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2,3,7,8-Tetrachlorodibenzo-^-dioxin (TCDD) and related polycyclic and halogenated aromatic hydrocarbons (PAH/HAH) are ubiquitous environmental contaminants that are the unintentional by-products of industrial combustion (Bertazzi et al., 1989, 2001). Exposure to these compounds results in a variety of lesions in mammals, including alterations in liver function and lipid metabolism, weight loss, immune system suppression, endocrine and nervous system dysfunction, as well as severe skin lesions (Mukerjee, 1998). TCDD is of particular interest due to its persistence in biological tissues (DeVito et al., 1995; Ott and Zober, 1996). TCDD exposure occurs mainly through oral ingestion and is concentrated through the food chain. As TCDD accumulates in the adipose tissue, an individual's

'Abbreviations: ADH, alcohol dehydrogenase; AhR, aryl hydrocarbon receptor; ALDH, aldehyde dehydrogenase; Arnt, AhR nuclear translocator; atRA, all-trans RA; CRABP, cellular retinoic acid-binding protein; CRBPI, cellular retinol-binding protein type I; CYP450, cytochrome P450; GST, glutathione S-transferases; HAT, histone acetyltransferase; HDACs, histone deacetylases; HMTs, histone methyltransferases; LRAT, lecithin:retinol acyltransferase; MMPs, matrix metalloproteinases; RAL, retinal; RALDH, retinaldehyde dehydrogenase; RAR, RAR gene; RAREs, retinoic acid response elements; RARs, retinoic acid receptors; RBP, retinol-binding protein; RDH, retinol dehydrogenase; RE, retinyl ester; REHs, retinyl ester hydrolases; ROH, retinol; RXR, RXR gene; RXRs, retinoid X receptors; SCADs, short-chain alcohol dehydrogenases; SMRT, silencing mediator of retinoid and thyroid receptors; TCDD, 2,3,7, 8-tetrachlorodibenzo-p-dioxin; UGTs, UDP-glucuronosyltransferases; XREs, xenobiotic response elements; N-CoR, nuclear receptors corepressor; RA, retinoic acid.

body burden increases with age (DeVito et al., 1995). Although the exact mechanism underlying TCDD-mediated pathologies has not been completely elucidated, it is accepted that TCDD mediates the majority of these effects through activation of the aryl hydrocarbon receptor (AhR)-signaling pathway. However some AhR-independent effects of TCDD have been reported (Ahmed et al., 2005; Kondraganti et al., 2003; Park et al., 2003, 2005a,b; Sanders et al., 2005).

Retinoic acid (RA) is a natural product (lipid soluble hormone) derived from the metabolism of vitamin A. Vitamin A is an essential nutrient obtained from food either as preformed vitamin A (retinyl ester, retinol, and small amounts of RA) from animal products (eggs, liver, and milk) or as provitamin A (carotenoids) from fruits and vegetables (Fisher and Voorhees, 1996; Sporn et al., 1994). Vitamin A and its natural and synthetic derivatives are also known as retinoids. Dietary-derived all-trans RA (atRA) is the main signaling retinoid in the body and is vital for biological functions such as embryogenesis, growth and differentiation, as well as for vision and reproduction (Dragnev et al., 2000). Levels of atRA in the tissue are tightly regulated through its biosynthesis, metabolism, and storage in the liver

The observation that TCDD exposure results in lesions that are reminiscent of those observed in vitamin A-deficient animals of several species, including reduced growth, abnormal immune function, and developmental abnormalities, was the first suggestion that TCDD and related compounds had an impact on retinoid homeostasis and the RA-signaling pathway (Table I). In addition, the low endogenous retinoid levels in the kidney are increased by both exposure to TCDD (Hakansson and Ahlborg, 1985) and vitamin A deficiency (Morita and Nakano, 1982). These observations led to the hypothesis that TCDD and the AhR pathway were altering retinoid metabolism to mimic a vitamin A-deficient state. Indeed, a reduction in hepatic retinoid storage following exposure to TCDD was observed in a variety of species (Fletcher et al., 2001; Hakansson et al., 1991). Evidence for a link between TCDD exposure and vitamin A deficiency is further strengthened by findings demonstrating that rats pretreated with TCDD store and metabolize an oral dose of vitamin A as if they were deficient, despite considerable retinoids in storage (Hakansson and Ahlborg, 1985). Further, vitamin A-administered post-TCDD exposure accumulates to a lesser extent than in control rats, and endogenously stored retinoids are released more rapidly following TCDD treatment (Hakansson and Ahlborg, 1985; Hakansson and Hanberg, 1989; Kelley et al., 1998, 2000).

