Due to children physiological immaturity, they are particularly vulnerable to pollutants. Transplacental transfer that occurs during the fetal period, Breast feeding are also significant sources of exposure to pollutants [7].

At the early weeks of development, the fetus is very sensitive to teratogenic insults. Environmental chemicals can cause death of cells, alter normal growth of tissues, or interfere with normal cellular differentiation or other morphologic processes, which  may cause fetal loss, growth restriction, birth defects, or impaired neurologic performance [8].

Dose and timing are important determinants of fetal effects. Thus, exposures occurring at “critical periods” in development have specific effects related to the developmental stage of the fetal organs and exposure to the same agent at different times may cause different anomalies. Exposure to these chemicals at the last months of pregnancy may induce only minor abnormalities, but can still impair growth  and development [8].

Central nervous system (CNS) of the fetus is most vulnerable system to developmental injury throughout pregnancy. The fetal brain is particularly sensitive to toxins due to incomplete blood-brain barrier; continued myelination, proliferation and pruning of neurons; and sensitivity to hypoxia. Exposure to chemicals can adversely affect normal development.

Environmental chemicals associated with  normal growth disruption can be classified into two main groups, Endocrine disruptors and Heavy metals.[9].

An endocrine-disrupting compound was as “an exogenous agent that interferes with synthesis, secretion, transport, metabolism, binding action, or elimination of body hormones and are responsible for growth,  homeostasis, reproduction, and developmental process.”

Endocrine-disruptors induce their effects by acting through many receptors, as  thyroid receptors (TRs), estrogen receptors (ERs), progesterone receptors, androgen receptors (ARs), and retinoid receptors.. Many enzymatic pathways involved in steroid biosynthesis and/or metabolism, and numerous other mechanisms that converge upon endocrine and reproductive systems[10].

Endocrine disruptors  are different chemicals include synthetic materials used as industrial solvents/lubricants and their byproducts [polychlorinated biphenyls (PCBs), polybrominated biphenyls (PBBs), dioxins], bisphenol A (BPA), phthalates, pesticides [methoxychlor, chlorpyrifos, dichlorodiphenyltrichloroethane (DDT)], fungicides (vinclozolin), and pharmaceutical agents [diethylstilbestrol (DES)] [11].

Bisphenol A (BPA)

BPA is a monomer used to harden polycarbonate plastics, and some epoxy resins. These plastics are used in plastic bottles, and some medical devices. The BPA containing epoxy resins are used to coat metal products, such as food cans, and are also used in some dental sealants and composites. The primary route of exposure is ingestion through the diet, since BPA can migrate into food from food and beverage containers [12].

A report from the United States Department of Health and Human Services’ National Toxicology Program (NTP) has been done to discuss effects of bisphenol A on human growth and reproduction. This report concluded that there is “some concern” for neural and behavioral effects in fetuses, infants, and children at current human BPA exposures [13].

Phthalates

These chemicals recently received considerable attention due to its widespread use and reported endocrine disruption activities. Phthalate esters are chemicals used as plasticizers in plastics to impart flexibility. They are also used as emulsifying agents, surfactants, and lubricants in numerous industrial, medical, and cosmetic products. These compounds can leach with chronic use and ultraviolet light exposure, making them available for biological exposure. Detectable levels of various phthalate metabolites have been observed in the urine of the general population by the United States Centers for Disease Control and Prevention.

Endocrine-disrupting activities of phthalates  recognized by the National Toxicology Program (NTP) in 1991 demonstrated alterations to reproductive tract structure, degeneration of seminiferous tubule, and sperm counts abnormalities in male pups exposed to di-(n-butyl) phthalate (DBP) during mid to late gestation [13].

Experiments done on rats showed that phthalates exhibit dose-dependent effects on the developing male reproductive tract, including hypospadias, hypo spermatogenesis, increased seminiferous cord diameter, cryptorchidism, and the formation of multinucleated germ cells [14].

The antiandrogenic mode of action was confirmed when it was shown that DBP and its active monoester metabolite, mono-(n-butyl) phthalate (MBP), could lower both the expression of steroidogenic genes and intratesticular testosterone content without interacting with the AR.

Airborne polycyclic aromatic hydrocarbons (PAHs)

Polycyclic aromatic hydrocarbons (PAHs) are released into the air from incomplete combustion of fossil fuels, tobacco smoke, and other organic material. Air pollution and environmental tobacco smoke are the most common sources of PAH exposure. PAH exposure may adversely affect children’s IQ. One study measured PAH exposure through personal air sampling in non-smoking black or Dominican-American women during the third trimester of pregnancy and then tested their 249 children with neurobehavioral testing (Wechsler Preschool and Primary Scale of Intelligence-Revised) at age 5 years. Multivariate regression models were used to test associations between prenatal PAH exposure and IQ. After adjustments for various factors, high PAH levels (above the median of 2.26 ng/m3) were inversely associated with decrements in full-scale IQ and verbal IQ scores. Children in the high exposure group had full-scale and verbal IQ scores that were 4.31 and 4.67 points lower, respectively, than those of less-exposed children [15].

