Gastrointestinal Tract Raman Sreedharan, MD*, and Devendra I. Mehta, MD‡ ABSTRACT. The developing gastrointestinal tract maturation. In addition to recognized environmental from conception to adolescence is in constant direct in- toxic agents, in this rapidly changing world, the ar- teraction with an increasingly complex environment. ray of novel toxins that make their way into the GI This sets up the potential for unrecognized acute as well tract poses significant threats and needs to be better as chronic disorders, some of which may be difficult to understood. pinpoint in a developing infant and child, given the wide variations that exist. It is startling to note how early some environmental toxins can come into contact with the ROUTES OF ENTRY developing human, where vulnerability may be height- ened and maturation of detoxifying pathways may be Environmental toxins taken orally may be modi- incomplete. Although the complex process of recogniz- fied in the GI tract by gastric pH, digestive enzymes, ing, detoxifying, and avoiding the toxic substance by the or even bacteria that live in the intestines. Environ- body has presumably evolved over a substantial period mental toxins that are internalized by skin absorp- of time, in this rapidly changing world, the array of novel tion or by inhalation may be secreted into the lumen toxins that make their way into the gastrointestinal tract through the biliary system and lead to toxicity. Also, is increasing. There remain many gaps in understanding toxins suspended in air make their way into the the effects of environmental toxins on all of the devel- opmental stages from conception to adolescence. Al- intestinal tract by drainage from the sinuses into the though threshold levels have typically been derived from pharynx and esophagus. adult or animal data, factors such as size, relative differ- ences in consumption in proportion to size especially in infancy, and variable physiologic maturation of meta- Mucosal Factors bolic pathways are not well understood. The vulnerabil- A thin preepithelial water layer (“unstirred water ity may be further accentuated by physical factors that layer”) and a mucous layer cover the intestinal mu- alter with maturity, such as permeability and critical cosa and limit absorption to toxins that can diffuse. times during organogenesis or organ maturation. Also of Lipid solubility will increase the absorption, as will concern is how little is known about low-dose, long-term smaller particle size. The intestinal luminal pH plays exposure, as well as any interplay with common ill- nesses. This article focuses on environmental toxins that a role by altering the ionization of molecules so that have been shown to have toxic effects on the gastrointes- nonionized forms of the weak bases and acids are tinal tract. Pediatrics 2004;113:1044–1050; development, absorbed more rapidly than the ionized forms. The intestinal mucosa, toxins. mucous binding and absorption of metals such as cobalt, zinc, lead, and iron are pH dependent. The rapid turnover of the intestinal mucosa helps ABBREVIATIONS. GI, gastrointestinal; CYP, cytochrome P450. to protect the mucosa and the body against toxic injuries. The regenerative capacity after injury and he gastrointestinal (GI) tract, like the skin and damage are remarkable because of the mucosa’s ca- the respiratory system, is in constant direct pacity for rapid turnover and has been studied ex- Tinteraction with the environment. The func- tensively with the dog ileum after interruption of tions of the GI tract as a protective barrier are as blood supply. The lower two thirds of the crypts important as its functions of digestion and absorp- form the proliferative compartment of the mucosa tion but vary with age and maturity. The large sur- and, because of their location, are protected from the face area and prolonged exposure time increase risk reach of toxic substances. This could explain the low of toxin-mediated damage, and increased permeabil- incidence of small intestinal carcinoma despite its ity in early infancy may augment this further. Com- large area. The presence of cytotoxic substances stim- plex processes of recognizing, detoxifying, and ulates exfoliation of the cells into the lumen. Also, avoiding toxic substances also undergo physiologic studies have demonstrated that during the periods of cytotoxic exposure, glucose absorption and enzyme From the *Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania; activities are decreased. and ‡Nemours Children’s Clinic, Wilmington, Alfred I. duPont Hospital for Children, Wilmington, Delaware. Received for publication Oct 7, 2003; accepted Oct 20, 2003. Detoxification Reprint requests to (D.I.M.) Division of Gastroenterology, NCC-Wilming- The detoxification