Cytosolic sulfotransferases in endocrine disruption

The mammalian cytosolic sulfotransferases (SULTs) catalyze the transfer of a sulfuryl (SO₃) group from 3′-phosphoadenosine-5′-phosphosulfate (PAPS) to oxygen and nitrogen atoms within a diverse array of drugs, environmental chemicals, and other xenobiotics as well as endogenous hormones, neurotransmitters, and bile acids [1–11]. Many endocrine-disrupting chemicals (EDCs) are among the xenobiotics that interact with SULTs either directly as substrates and inhibitors or indirectly as agents that regulate the expression of these enzymes. EDCs alter the functioning of the endocrine system and elicit adverse health effects through disruption of the actions of hormones or hormone receptors, and a recent consensus statement addresses their key characteristics, sources, and related toxicities [12].

Many EDCs interact with human SULTs as substrates or inhibitors, and the chemical structures of several representative examples are shown in Figure 1. The sulfation of such molecules can be an important component in their detoxication and excretion, but other consequences may occur. Since the sulfation of endogenous estrogens, androgens, thyroid hormones, and other regulatory molecules often results in signal-termination, inhibitors of the specific SULTs involved can alter the concentrations of active forms of the hormones within tissues. Additionally, the sulfation of some EDCs may produce sulfate esters that are ligands for hormone receptors, thus altering the signaling processes that are under the control of those receptors. Finally, the sulfation of EDCs may also provide a mechanism for transport, uptake, and intracellular regeneration of the original EDC through the action of sulfatases. This review focuses on those human SULTs that are important in the metabolism and toxicities of EDCs and on the potential roles that these interactions have in disrupting cellular functions that are mediated by endocrine hormones.

The cytosolic sulfotransferases constitute a superfamily of enzymes with a system of nomenclature that is based on protein sequences and gene families [13]. This nomenclature utilizes a prefix, SULT for the protein or SULT for the gene, followed by a numeral that delineates the protein/gene family (at least 45% amino acid sequence identity). A capital letter is then used to designate the subfamily (at least 60% amino acid sequence identity), and this is followed by a second numeral to indicate the individual enzyme [13]. Single nucleotide variants are indicated by an asterisk and additional number after the second numeral. A lowercase letter following the second numeral identifies a transcriptional or splice variant. Thus, SULT1A1*3 is a single nucleotide variant, and SULT1A1b is a specific splice variant, of SULT1A1. In humans, enzymes of the SULT1 and SULT2 families (i.e., SULT1A1, SULT1A2, SULT1A3, SULT1B1, SULT1C2, SULT1C3, SULT1C4, SULT1E1, SULT2A1, SULT2B1a, and SULT2B1b) display the broadest specificity for substrates [2,4,7,8,10,14,15]. SULT4A1 and SULT6B1 are also expressed in humans, but their substrate specificities and metabolic functions are not yet as fully defined [16–19].

As with many xenobiotic-metabolizing enzymes, the individual SULTs possess distinct yet overlapping specificities for substrates [1,2,5,8,15,20]. Differences in individual amino acids at the substrate-binding sites of the SULTs are primarily responsible for these distinctions even though many aspects of the overall 3D structures of the SULTs are strongly conserved [7]. The SULT1A1, SULT1A2, and SULT1A3 enzymes have varied abilities to catalyze the sulfation of endogenous steroids, thyroid hormones, and neurotransmitters as well as a wide range of xenobiotic phenols, alcohols, N-hydroxy arylamines, oximes, secondary nitroalkanes, and secondary amines [10,21,22]. SULT1B1 catalyzes the sulfation of thyroid hormones in addition to many xenobiotic phenols [22,23]. Other family 1 SULTs that also catalyze the sulfation of iodothyronines include SULT1A1, SULT1A3, SULT1E1, SULT1C2, and SULT1C4, although catalytic efficiencies vary with the individual iodothyronine substrate [24]. SULT1E1 catalyzes the sulfation of a diverse array of phenols, but it has often been referred to as the human estrogen sulfotransferase due to its highly favorable kinetic properties in relation to the likely intracellular concentrations of estrogens [25,26].