Polychlorinated biphenyls (PCBs)

They are persistent, lipophilic contaminants that were used as heat transfer fluids in transformers until 1970s. They are still detected in children’s blood at low levels and have been identified as endocrine disruptors that could interfere with fetal and postnatal growth and development [4].

Particularly, children are vulnerable to these contaminants due to their physiological immaturity and the transplacental transfer that occurs during the fetal period. Many health and neurobehavioral effects of pre and post natal PCB exposure have already been reported among children [16].

Some of chlorophenols, such as 2,4,6-trichlorophenol (2,4,6-TCP), 2,4- dichlorophenol (2,4-DCP), and pentachlorophenol (PCP) have been considered as priority pollutants by the US Environmental Protection Agency (EPA), European Commission (EC) Environmental Directive (2455/2001/EC) and China due to their high toxicity, persistence and bioaccumulation potential [16].

Exposure to PCPs has attracted growing public concern because certain CPs have been suspected to disrupt the endocrine function and thus affect reproduction and development in human. For example, paternal PCP exposure was associated with spontaneous abortion in humans, and obesity. Pubertal development in adolescent girls  were affected  by exposure to 2.5-DCP due to its potential endocrine disrupting activity. Moreover, exposure to high levels (>3.58 mg/g) of urinary 2,4,6-TCP may increase the risk of attention deficit hyperactivity disorder among US school-aged children [17].

Also paternal exposure to chlorophenates in the sawmill industry was associated with certain developing congenital anomalies of their offspring. It was reported that maternal occupational exposure to CPs might be associated with small for gestational age infants at birth. However, few studies have focused on associations between prenatal multiple CPs exposure in the general pregnant population and adverse birth outcomes including weight, length and head circumference at birth [18].

Perfluorinated Compounds

Perfluorinated compounds such as the perfluoroalkyl acids (PFAAs) and their derivatives are important man-made chemicals that have wide consumer and industrial applications. They are relatively contemporary chemicals, being in use only since the 1950s and until recently have been considered as biologically inactive. However, during the past decade, their global distribution, environmental persistence, presence in humans and wildlife, and adverse health effects in laboratory animals have come to light, generating scientific, regulatory, and public interest on an international scale [19].

Exposure to PFAAs can induce reduction of thyroid hormones. In addition to thyroid hormone disruption, changes in sex steroid hormone biosynthesis by PFAAs have also been reported. In brief, (PFAAs) has been shown to decrease serum and testicular testosterone and to increase serum estradiol in male rats, presumably via induction of hepatic aromatase [20].

Exposure to (PFAAs) during pregnancy in rats and mice produced overt anatomical defects in offspring (such as cleft palate) only at high doses, while other morphological abnormalities noted in fetuses chiefly reflected developmental delays. Early pregnancy loss was noted with (PFAAs) exposure but only at very high doses, and the etiology of this effect is not clear. No frank  fetotoxicity was observed after gestational exposure to PFBA or PFDA.

Endocrine disruptors and obesity

Obesity, defined as body fat greater than 25% in men or greater than 30% in women, is fast becoming a significant human health crisis.

The estrogenic pharmaceutical chemical DES illuminates the relationship between perinatal exposures and latent development of high body weight and obesity. Moreover, there is a complex relationship between the concentration of estrogen to which pregnant animals are exposed and the weight of the offspring in adulthood.  Specifically, according to a study by Newbold et al., mice neonatally exposed to DES experience increased body weight in adulthood associated with excess abdominal body fat [21]

Heavy metals and growth

Lead

Lead is a naturally occurring bluish-gray metal present in small amounts in the earth’s crust. Although lead occurs naturally in the environment, anthropogenic activities such as fossil fuels burning, mining, and manufacturing contribute to the release of high concentrations. Lead has many different industrial, agricultural, and domestic applications [22].

Exposure to lead occurs mainly via inhalation of lead-contaminated dust particles or aerosols and ingestion of lead-contaminated food, water, and paints. Adults absorb 35–50% of lead through drinking water, and the absorption rate for children may be greater than 50%. Lead absorption is influenced by factors such as age and physiological status. In the human body, the greatest percentage of lead is taken into the kidney, followed by the liver and the other soft tissues such as heart and brain; however, the lead in the skeleton represents the major body fraction [22].

