Endocrine disrupting compounds (EDCs) – exogenous compounds that can disrupt normal hormone signalling systems – are ubiquitous in our modern environment. The heightened awareness of the potential effects of EDCs on foetal and child development has coincided with the increase in rates of childhood obesity, premature birth and low birth weight, and disorders of sexual development. Accompanying the explosion of knowledge about EDCs and their effects is a debate about the significance of the new knowledge to public health and which data should be used by governmental bodies to make decisions about regulation. This review will first present the ongoing debate on the significance of the published scientific data, using bisphenol A (BPA) as an example. Then, new information about rates of exposure of children and data describing effects of EDCs on developmental outcomes will be discussed.
ENDOCRINE DISRUPTING COMPOUNDS: A PRIMER
EDCs disrupt normal endocrine homeostasis by binding nuclear or non-nuclear steroid receptors, nonsteroid receptors or disrupting steroid synthesis and metabolic pathways. Synthetic EDCs are broadly categorized into persistent organic pollutants (POPs) and short-lived pollutants that are ubiquitous in the environment. POPs include the organochlorine pesticides dichlorodiphenyltrichloroethane (DDT) and dichlorodiphenyldichloroethylene (DDE), industrial byproducts such as dioxins and polychlorinated biphenyls (PCBs), surfactants such as polyflouroalkyls (PFOAs) and flame retardants such as polybrominated diphenyl ethers (PBDEs). Short-lived pollutants include phthalates and BPA, found ubiquitously in plastics. With POPs, there is persistence in the environment, so there is human exposure despite bans on use (e.g. DDT), allowing for transgenerational exposure, magnification of doses up the food chain and increased exposure of populations with high-fat intake (infants). Although phthalates and BPA are short-lived, their ubiquity implies a constant, if inconsistent exposure. Both epidemiological and animal studies will be discussed, as epidemiological studies give data on population exposure and disease association, whereas animal studies give insight into mechanisms of disease underlying the associations. Much of the recent data have focused on phthalates and BPA, so this review will primarily present studies of these EDCs.
ENDOCRINE DISRUPTING COMPOUNDS: ONGOING DEBATES
Reliable data on the extent of human exposure to each EDC and the lowest concentrations that cause endocrine disturbance are crucial for governmental agencies to make decisions on the regulation of EDC manufacture and use, and thus are subjects of great debate. At the heart of the debate is the difference in opinion about the reliability and validity of the scientific data used to reach conclusions. The sides of the debate in the case of BPA are presented here.
Determinations of the lowest concentrations that cause endocrine disturbance are generally extrapolated from animal studies. There is agreement that BPA has adverse effects at relatively high doses (reviewed in ). The current lowest observed adverse effect level (LOAEL) for humans adopted by the Environmental Protection Agency (EPA) is extrapolated from studies conducted in the 1980s. Since then, many scientific studies have suggested that BPA induces adverse effects in animals at levels much lower than originally thought; this evidence was summarized in a statement by an expert panel of academic researchers convened by the National Institutes of Environmental Health Sciences (NIEHS) . The expert panel concluded that ‘human exposure to BPA is within range that is predicted to be biologically active in over 95% of people sampled’. National Toxicology Program (NTP) panels were convened to critically examine the available evidence of the effects of BPA on human health . Weighing the evidence, the panel had ‘negligible concern’ that in-utero exposure to BPA resulted in birth defects or offspring growth disparities, ‘minimal concern’ for effect on age of pubertal onset and ‘some concern’ for effects on behaviour of children at current human exposures. The panel cited concerns of experimental design, use of controls and reproducibility of so-called ‘low dose’ studies as reasons for the conservative statements. After its initial Assessment of BPA in 2008, the US Food and Drug Administration (FDA) independently reviewed the low-dose studies cited in the NTP panel and judged the studies on the basis of established FDA and EPA guidelines . The FDA updated statements in 2010 about the use of BPA, stating that it ‘supports steps to reduce exposure of infants to BPA in the food supply’, but made no mention about older children or adults .