Early studies on family 2 SULTs often referred to them as hydroxysteroid sulfotransferases, bile-acid sulfotransferases, or alcohol sulfotransferases. Indeed, SULT2A1 catalyzes the sulfation of many physiologically important steroids such as dehydroepiandrosterone (DHEA), androsterone, Δ⁴-3-ketosteroids, 25-hydroxyvitamin D₃, bile acids, and others [5,8,27–30]. However, it also catalyzes the sulfation of many xenobiotics containing chemical functional groups ranging from phenols and alcohols to some amines and arylhydroxamic acids [1,2,10]. Depending upon the transcriptional start site used, the expression of the SULT2B1 gene yields one of two enzymes, SULT2B1a or SULT2B1b, that have different N-terminal sequences. The structural and functional differences between SULT2B1a and SULT2B1b as they relate to the sulfation of physiological steroids and xenobiotics have been reviewed [2,8,31,32].

The actions of some EDCs are dependent upon the inhibition of SULTs that catalyze the sulfation of hormones, and several kinetic mechanisms for this inhibition are possible. Competitive inhibition often occurs when a molecule binds with high affinity at the substrate-binding site of a SULT but does not undergo the sulfation reaction. Competing substrates for SULT1 and SULT2 enzymes may also serve as competitive inhibitors in the sulfation of endocrine hormones. This type of inhibition depends upon the individual SULT, the kinetics of each sulfation reaction, and the localized concentrations of both the hormone substrate and the EDC substrate. The SULT1 and SULT2 enzymes are also subject to allosteric inhibition by many xenobiotics [33–37], and such inhibitors include various EDCs.

Selective regulation of the expression of SULTs within tissues and cell-types also affects the sulfation of endocrine hormones. Examples of nuclear receptors and other transcription factors that can control expression of one or more SULTs include the aryl hydrocarbon receptor (AhR), pregnane X receptor (PXR), farnesoid X receptor (FXR), vitamin D receptor (VDR), liver X receptor (LXR), peroxisome proliferator-activated receptors α and γ (PPARα and PPARγ), retinoid-related orphan receptors (RORs), estrogen-related orphan receptors (ERRs), CCAA/T/enhancer binding proteins, steroidogenic transcription factor 1, and the hepatocyte nuclear factor (HNF) family of transcription factors [38–43]. Those EDCs that interact with these receptors can alter localized tissue concentrations of individual SULTs and thereby affect sulfation reactions that are involved in the metabolism of endocrine hormones.

Differences in the constitutive distribution of individual SULTs among tissues may also affect the localized action of endocrine hormones. While SULT1A1, SULT1B1, SULT1E1, and SULT2A1 are most prominently expressed in adult human liver, SULT1A1, SULT1A3, SULT1B1, SULT1E1, SULT1C2, SULT2A1, and SULT2B1b are also expressed to varying extents in adult lung, intestine, kidney, adrenal, and brain [2,8,44–46]. Tissue distributions of individual SULTs in adults, however, often differ from those seen in human fetal tissues, and they change during development [44,47,48]. Functional differences for a SULT may also exist between fetal and adult tissues. For example, the high levels of SULT2A1 in the fetal adrenal are critical for the production of the DHEA sulfate that is required for placental estrogen biosynthesis in the late stages of pregnancy [2,44,49,50].

The sulfation of estrogens such as estradiol and estrone results in a loss of activity at estrogen receptors, and this can modulate intracellular estrogen signaling. Alterations in the localized regulation of estrogen sulfation are implicated in such diverse physiological responses and disease states as adipocyte differentiation, thrombotic fetal loss, endothelial cell function, glucose homeostasis, cancer, hepatic diseases, and cystic fibrosis [6,41,51–57]. Although several SULTs catalyze the sulfation of estrogens, SULT1E1 is usually considered the primary sulfotransferase involved due to its having the lowest K_m and highest catalytic efficiency for estrogens [25,58]. As outlined below and in Figure 2, many studies linking the effects of EDCs with the sulfation of estrogens have focused on their action as inhibitors and competing substrates for SULT1E1. For example, crystallographic analysis of the interaction of SULT1E1 with TBBPA, a brominated flame retardant EDC, has revealed structural features analogous to those seen in the binding of estradiol to the enzyme (Figure 3) [59]. Furthermore, the interactions of EDCs or their metabolites as ligands for the nuclear receptors that regulate expression of SULT1E1 can also alter intracellular estrogen concentrations and estrogen signaling [6,41,57]. Examples of nuclear receptors that can regulate expression of SULT1E1 include PPARα, PPARγ, LXR, FXR, RORα, and HNF4α [6].