Elevated blood lead levels adversely affect prenatal growth, but this has not been noted in all studies. A frequent finding among children is reduced length/stature in association with increased blood lead levels. Many studies have investigated the association between lead exposure and children’s growth. The majority of these studies focused on postnatal exposure and found some evidence of associations between lead exposure during childhood and children’s growth.  Lead is particularly dangerous for the fetus because it crosses the placenta and may cause adverse birth outcomes, including low birth weight and preterm birth [23].

There are many ways by which lead might interfere with growth in early life. Lead may alter bone cell function directly (through changes in circulating hormones or by impairing their ability to synthesize or secrete other components of the bone matrix) or indirectly (by perturbing the ability of bone cells to respond to hormonal regulation, or by effecting or replacing calcium in the active sites of its messenger system [24].

It may induce a reduction of circulating maternal thyroid hormone that impacts overall growth trajectories. Lead could disrupt heme-mediated generation of critical enzymes involved in metabolism and other metabolic functions such as the synthesis of vitamin D which regulates calcium metabolism. Further, lead may impair growth by altering the hypothalamic-pituitary-growth axis function [13].

Greater reductions in linear growth were observed at higher blood lead levels. The observations were consistent with experimental data suggesting a major influence of lead on linear bone growth, specifically proliferation of chondrocytes, hypertrophy and matrix calcification at the growth plates of long bones. Other potential targets for lead are reduced osteoblast activity and bone remodeling [24].

Lead and neurobehavioral Development

The nervous system is the most vulnerable target of lead poisoning. Headache, poor attention spam, irritability, loss of memory, and dullness are the early symptoms of the effects of lead exposure on the central nervous system.

Among 6 year old children, for example, elevated blood lead levels had a negative influence on visual- motor control, bilateral coordination, and upper limb speed of movement, dexterity and fine motor coordination, and on finger tapping speed. Visual-motor integration, eye-hand coordination and spatial relations were reduced among 8–10 year old children with elevated blood lead. Thus, neurobehavioral effects of lead seemingly persist and perhaps the deficits may be irreversible, i. e., they do not diminish or disappear as the child grows [25].

Lead and Sexual Maturation

Information on the influence of elevated blood lead levels on indicators of biological maturation commonly used in growth studies is limited largely to age at menarche and to a lesser extent stages of puberty (breast and pubic hair development in girls, genital and pubic hair development in boys) using criteria described by Tanner. Data relating blood lead to skeletal maturation, the only maturity indicator that spans childhood through adolescence, are apparently not available. Longitudinal data for height that span adolescence are required for estimates of the timing and magnitude of the adolescent growth spurt associated with elevated blood lead [26].

Blood lead levels 3 μg/dL were associated with later estimated attainment of stages of breast and pubic hair maturation in American girls from the Third National Health and Nutrition Examination Survey, 1988–1994 (NHANES III). Later attainment of stages of puberty was most apparent in American Black girls and to a lesser extent in Mexican American girls with 3.0 μg/dL of blood lead compared to those with 1.0 μg/dL. Later pubertal maturation was noted in American White girls with 3.0 μg/dL of blood lead, but the effect was not statistically significant [26].

Corresponding data for lead and sexual maturation of boys are limited to a prospective study of testicular volume and stages of pubic hair and genital maturation in Russian boys. Later onset of puberty was associated with blood lead levels 5.0 μg/dL compared to boys with 5.0 μg/dL in two separate analyses of the same data base. [27].

Arsenic and Cadmium

Both arsenic exposure and cadmium exposure are inversely associated with infant size at birth, and this relationship may vary between boys and girls [28].

Cadmium and arsenic have endocrine disrupting properties, which may disrupt growth in young children, particularly in a sex-specific fashion. Evidence in humans and experimental animals suggests that cadmium disrupts steroidogenesis, particularly in the placenta, and acts as an endocrine-disrupting chemical, capable of mimicking or inhibiting the functions of endogenous estradiol [29].

Cadmium exposure in adolescents was associated with decreased height and body mass index, as well as lower circulating levels of estradiol and testosterone in the blood [30].

Additionally, in experimental animals, high doses of cadmium have been found to lower plasma concentrations of insulin-like growth factor 1, a hormone critical for childhood growth. Arsenic may affect insulin signaling and glucose metabolism, eventually leading to glucose intolerance and diabetes in exposed populations [30].

Early disruption of glucose uptake by tissues may plausibly lead to impaired growth. This mechanism may be more pronounced in children with better overall nutrition, potentially explaining our observations of arsenic’s effects after stratification by SES.

Shortly, it is proved that environmental exposures to cadmium and arsenic during early life may contribute to poor growth.

Conclusions:

Several environmental pollutants as endocrine disruptors and heavy metals  have been suspected of having effects on the growth and development of humans.

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