drug exposure during pregnancy constitutes a major legal issue and a public health concern. Drug and metabolite determination in biological matrices from mother and newborn is an objective indication of prenatal drug exposure. However, limited data are available regarding the interpretation of these analytical results in terms of window of detection and degree of exposure. We collected paired maternal hair, meconium, placenta, and umbilical cord from 727 mother‐newborn dyads. We analyzed these specimens by liquid chromatography‐tandem mass spectrometry for the determination of cocaine, opioids, methadone, and amphetamines, and compared the analytical results from the four different matrices. The cases were divided in non‐exposure, low, and frequent exposure, based on maternal hair concentrations and segmental analysis by trimesters. For cocaine, 62 cases tested positive in hair, 9 in meconium, 6 in placenta and 7 in umbilical cord. In the case of opioids, 14 maternal hair cases were positive, 11 meconium and umbilical cord and 9 placenta samples. For methadone, 11 cases were positive in hair, 9 in meconium and 6 in placenta and umbilical cord. For amphetamines, 18 cases were positive according to maternal hair, but all meconium, placenta, and umbilical cord tested negative. Maternal hair was the most sensitive specimen to detect drug exposure during pregnancy. Meconium, placenta, and umbilical cord tested positive if hair concentrations showed frequent drug use during the whole pregnancy, especially during the third trimester. Meconium, placenta, and umbilical cord also tested positive for morphine and metabolites, if this drug was administered during labour and delivery. Copyright © 2016 John Wiley & Sons, Ltd.     

Comparison of the concentrations of polychlorinated dibenzo-p-dioxins, dibenzofurans, and dioxin-like polychlorinated biphenyls in maternal and fetal blood, amniotic and allantoic fluids in cattle

To characterize the maternal-fetal transport of lipophilic endocrine disrupting chemicals, concentrations of polychlorinated (2,3,7,8-substituted) dibenzo-p-dioxins (PCDDs), dibenzofurans (PCDFs), and dioxin-like polychlorinated biphenyls (PCBs) were measured in maternal and fetal blood, and amniotic and allantoic fluids in cattle. Total toxicity equivalent quantity (TEQ) was highest in amniotic fluid on a fat-weight basis, whereas it was highest in maternal blood on a total weight basis. TEQ was lowest in allantoic fluid on either basis; 26 of 29 congeners analyzed in this experiment were detected in one or more samples. The largest number of congeners was detected in amniotic fluid. O8CDD, 2,3,4,7,8-P5CDF and 2,3',4,4',5-P5CB were the major congeners in PCDDs, PCDFs and PCBs, respectively. The O8CDD concentration was higher in fetal blood than in maternal blood on a fat-weight basis, whereas concentrations of other congeners were lower in fetal blood than in maternal blood. Furthermore, on a fat-weight basis, the O8CDD concentration was considerably higher in allantoic fluid compared with other samples. Concentrations of major PCB congeners were higher in amniotic fluid than in maternal and fetal blood on a fat-weight basis. In conclusion, it is suggested that lipophilic endocrine-disrupting chemicals contained in maternal blood are all transferred to the fetal circulation via the placenta in cattle. Furthermore, the results of this experiment imply that O8CDD has different transportation systems from other dioxins in the circulation, and that a considerable amount of PCBs is excreted and accumulated in amniotic fluid during the fetal stage in cattle.     

Prenatal environmental exposures, epigenetics, and disease

This review summarizes recent evidence that prenatal exposure to diverse environmental chemicals dysregulates the fetal epigenome, with potential consequences for subsequent developmental disorders and disease manifesting in childhood, over the lifecourse, or even transgenerationally. The primordial germ cells, embryo, and fetus are highly susceptible to epigenetic dysregulation by environmental chemicals, which can thereby exert multiple adverse effects. The data reviewed here on environmental contaminants have potential implications for risk assessment although more data are needed on individual susceptibility to epigenetic alterations and their persistence before this information can be used in formal risk assessments. The findings discussed indicate that identification of environmental chemicals that dysregulate the prenatal epigenome should be a priority in health research and disease prevention.     