A significant component of the estrogenic properties of polyhalogenated phenols involves their direct interactions with SULT1E1 and other SULTs [60]. Hydroxylated polychlorinated biphenyls (OH-PCBs) were first reported as potent inhibitors of SULT1E1 [61], and this was later extended to halogenated derivatives of bisphenol A and to hydroxylated metabolites of polychlorinated dibenzo-p-dioxins (OH-PCDDs), polychlorinated dibenzofurans (OH-PCDFs), and polyhalogenated diphenyl ethers (e.g., OH-PBDEs) [62]. OH-PCBs have proven to be useful models for examining the potential for endocrine disruption through inhibition of the SULT1E1-catalyzed sulfation of estrogens. X-ray crystallography [63] and spin-labeled NMR [64] techniques have elucidated structural aspects of this inhibition. Furthermore, studies on SULT1E1-transfected cells have established functional relationships among the OH-PCB-mediated inhibition of the enzyme, the intracellular estrogen concentration, and the activation of an estrogen receptor [64]. Additional aspects of the roles of SULTs in the toxicities of OH-PCBs have been recently reviewed [65]. Another chlorinated phenol that has been extensively investigated both in vitro and in vivo as a model EDC acting through potent inhibition of SULT1E1 is the antimicrobial agent Triclosan [52,66–68]. The effects of Triclosan on endocrine function and on other pharmacological and toxicological processes have been reviewed [69]. More generally, inhibitors of SULT1E1 and other family 1 SULTs also include a diverse array of drugs as well as environmental estrogens and dietary natural products (e.g., flavonoids, isoflavonoids, and others) that are either allosteric inhibitors or alternate substrates [6,33,35,70–74].

The family 2 SULTs are also potential targets for EDC-mediated disruption of steroid signaling. For example, SULT2A1 catalyzes the sulfation of DHEA to form DHEA sulfate which is then transported to peripheral tissues for uptake, intracellular hydrolysis to DHEA, and subsequent use in localized biosynthesis of androgens and estrogens [75]. Many OH-PCBs and other polychlorinated phenols are excellent inhibitors of the SULT2A1-catalyzed sulfation of DHEA as either alternative substrates or allosteric inhibitors [76–79]. The inhibition of SULT2A1 by 4-n-nonylphenol, 4-n-octylphenol, 4-tert-octylphenol, bisphenol A, benzyl butyl phthalate, and dibutyl phthalate has also been described [74,80]. While these EDCs are inhibitors of SULT2A1, additional studies will be needed to determine the extent to which this inhibition may affect intracellular biosynthesis of androgens and estrogens in vivo. Another family 2 SULT, SULT2B1b, is of interest due to its catalyzing the sulfation of 3β-hydroxysteroids, and a site for allosteric regulation of the enzyme has recently been identified [37]. SULT2B1b has a high selectivity for cholesterol as a substrate, and inhibition of the enzyme might be significant due to the role of cholesterol as a precursor to many steroid hormones. The extent to which EDCs interact with the allosteric site on SULT2B1b is, however, not currently known.