mechanism that exists in the ton, Alfred I. duPont Hospital for Children, Box 269, Wilmington, DE 19899. intestinal mucosa serves as a second-line barrier and E-mail: [email protected] PEDIATRICS (ISSN 0031 4005). Copyright © 2004 by the American Acad- has been studied well in animal models and also to emy of Pediatrics. an extent in humans. Regional differences are also 1044 PEDIATRICS Vol.Downloaded 113 No. 4 from April www.aappublications.org/news 2004 by guest on September 26, 2021 noted, with most enzymes diminishing in expression DIFFERENTIAL VULNERABILITIES AND CRITICAL in distal small bowel. Studies conducted in rat small WINDOWS OF EXPOSURE OF THE GI TRACT: intestines have shown that cytochrome P450 (CYP), FROM CONCEPTION TO ADOLESCENCE NADPH-CYP reductase, p-nitroansole o-demethyl- ase, and benzpyrene hydroxylase activities are ex- Antenatal pressed 3 to 10 times more in the upper villous cells Maternal diet is the major factor governing expo- of the proximal small bowel.1 This may represent an sure at conception and in utero. The rapidly growing evolutionary adaptation as the highest concentra- fetus is susceptible, but the placenta acts as barrier. tions of environmental toxins are presented to the Although transplacental transport of environmental upper small bowel. toxins, such as lead and mercury, is recognized, tox- Pharmacokinetic differences may play a part in the ins in amniotic fluid, such as nicotine and cotinin, have been poorly studied for possible absorption by age-related differences in the incidence of adverse 7 effects of environmental toxins. Phase I reactions either the skin or the GI tract. Specific GI effects of depend predominantly on CYP enzymes, particu- maternal smoking are cleft lip and palate and post- natal growth retardation. larly as most drugs are lipophilic. Specific CYP en- zymes are developmentally regulated and affect pro- Postnatal Changes duction of metabolites, including possibly toxic ones, The postnatal maturing GI tract undergoes several as well as efficacy of drug therapy. Thus, CYP2D6 Ͻ changes that may significantly alter risk of toxicity activity is 1% of the adult level and remains low (Table 1). Changes in vulnerability to toxins as a until after 28 days of age. Drugs that use these path- ␤ result of many of these factors have largely been ways, such as -blockers and tricyclic antidepres- studied only in animal models and may not be ap- sants, could result in toxicity, including anticholin- plicable. Mucosal permeability to macromolecules 2 ergic gastrointestinal side effects. Conversely, diminishes in the first few days of life in humans but CYP3A, used to metabolize a large number of drugs, diminishes much later in animals. In addition, influ- is present in significant amounts in the fetal liver. ence of GI disease, more common in infancy and Extraintestinal CYP3A may be the most important early childhood, may alter absorption by changes in enzyme for orally administered drugs, although the motility, mucosal integrity, or surface area. Lead ontogeny has not been evaluated.3 Indeed, the activ- (Table 2) and cadmium absorption is markedly in- ity of these enzymes is greater in infants and children creased in early childhood. Absorption of both met- compared with adolescents and adults. In children, als increases in iron deficiency states as the number CYP-catalyzed metabolism is increased, and uridine of carriers shared by all 3 metals increases in the diphosphate-glucuronosyltransferase–catalyzed me- duodenum.8 tabolism is not significantly different from that in Low gastric acid production in infants may lead to adults.4 increased small bowel bacterial overgrowth. Methe- Phase II enzymes also show developmental regu- moglobinemia in infants may have resulted from lation that affect drug metabolism. N acetyl trans- conversion of nitrate from contaminated well water ferase 2 activity is low in infants and children to nitrite.9 younger than 3 years, essentially making them phe- The disposition of drugs and other environmental notypically resemble slow metabolizers. By extrapo- toxins varies at different stages of child develop- lation, slow metabolizers are at greater risk of toxic- ment. Generally, absorption is slower in younger ity, including toxic epidermal necrolysis and children. The extracellular volume is higher, and the Stevens-Johnson syndrome.5 In contrast, higher red extent of protein binding is lower. Renal excretion is blood cell thiopurine methyltransferase activity ob- lower, and environmental toxin metabolic pathways served in newborn infants may have therapeutic im- that depend on glucuronidation activity in the liver may increase concentration of toxins. Animal studies plications in terms of levels of azathioprine and show diminished