The different conclusions of the panel epitomize the fact that there is an ongoing disagreement about which studies to include in evaluation of BPA effects and safety. This is true both for animal studies and human studies. For animal studies, one side of the debate states that the studies meeting FDA and EPA guidelines have methodological flaws, lack of controls and are a select few, ignoring much of the gathered data [5–7]. In response, researchers on the other side of the debate cite that studies not included often cannot be replicated and have small sample sizes, thus are not appropriate for consideration by regulatory agencies [8,9]. For human studies, the NTP panel acknowledged that epidemiological studies report BPA in urine and other human tissues but did not comment on whether levels of human exposure were in the range associated with adverse effects . In their evaluation, the FDA reviewed two human studies on rates of excretion, thus metabolism of BPA given to research participants (so-called toxicokinetic studies), and referred to their own data on rates of BPA release from plastic bottles and food containers, but did not include biomonitoring studies in their assessment . Biomonitoring studies measure the EDC of interest in a tissue of a population, and thus take into account all routes of entry into the body and everyday environmental exposure. The FDA stated that they did not use the available biomonitoring studies because these studies had experimental limitations, did not collect data on children younger than 6 years and the FDAs’ report concentrated on infants . Vandenberg et al. found that of greater than 80 studies that tested tissues for BPA and its metabolites in different demographic groups, only three studies reported no detectable BPA. Between 75 and 100% of the participants in studies had detectable BPA in urine, blood or saliva, albeit at a wide range of concentrations. The authors criticized the methodology of the FDA-included toxicokinetic studies and pointed out that data from the toxicokinetic studies had to be extrapolated to infants, just as data from the biomonitoring studies . In a separate commentary, the authors urged US and European regulatory bodies to include so-called biomonitoring studies in their evaluation of current human exposure to BPA. Recently, the Endocrine Society released a statement that not only outlined research needs of the field but also called upon regulatory agencies to include a wider range of scientists and scientific evidence in their weight of evidence determination of EDC safety [12▪▪].
EXPOSURE TO ENDOCRINE DISRUPTING COMPOUNDS
Exposure to EDCs is via ingestion of contaminated food or water, inhalation of aerosolized solvents, absorption through skin or mucous membranes, absorption through invasive medical instruments and tubing, or during gestation. Children may have higher exposure to environmental EDCs, as they consume more calories per body surface area and have higher minute ventilation. Exposure during foetal development could not only affect proper anatomical and functional development of endocrine organs but could also impart a lifelong risk of disease development, as outlined in the now widely accepted concept of the foetal basis of adult disease; the environmental and hormonal milieu of the developing organism interacts with its genes to programme disease susceptibility in later childhood and adult life.
The National Health and Nutrition Examination Survey (NHANES) provides researchers with a large number of tissue samples across a wide range of ages, socioeconomic categories and geographic areas of the USA and can provide a snapshot of EDC exposure. Calafat et al. determined the concentrations of oxidative metabolites of common phthalates in the urine of NHANES participants and found that children have the highest concentrations of oxidative metabolites, and concluded that previous studies that did not measure these metabolites underestimated the exposure of children to phthalates. Multiple potential EDCs, including DDE, phthalates, PCBs and PBDEs were detected in the serum of pregnant women participating in the NHANES, with certain compounds present in 0% of women, whereas other compounds were present in 100% of women [14▪]. Urine concentrations of the short-lived phthalates and BPA varied considerably before and during pregnancy consistent with a constant, but variable exposure .
ENDOCRINE DISRUPTING COMPOUNDS, PREMATURITY AND LOW BIRTHWEIGHT
The rate of preterm birth in the USA has risen by more than one-third since the early 1980s, plateauing in the 2000s, although the percentage of low birthweight (LBW) babies has increased 20% . There are multiple factors contributing to this trend, and a few epidemiological studies reveal an association between prematurity or LBW and EDC exposure. In a population of third trimester women in Mexico City, higher levels of BPA were observed in the urine of women who delivered before 37 weeks’ gestation than those who delivered at term . In the same cohort, higher levels of phthalates were also associated with preterm birth . These findings are in contrast to previous studies, which indicated no association between phthalate exposure and preterm birth [19,20]. The differences between studies may be due to the different metabolites measured, underscoring the need for consistency between studies.
LBW has also been associated with EDC exposure during gestation. A meta-analysis of 12 studies encompassing 8000 women and births, a decreased birthweight was associated with low levels of PCBs in maternal or cord blood, but not consistently with DDT . To add to the debate, a recent study  found a relationship between cord blood DDT and its metabolites and birth size and length, but not PCBs. In contrast, maternal preconception and first trimester PCB levels were associated with LBW . Other studies have found an association between LBW and phthalates , BPA  and PBD .
ENDOCRINE DISRUPTING COMPOUNDS AND OBESITY
The prevalence of obesity has notoriously increased in adults and children in the USA and worldwide. Studies have been inconsistent in finding associations between EDC (specifically POPs) and obesity in childhood (reviewed in  and ). Cross-sectional studies have suggested that phthalates are associated with obesity in adolescents and adults . A prospective study  indicated an association between certain phthalate metabolites and body size 1 year later. BPA is associated with obesity in adults [30,31], but has not been studied in children. Recognizing the accumulating data on the association between EDCs in obesity, the National Toxicology Program of the NIEHS convened a workshop to examine the issue. Participants of the workshop concluded that ‘the existing literature provides plausibility that exposure to environmental chemicals may contribute to the epidemic of diabetes and/or obesity’ [32▪▪].