Inhibition of the sulfation of thyroid hormones represents another potential mechanism of action for some EDCs. Sulfate esters of iodothyronines are inactive at thyroid hormone receptors, and they are also inactive as substrates for two of the deiodinases that are essential for metabolism of thyroid hormones [24]. Conversely, a third deiodinase, type D1, exhibits increased catalytic activity with the sulfate esters of thyroxine (T4), 3,3′-diiodothyronine (3,3′ T2), and 3,3′,5-triiodothyronine (T3) when compared with the corresponding unsulfated iodothyronines [24,81]. SULT1A1, SULT1A3, SULT1B1, SULT1E1, SULT1C2, SULT1C4, and SULT2A1 catalyze the sulfation of iodothyronines with varied but overlapping specificities [24]. Thus, depending upon the individual SULT, its tissue-specific concentration, and the concentrations of the iodothyronine and EDC involved, allosteric inhibition or substrate-competition could alter thyroid hormone signaling. Some examples of EDCs that inhibit these SULTs include OH-PCBs, polyhalogenated phenols (e.g., trichlorophenol, tribromophenol, trifluorophenol, pentachlorophenol, and others), Triclosan, bisphenol A (BPA), halogenated derivatives of BPA such as tetrabromobisphenol A (TBBPA), and hydroxylated metabolites of polychlorinated dibenzo-p-dioxins (OH-PCDDs), polychlorinated dibenzofurans (OH-PCDFs), and polybrominated diphenyl ethers (OH-PBDEs) [62,65,66,82,83].

In addition to EDCs serving as inhibitors of the SULTs that catalyze inactivation of endocrine hormones, sulfate ester metabolites of EDCs (EDC-sulfates) might interact directly with receptors to alter a hormonal response. Cellular uptake and receptor interactions of the mono- and di-sulfate esters of physiological steroids are well known [5,84,85], and this suggests that other organic sulfate esters, such as EDC-sulfates, may act similarly. For example, a sulfate conjugate of TBBPA is a ligand for the nuclear receptor PPARγ [86], and sulfate esters of OH-PCBs are high-affinity ligands for the thyroid hormone carrier protein transthyretin [87].

Endocrine disruption by EDC-sulfates, however, has often been difficult to observe and interpret. One reason for this difficulty is that these EDC-sulfates may exhibit nonmonotonic responses, where biological effects are non-linear with respect to dose and may occur only at lower concentrations than those that are usually assessed in toxicological studies. Such responses are common for EDCs, and experiments conducted within a relatively high or limited range of concentrations may lead to erroneous conclusions about effects on toxicologic endpoints [88]. Examples of nonmonotonic dose responses with EDC-sulfates include the results of studies on estrogenic, anti-estrogenic, androgenic, and anti-androgenic activity of PCB sulfates in E-screen (MCF-7 BOS cells) and A-screen (MCF7-AR1 cells) assays [89]. Several sulfate ester metabolites of OH-PCBs (i.e., 2′-PCB 3 sulfate, 3′-PCB 3 sulfate, 4′-PCB 3 sulfate, and 4-PCB 39 sulfate) exhibited anti-estrogenic activity at 1 pM concentrations with nonmonotonic dose-response relationships [89]. Furthermore, 3′-PCB 3 sulfate, 4′-PCB 3 sulfate, 4-PCB 11 sulfate, 4-PCB 39 sulfate and 4′-PCB 53 sulfate were androgenic with nonmonotonic dose-response relationships [89]. Such results demonstrate both the potential for interactions of low concentrations of EDC-sulfates with endocrine receptors and the complexity of investigating these effects.

Interactions of PCB sulfates with thyroid hormone receptor α (TRα) have also been examined, but the results are conflicting. Dose-dependent activity in a GH-3 cell-based TRα-driven luciferase reporter assay was observed for 4′-PCB 3 sulfate, 4-PCB 11 sulfate, and 4′-PCB 12 sulfate at concentrations of 1.5–25 µM [90]. In other studies, however, examination of 4′-PCB 3 sulfate, 4-PCB 8 sulfate, 4-PCB 11 sulfate, and 4-PCB 52 sulfate at concentrations of 10 pM to 10 µM in a GH-3 cell-based thyroid hormone receptor assay yielded no significant activity [91]. It is, however, difficult to compare these two studies due to several methodological differences. For example, there was a difference in the time of exposure to the PCB sulfates: one protocol used a 48 h incubation time [90], while the other method employed a 24 h incubation period [91]. The potential effects of this as well as other procedural differences remain to be investigated.