However, not all data support the conclusion that exposure to TCDD and related compounds results in a vitamin A-deficient state. Some data indicate that exposure perpetuates a vitamin A-excess state, particularly in reference to bone lesions (Jamsa et al., 2001; Lind et al., 2000) and teratogenesis (Abbott and Birnbaum, 1990; Peters et al., 1999). Therefore, although it is clear that

FIGURE 1. Vitamin A is obtained from food either as preformed vitamin A (retinyl ester), retinol, and small amount of RA from animal products (eggs, liver, milk) or as provitamin A (carotenoids) from fruits and vegetables. In the small intestine, retinyl esters (REs) are hydrolyzed to retinol (ROH) by retinyl ester hydrolases (REHs) on the cell surface of the enterocyte or in the intestinal lumen. While in the enterocyte, the ROH is bound to cellular retinol-binding protein II (CRBPII) and is reesterified back to RE by lecithin:retinol acyltransferase (LRAT). The REs are incorporated along with other dietary lipids into chylomicrons and transferred into the lymphatic system. These chylomicrons are specifically internalized into the hepatocytes of the liver, where the RE is converted to ROH through the action of REHs. Within the hepatocytes and stellate cells, the ROH is bound to CRBPI which is thought to transfer the ROH to the RBP for transport out of the liver, where the RBP-ROH complex is transferred to the circulation for use in extrahepatic tissues. In situations where vitamin A is in excess, it is stored in the stellate cells as RE.

FIGURE 1. Vitamin A is obtained from food either as preformed vitamin A (retinyl ester), retinol, and small amount of RA from animal products (eggs, liver, milk) or as provitamin A (carotenoids) from fruits and vegetables. In the small intestine, retinyl esters (REs) are hydrolyzed to retinol (ROH) by retinyl ester hydrolases (REHs) on the cell surface of the enterocyte or in the intestinal lumen. While in the enterocyte, the ROH is bound to cellular retinol-binding protein II (CRBPII) and is reesterified back to RE by lecithin:retinol acyltransferase (LRAT). The REs are incorporated along with other dietary lipids into chylomicrons and transferred into the lymphatic system. These chylomicrons are specifically internalized into the hepatocytes of the liver, where the RE is converted to ROH through the action of REHs. Within the hepatocytes and stellate cells, the ROH is bound to CRBPI which is thought to transfer the ROH to the RBP for transport out of the liver, where the RBP-ROH complex is transferred to the circulation for use in extrahepatic tissues. In situations where vitamin A is in excess, it is stored in the stellate cells as RE.

TCDD has an impact on retinoid homeostasis, it is less clear as to whether it pushes the system toward a vitamin A-deficient state or simulates a vitamin A-excess state.

A situation where TCDD appears to mimic vitamin A excess is demonstrated by the synergistic effect of TCDD and atRA on palatal development in mice. Both excess atRA and TCDD cause developmental defects in mice and share a common target, the developing palate (Birnbaum et al., 1989), and data demonstrate a synergistic effect of TCDD and atRA on palate defects. These studies show that coadministration of atRA and TCDD result in 100% cleft palate formation at lower concentrations than required when atRA or TCDD is administered separately. The increase in cleft palate is attributed to increased expression of growth factors such as transforming growth factor (TGF)-bl (Abbott and Birnbaum, 1990). This effect can be recapitulated in

TABLE I. TCDD Exposure Produces Lesions That Are Similar to Vitamin A Deficiency in a Variety of Animal Model Systems

Vitamin A deficiency

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