Sports drug testing and the athletes' exposome

Similar to the general population, elite athletes are exposed to a complex set of environmental factors including chemicals and radiation and also biological and physical stressors, which constitute an exposome that is, unlike for the general population, subjected to specific scrutiny for athletes due to applicable antidoping regulations and associated (frequent) routine doping controls. Hence, investigations into the athlete's exposome and how to distinguish between deliberate drug use and different contamination scenarios has become a central topic of antidoping research, as a delicate balance is to be managed between the vital and continually evolving developments of sensitive analytical techniques on the one hand, and the risk of the athletes' exposome potentially causing adverse analytical findings on the other.     

Analysis of hemoglobin adducts from acrylamide, glycidamide, and ethylene oxide in paired mother/cord blood samples from Denmark

The knowledge about fetal exposure to acrylamide/glycidamide from the maternal exposure through food is limited. Acrylamide, glycidamide, and ethylene oxide are electrophiles and form adducts with hemoglobin (Hb), which could be used for in vivo dose measurement. In this study, a method for analysis of Hb adducts by liquid chromatography-mass spectrometry, the adduct FIRE procedure, was applied to measurements of adducts from these compounds in maternal blood samples (n = 87) and umbilical cord blood samples (n = 219). The adduct levels from the three compounds, acrylamide, glycidamide, and ethylene oxide, were increased in tobacco smokers. Highly significant correlations were found between cord and maternal blood with regard to measured adduct levels of the three compounds. The mean cord/maternal hemoglobin adduct level ratios were 0.48 (range 0.27-0.86) for acrylamide, 0.38 (range 0.20-0.73) for glycidamide, and 0.43 (range 0.17-1.34) for ethylene oxide. In vitro studies with acrylamide and glycidamide showed a lower (0.38-0.48) rate of adduct formation with Hb in cord blood than with Hb in maternal blood, which is compatible with the structural differences in fetal and adult Hb. Together, these results indicate a similar life span of fetal and maternal erythrocytes. The results showed that the in vivo dose in fetal and maternal blood is about the same and that the placenta gives negligible protection of the fetus to exposure from the investigated compounds. A trend of higher levels of the measured adducts in cord blood with gestational age was observed, which may reflect the gestational age-related change of the cord blood Hb composition toward a higher content of adult Hb. The results suggest that the Hb adduct levels measured in cord blood reflect the exposure to the fetus during the third trimester. The evaluation of the new analytical method showed that it is suitable for monitoring of background exposures of the investigated electrophilic compounds in large population studies.     

Mercury levels in parturient and newborns from Aveiro region,Portugal

ABSTRACT

Since the outbreak of methylmercury (MeHg) poisoning in Japan and Iraq, mercury (Hg) is classified as well-established teratogen. The Portuguese region of Aveiro faced some decades ago an environmental Hg contamination due to activities from a chlor-alkali plant. Until now, no apparent evaluation was conducted regarding prenatal exposure to Hg in this area. The main objectives of this study were to: i) assess maternal and fetal exposure to Hg in the Aveiro region using noninvasive biological matrices; ii) examine the influence of variables that may contribute to Hg exposure during pregnancy; and iii) improve knowledge regarding metal accumulation and distribution over the maternal–fetal–placental unit. This study was performed in 50 mother–newborn pairs from the Aveiro district. Total Hg (THg) was quantified in maternal scalp hair, placenta, amniotic membrane, and umbilical cord. Maternal hair presented THg levels with a mean value of 900 ng/g, which is lower than the USEPA and WHO acceptable threshold. Regarding THg levels in placenta and umbilical cord, mean values were similar (decidua basalis: 32.84 ng/g; chorionic plate: 30.18 ng/g; umbilical cord: 30.67 ng/g). The amniotic membrane presented the highest THg levels with a mean concentration of 42.35 ng/g, reaching a maximum of 134.1 ng/g. Further, a significant positive correlation was noted between THg levels found in hair, and all matrices analyzed reinforcing the use of hair in biomonitoring studies with respect to maternal exposure to Hg. In general, levels of THg found in our study were lower than those in previous studies performed in Europe. Consumption of fish rich in selenium and bottled water was negatively correlated with THg levels. Finally, data demonstrated that Hg is capable of crossing the placental barrier and accumulate in placental tissues. Amniotic membrane seemed to play a role in metal detoxification, but further investigations are necessary to examine whether this catabolic process affects Hg accumulation.     