EDC-sulfates may either be excreted in the urine and feces or transported in serum to other tissues. Those EDC-sulfates that undergo biliary secretion may be subject to metabolism by the gut microflora that includes hydrolysis of the sulfate ester. One example of this is provided by studies in the rat that utilized an intravenous injection of a single dose of 4-PCB 11 sulfate [92]. While approximately 30% of an administered dose was secreted in the bile within 24 h, 4-PCB 11 sulfate was not detectable in the feces after the same period, and only 4% of the administered dose was found in the urine [92]. Studies in mice, however, have indicated that an oral dose of a PCB mixture yielded fecal samples containing various PCB sulfate congeners with higher total amounts in germ-free versus conventional animals [93]. Hydrolysis reactions catalyzed by sulfatases within intestinal microorganisms enable enterohepatic circulation involving both xenobiotic and endogenous sulfate esters [94,95], and 1391 genes coding for gut microbial sulfatases have been identified from the Integrated Gene Catalogue Database and the Human Microbiome Project Stool Sample Catalog database [96]. Additionally, uptake and efflux transporters play highly significant roles in the fate of sulfate conjugates and their hydrolysis products by selectively enabling the crossing of intestinal as well as other tissue barriers [97].

Sulfate ester metabolites derived from OH-PCBs and from BPA have been quantitated in human serum samples [98–100]. As exemplified by PCB-sulfates, the retention of EDC-sulfates may be facilitated by reversible binding to serum proteins such as human serum albumin (HSA) and transthyretin (TTR) [87,101]. HSA is involved in the retention, transport, and disposition of many xenobiotics as well as endogenous hormones, fatty acids, heme, and metal ions [102]. While it is the most abundant protein in human plasma, an exchange of HSA between intravascular and extravascular compartments also occurs [103]. HSA binds a diverse array of organic chemical anions, and sulfation of xenobiotics generally increases their affinity for reversible binding to the protein [104]. TTR (previously named as thyroxine-binding prealbumin) participates in the transport of thyroxine in serum, although thyroid binding globulin and HSA provide the highest capacity for this transport in human serum [105,106]. TTR is, however, the major human carrier for thyroxine in cerebrospinal fluid and in the developing fetus [107–109]. The roles of HSA and TTR in the retention and transport of OH-PCBs and PCB-sulfates have been recently reviewed [65], and the fundamental principles involved may be applicable to other EDCs and EDC-sulfates. Furthermore, other serum proteins that bind organic anions may serve similar functions in the retention and transport of EDC-sulfates, and future studies in this area are needed.

Steroid sulfates such as dehydroepiandrosterone sulfate (DHEAS) and estrone sulfate provide a model for serum protein binding, transport, and cellular uptake of EDC-sulfates. Circulating steroid hormone sulfates are taken up by peripheral tissues, hydrolyzed to the non-sulfated steroids in reactions catalyzed by intracellular sulfatases, and then used either for intracellular signaling or for biosynthesis of other steroid hormones [75,85,110]. The active transport needed for cellular uptake of steroid sulfates usually requires organic anion-transporting polypeptides (OATPs), organic anion transporters (OATs), or sodium-dependent organic anion transporters (SOATs) [85,110]. These transporters for steroid sulfates are differentially expressed in tissues, and they also utilize xenobiotic sulfates as substrates [97,111].

