Abstract

Endocrine-disrupting chemicals (EDCs) are exogenous substances that interfere with hormone synthesis, metabolism, or action. In addition, some of them could cause epigenetic alterations of DNA that can be transmitted to the following generations. Because the developing organism is highly dependent on sex steroids and thyroid hormones for its maturation, the fetus and the child are very sensitive to any alteration of their hormonal environment. An additional concern about that early period of life comes from the shaping of the homeostatic mechanisms that takes place also at that time with involvement of epigenetic mechanisms along with the concept of fetal origin of health and disease. In this chapter, we will review the studies reporting effects of EDCs on human development. Using a translational approach, we will review animal studies that can shed light on some mechanisms of action of EDCs on the developing organism. We will focus on the major hormone-dependent stages of development: fetal growth, sexual differentiation, puberty, brain development, and energy balance. We will also discuss the possible epigenetic effects of EDCs on human development.

Keywords

Fetal growth; Puberty; Sex differentiation; Brain development; Cognitive function; Epigenetics; Energy balance; Bisphenol A; Polychlorinated biphenyls

1 Introduction

Endocrine-disrupting chemicals (EDCs) are exogenous substances that interfere with hormone synthesis, metabolism, or action. Moreover, it appears that some of them could cause epigenetic alterations of the DNA that can be transmitted to the following generations. Animal and human studies have brought evidence that EDCs affect male and female reproduction, thyroid function, and control of energy balance. They could increase the risk of breast or prostate cancer as well as the risk of metabolic syndrome (Diamanti-Kandarakis et al., 2009). Because the developing organism is highly dependent on sex steroids and thyroid hormones for its maturation, the fetus and the child are very sensitive to any alteration of their hormonal environment. An additional concern about that early period of life comes from the shaping of the homeostatic mechanisms that takes place also at that time with involvement of epigenetic mechanisms along with the concept of fetal origin of health and disease (Gluckman, Hanson, & Low, 2011). Most studies have identified the perinatal period as a specific window of sensitivity. However, most of the reported effects were observed later in life. A review of the existing literature underlines the need for identification of early markers of exposure to EDCs. In this chapter, we will review the studies reporting effects of EDCs on human development. Using a translational approach, we will review animal studies that can shed light on some mechanisms of action of EDCs on the developing organism. We will focus on the major hormone-dependent stages of development: fetal growth, sexual differentiation, puberty, brain development, and energy balance. We will also discuss the possible epigenetic effects of EDCs on human development.

2 Challenges in Evidencing Endocrine Disruption

Before we discuss the different aspects of growth and maturation that are possibly altered by endocrine disruption, it is important to be aware of some challenges (Table 1.1) that we face in this area and that are relevant to all the specific aspects we will discuss later. Because the persistence of EDCs in the body and the environment is highly variable between few days such as for bisphenol A (BPA) (Rudel et al., 2011) and several decades such as for 1,1-dichloro-2,2-bis (p-chlorophenyl) ethane (DDE) (Kirman, Aylward, Hays, Krishnan, & Nong, 2011), linking any disorder with previous EDC exposure is most difficult especially when latency is long between exposure and manifestation of health consequences. Also, the effects of EDCs can vary depending on the critical periods and duration of exposure. As will be discussed in the next sections, prenatal and early postnatal life is a period characterized by organization of the mechanisms that will drive homeostatic processes such as control of reproduction and energy balance. Obviously, EDC interference during those organizing periods could have much more severe consequences than later in life. Among the features of endocrine systems, they involve a cascade of activation or inhibition at different levels where EDCs play disturbing roles. We will see illustrations with puberty and reproduction that can be altered by effects at the hypothalamic–pituitary level as well as in target tissues (e.g., breasts). This also applies to energy balance through involvement of hypothalamic centers as well as fat tissue. Moreover, the physiological feedback systems through factors such as sex steroids and leptin, respectively, will also be disturbed by EDCs. Further challenges come from observations that are inconsistent with classical toxicology: Low-dose mixtures that are consistent with human exposure can have effects not conforming to simple additive models (Christiansen et al., 2012; Kortenkamp, 2008); the dose–response relationship can be nonmonotonic such as seen for BPA with U-shaped dose–response curves (Vandenberg et al., 2012). For both reasons, setting a threshold dose for EDC effects has become meaningless. A final issue is the highly variable latency between exposure and effects including multigenerational impact.

3 Endocrine-Disrupting Chemicals and Fetal Growth

Data concerning EDCs effects on fetal growth are scarce. However, one can hypothesize that fetal growth could be altered by endocrine disruption. Indeed, several EDCs cross the placental barrier and accumulate in the embryo or amniotic fluid (Diamanti-Kandarakis et al., 2009). The fetus is particularly sensitive to the effects of EDCs because of its dependency on hormones for development (Diamanti-Kandarakis et al., 2009). Moreover, animal studies have shown that most biotransformation enzymes are not produced until after birth (Pottenger et al., 2000), which means that fetuses might be exposed longer to higher concentration of EDCs. Clearance of BPA from fetal circulation, for instance, is slower than from maternal circulation (Takahashi & Oishi, 2000). It remains very complex to evaluate the effects of prenatal exposure to EDCs on fetal growth in human. Most studies focus on correlations between birth weight and serum or urinary levels of EDCs during pregnancy or at birth. Because of some limitations discussed later, few studies have identified a link between prenatal exposure to EDCs and fetal growth. We will review here some of the most significant human data as well as supporting animal studies.

For BPA, for instance, few studies have been published and lead to various results. Miao et al. have shown that maternal exposure to BPA in the workplace was associated with decreased birth weight (Miao et al., 2011b) after adjusting for confounding factors. BPA exposure during pregnancy was evaluated through personal air-sampling measurements and exposure history. Chou et al. (2011) reported an increased risk of low birth weight in male newborn exposed prenatally to higher levels of BPA, while Padmanabhan did not report any effect of BPA neither on birth weight nor on length (Padmanabhan et al., 2008). In both studies, prenatal exposure to BPA was evaluated through a single measurement of BPA in maternal or cord blood. Philippat et al. have shown an association between urinary BPA concentration (in one urinary sample between 24 and 30 weeks of gestation) and birth weight following an inverse U shape (Philippat et al., 2012). However, serial urinary measurements before and during pregnancy have been shown to be highly variable and this variability was even increased during pregnancy (Braun et al., 2011a). Given this variability, it appears that more than one sample may be necessary to adequately classify gestational exposure to BPA especially because the half-life is short and the clearance rate is rather rapid as opposed to other EDCs. Rudel et al. (2011) showed that urinary excretion of BPA fell significantly 2–3 days after changing habits regarding food, drinks, and containers. In addition, for feasibility reasons, most studies focus on one or a few compounds and might miss exposure to other EDCs. Another limitation of current...