EDCs are theorized to promote adipogenesis and lipid accumulation by interacting with the nuclear receptors peroxisome proliferator-activated receptors (PPARs), interacting with sex steroid or corticosteroid receptors, affecting cortisol or sex steroid metabolism, or inducing epigenetic modifications in obesity-related genes (reviewed in ).
Phthalates have been shown to interact with PPAR receptors in vitro; most studies have demonstrated that they interact with PPARα more readily than PPARγ. A recent study  indicated that mice with native PPARα exposed to high-dose phthalates were protected from weight gain on a high-fat diet, but mice with human PPARα did not experience the protective effect, indicating a species-specific effect of phthalates on the PPARα receptor. In the liver, phthalates activate PPAR receptors and the nuclear receptor constitutive androstane receptor, which is involved in pathways important for lipid and glucose metabolism .
Prenatal exposure to the LOAEL dose of BPA has been associated with the development of glucose intolerance in rats or metabolic syndrome in rats on a high-fat diet . If doses at ‘ecologically relevant’ levels are given prenatally (about 100 times less than LOAEL) to mice, no effect on glucose tolerance of rate of metabolic syndrome after a high-fat diet is observed . Exposed newborn mice, however, are larger at birth and weaning, but not at adulthood. If prenatally exposed to levels slightly higher than the LOAEL, rats have higher birth weights, but only female rats have higher weights at weaning that persisted into adulthood. When weaning tissues were examined, BPA-exposed mice had more white adipose tissue and higher expression of genes associated with lipogenesis, possibly contributing to the higher weights on a high-fat diet of both sexes . The mechanism that mediates BPA's effects is not clear. BPA can bind the PPARγ receptor [39–41] or nuclear and membrane oestrogen receptors (reviewed in ), although as discussed above, whether BPA is equally potent or less potent than oestradiol is a matter of debate. In addition, BPA has been shown to effect DNA methylation in certain genes, thus inducing changes in the epigenome at high doses . When doses in the considered low range were given to rodents, some genes undergo methylation, whereas other genes do not , indicating differences in gene susceptibility to the effects of BPA.
ENDOCRINE DISRUPTING COMPOUNDS AND DEVELOPMENT OF REPRODUCTIVE TRACT
Possible effects of EDCs on reproductive tract development have mostly been studied in males. The hypothesis that congenital malformations in the male reproductive tract (hypospadias and cryptorchidism) and adult male reproductive disorders are part of a spectrum of disorders due to impaired testes differentiation is termed the testicular dysgenesis syndrome (TDS) . This hypothesis was rooted in the observation that the incidence of cryptorchidism and hypospadias has been increasing in some countries, and regional differences in rates of these birth defects parallel regional differences in adult male semen quality, serum testosterone and testes size . Given the geographic differences and temporal changes in disease incidence, EDC exposure as a cause of some cases of TDS has been postulated . There is debate as to whether the incidence of hypospadias and cryptorchidism is universally increasing, as some countries do not report an increase in these defects .
There is a growing body of evidence about an association between phthalate exposure and congenital male reproductive disorders. In-utero exposure to phthalates has been associated with shorter anogenital distance in boys [48,49]. Prenatally exposed rodents also develop shorter anogenital distances and hypospadias, but whether effects are seen at low exposures varies between studies [50–54]. One study  did not see an effect of phthalates on female reproductive development. Phthalates inhibit foetal Leydig cell hormone production in rats, but experiments with human foetal testes indicate that although exposed testes have increased apoptosis of germ cells, steroidogenesis is not affected [56,57▪,58▪]. Phthalate effects on testes is not via oestrogen or androgen receptors, as testes from mice deficient in these receptors still have reduced germ cells; thus, the mechanism of phthalate action on foetal testes is unknown .
Maternal occupational exposure to BPA is associated with reduced anogenital distance in newborn boys , but cord blood BPA levels are not different between normal and cryptorchid boys . In rodents, the effect of prenatal BPA on male reproductive tract development is not as well studied. Some studies report an effect at low doses [62,63], but most do not [64–67].
Accumulating evidence indicates that prenatal or early life exposure to EDCs has the potential to affect foetal and later growth and child development. Animal studies control for EDC exposure dose, age and time of exposure, but often yield different results because studies use different methodologies. Nevertheless, conclusions can be and are drawn from the large body of published data. With continued work and implementation of novel study and analysis tools, the mechanisms of EDC action and disease causality will be determined.
S.D. is supported by NIH K08HD056139.
Conflicts of interest
There are no conflicts of interest.
REFERENCES AND RECOMMENDED READING
Papers of particular interest, published within the annual period of review, have been highlighted as:
- ▪ of special interest
- ▪▪ of outstanding interest
Additional references related to this topic can also be found in the Current World Literature section in this issue (p. 77).
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