The expression of the various SULT enzymes appears to be under specific temporal and spatial regulation during fetal development, suggesting that these tissues have different requirements during key phases of tissue differentiation and maturation for the modulation of the chemical mediators produced by the fetus.

The human fetus produces very large amounts (compared with the adult) of iodothyronine sulfates (E. Stanley, R. Hume, and M.W.H. Coughtrie, unpublished work). The high levels of SULT1A1 in various fetal tissues (Cappiello et al., 1991; Pacifici et al., 1988; Richard et al., 2001) may provide an important chemical defense function, particularly in the absence from the liver of the other major conjugating enzymes such as UDP-glucuronosyltransferases (Coughtrie et al., 1988) although the fetal kidney does express some UDP-glucuronosyltransferase (Hume et al., 1995).

An interesting observation was the expression of SULT1A1 in fetal brain, with the choroid plexus being the major site of expression. The primary function of this brain region is the production of cerebrospinal fluid. It is also the most highly vascularized tissue of the developing brain and therefore a potential portal of entry of circulating toxins that may result from maternal exposure. Thus it seems reasonable for this tissue to have a high degree of chemical defense (Richard et al., 2001). SULT1A3 is also expressed at low levels in the developing fetal brain; however, the germinal eminence appears to be the principal site of expression. This is where the majority of neuroblast cell division occurs during mammalian brain development (Richard et al., 2001).

Substantial interindividual variation was observed in SULT1A1 expression. One possible source of this variation is a common functional polymorphism in the

SULT1A1 gene (Arg213 to His), which causes substantially reduced SULT1A1 enzyme activity and protein stability in platelets in individuals homozygous for the variant allele (SULT1A1*2; Coughtrie et al., 1999; Raftogianis et al., 1997). This is a likely explanation for a major component of the variation observed in SULT1A1. Another possible source of variation is difference in tissue quality resulting from the range of postmortem intervals encountered. To address this phenomenon, Richard et al. (2001) sampled freshly obtained liver over a period of 12 h postmortem and determined SULT1A1 and 1A3 enzyme activities. The results clearly show that the enzyme activities are stable at least up to 12 h postmortem. Thus suggesting that instability of enzyme protein resulting from variable postmortem intervals is unlikely to be a major factor in the observed variability in enzyme activities. The variability most likely arises from a combination of genetic and environmental influences on enzyme activity and expression.

The physiological relevance of the high level of SULT1A3 in fetal liver is unclear. It is reasonable to propose that the expression of SULT1A3 in fetal liver has a protective function against the biological activity of catecholamines. The timing of the developmental switch from liver to gastrointestinal tract as the major site of SULT1A3 expression is not known, however. The major functions of gastrointestinal SULT1A3 in the adult are likely protection against the potentially toxic effects of ingested catecholamines in the diet and production of the large amounts of dopamine sulfate present in the circulation. Humans (and presumably other higher primates) have evolved a specific SULT for this purpose, with a high degree of selectivity towards catecholamines (Dajani et al., 1998). It is likely that a similar protective function would be also required by the newborn infant, perhaps not immediately after birth (assuming that breast milk is catecholamine poor), but certainly in infancy with the introduction of a weaning diet. Clearly, further studies are required to address this issue. It is also possible that SULT1A3 has a yet unknown function in the hemopoietic cells of the fetal liver and that the reduced expression with advancing gestation parallels the disappearance of these cells from the liver (Richard et al., 2001).

In conclusion, the human fetus expresses a wide array of sulfotransferase enzymes — certainly more than the adult — suggesting an important role for sulfation of endo- and xenobiotics during human development. This is in stark contrast to the situation in most experimental animal species, where sulfation is not well developed until after birth. There are clear spatial and temporal changes in SULT expression patterns during development (e.g., SULTs 1A3, 1E1, and 1C2 display a predominantly fetal expression, whereas SULT1B1 is predominantly expressed in adult tissues). Sulfation probably represents the major detoxification system in the developing human; therefore, a thorough appreciation of the distribution, regulation, and genetics of this system is essential if we are to fully understand the role of sulfation in protecting the fetus from external and internal insult. The studies discussed here have provided us with a valuable information resource, but clearly further investigations into sulfation during development are urgently required.

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Once your pregnancy is over and done with, your baby is happily in your arms, and youre headed back home from the hospital, youll begin to realize that things have only just begun. Over the next few days, weeks, and months, youre going to increasingly notice that your entire life has changed in more ways than you could ever imagine.

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