DNA methylation alterations in response to prenatal exposure of maternal cigarette smoking: A persistent epigenetic impact on health from maternal lifestyle?

Despite increased awareness, maternal cigarette smoking during pregnancy continues to be a common habit causing risk for numerous documented negative health consequences in the exposed children. It has been proposed that epigenetic mechanisms constitute the link between prenatal exposure to maternal cigarette smoking (PEMCS) and the diverse pathologies arising in later life. We here review the current literature, focusing on DNA methylation. Alterations in the global DNA methylation patterns were observed after exposure to maternal smoking during pregnancy in placenta, cord blood and buccal epithelium tissue. Further, a number of specific genes exemplified by CYP1A1, AhRR, FOXP3, TSLP, IGF2, AXL, PTPRO, C11orf52, FRMD4A and BDNF are shown to have altered DNA methylation patterns in at least one of these tissue types due to PEMCS. Investigations showing persistence and indications of trans-generational inheritance of DNA methylation alterations induced by smoking exposure are also described. Further, smoking-induced epigenetic manifestations can be both tissue-dependent and gender-specific which show the importance of addressing the relevant sex, tissue and cell types in the future studies linking specific epigenetic alterations to disease development. Moreover, the effect of paternal cigarette smoking and second-hand smoke exposure is documented and accordingly not to be neglected in future investigations and data evaluations. We also outline possible directions for the future research to address how DNA methylation alterations induced by maternal lifestyle, exemplified by smoking, have direct consequences for fetal development and later in life health and behavior of the child.     

Blood lead and zinc in pregnant women and their offspring in intrauterine growth retardation cases

As part of our program to investigate the possible role of environmental pollutants in the incidence of intrauterine-growth retardation (IUGR) in India, we determined the lead and zinc levels in mothers and neonatal blood, collected at parturition, in cases with normal and IUGR babies. Both maternal and cord blood lead levels were significantly higher in IUGR cases than in normal cases (p < 0.05). The mean level of zinc was also higher in maternal blood of IUGR cases. Significantly, the mean cord blood lead level was > 10 microg/dL, which is greater than Centers for Disease Control's intervention level, in 54% of newborns. A good correlation (r = 0.53, p < 0.01) between maternal and cord blood lead levels confirmed the transfer of lead from mother to the fetus. There was a weak but significant relationhsip between cord blood lead levels and birth weight of newborns (r = -0.22, p < 0.05). The study may serve as a pointer to the perils of in utero exposure to chemical contaminants and a call for measures by the public health authorities for a continuous bio-monitoring program to evaluate impact of environmental pollutants on women and children's health.     

Biological matrices for the evaluation of in utero exposure to drugs of abuse

In recent years, the evaluation of in utero exposure to drugs of abuse has been achieved by testing biological matrices coming from the fetus or newborn (eg, meconium, fetal hair, cord blood, neonatal urine), the pregnant or nursing mother (eg, hair, blood, oral fluid, sweat, urine, breast milk), or from both the fetus and the mother (placenta, amniotic fluid). Overall, these matrices have the advantage of noninvasive collection (with the exception of amniotic fluid) and early detection of exposure from different gestational periods. Matrices such as amniotic fluid, meconium, fetal hair, and maternal hair provide a long historical record of prenatal exposure to certain drugs and can account for different periods of gestation: amniotic fluid from the early pregnancy, meconium for the second and third trimester of gestation, fetal hair for the third, and finally maternal hair (when long enough) for the whole pregnancy. Placenta may reveal the passage of a substance from the mother to the fetus. Cord blood and neonatal urine are useful for determining acute exposure to drugs of abuse in the period immediately previous to delivery. Drug detection in maternal blood, oral fluid, and sweat accounts only for acute consumption that occurred in the hours previous to collection and gives poor information concerning fetal exposure. Different immunoassays were used as screening methods for drug testing in the above-reported matrices or as unique analytical investigation tools when chromatographic techniques coupled to mass spectrometry were not commonly available. However, in the last decade, both liquid and gas chromatography-mass spectrometric methodologies have been routinely applied after appropriate extraction of drugs and their metabolites from these biological matrices.