Figure 4 outlines a general hypothetical model for the transport, uptake, and intracellular interconversion of EDC-sulfates that is followed by potential events that can affect endocrine functions. Following transport and cellular uptake, EDC-sulfates may undergo hydrolysis catalyzed by sulfatases. The microsomal steroid sulfatase (STS) (E.C. 3.1.6.2., arylsulfatase C) is the predominant enzyme catalyzing hydrolysis of steroid sulfates [85,112–115]. STS also catalyzes the hydrolysis of non-steroidal arylsulfates that range from analytical assay substrates for the enzyme such as 4-nitrophenyl sulfate, 4-methylumbelliferyl sulfate, and 6,8-difluoro-4-methylumbelliferone sulfate [116,117] to xenobiotic metabolites such as the sulfates of raloxifene and arzoxifene [118]. Both the regulation of the expression of STS and the inhibition of its catalytic activity have been reviewed [57,112,119]. While two other human sulfatases, arylsulfatases E and F, catalyze the sulfation of 4-methylumbelliferone sulfate as a model probe substrate [120,121], their specificities for other xenobiotic sulfates as substrates are not yet fully defined. Thus, although STS is likely the major enzyme catalyzing the hydrolysis of EDC-sulfates, other sulfatases may also be involved. Whether EDC-sulfates enter a cell through transport from blood or arise through intracellular SULT-catalyzed reactions, interconversion between an EDC and its EDC-sulfate may occur. Such dynamic intracellular cycling driven by the specific SULTs and sulfatases involved is a critical factor in the metabolism, pharmacokinetics, and biological activity of steroids as well as drugs and other xenobiotics [85,122–125].

BPA and BPA-sulfate provide an example of a role for sulfatases in the biological actions of EDC-sulfates. BPA-sulfate is a metabolic product derived from the sulfation of BPA, and it has approximately 10-fold lower activity than BPA with an estrogen receptor derived from the breast cancer cell line MCF-7 [126]. BPA-sulfate is, however, taken up by MCF-7 cells, and its cellular conversion to BPA results in an estrogenic response as determined by stimulation of cell growth [126]. A BPA-sulfate-sulfatase pathway has also been observed in studies with human placenta-derived BeWo cytotrophoblasts, where BPA-sulfate entered these cells, and a subsequent STS-dependent conversion to BPA enabled initiation of cell cycle disruption [127].

Studies on OH-PCBs and PCB-sulfates provide additional examples of the interconversion of EDCs and EDC-sulfates within intracellular environments. In cell culture models, OH-PCBs and PCB-sulfates were taken up and interconverted via SULT- and sulfatase-catalyzed reactions that were specific to the OH-PCB or PCB-sulfate congener and the cell-type studied [128]. For example, OH-PCBs and PCB-sulfates were taken up and interconverted by HepG2 cells, a human hepatic-derived cell line [128–131]. Subsequent studies utilizing hepatic microsomal fractions isolated from human organ donors indicated that the sulfatase(s) present catalyzed the hydrolysis of PCB-sulfates at varying catalytic efficiencies that were often greater than those determined with the physiological substrate DHEAS [132]. Additional investigations on several OH-PCBs and their corresponding PCB sulfates with two neural cell lines (rat midbrain-derived N27 cells and human neuroblastoma-derived SH-SY5Y cells) revealed that although these OH-PCBs entered the cells, they were not converted to PCB sulfates [128]. Some of the PCB sulfate congeners were, however, taken up by the neural cells and hydrolyzed to the corresponding OH-PCBs [128]. Thus, these studies on OH-PCBs and PCB-sulfates suggest that the chemical structures of the EDC and its EDC-sulfate in relation to the presence or absence of the required SULT(s) or sulfatase(s) within individual cell-types are critical for determining the intracellular concentration of an active EDC.

Although several roles of the SULTs in endocrine disruption are known, we do not yet fully understand the scope of interactions of EDCs with these enzymes and the related mechanistic connections to changes in hormonal signaling. Areas for future research include obtaining a detailed knowledge of the intracellular concentrations of EDCs that are either substrates or inhibitors of SULTs. This must then be related to the intracellular concentrations of the specific SULT(s) involved and to changes in endocrine hormone signaling within those tissues and cell-types. Moreover, a better understanding of the effects of individual EDCs on regulating the expression of the specific SULTs involved in metabolism of endocrine hormones in those tissues is also required. Further studies are also needed to elucidate which serum proteins are responsible for retention of specific EDC-sulfates, to identify the location and specificity of those transporters required for cellular uptake and efflux of individual EDC-sulfates, and to understand the catalytic specificity and regulation of expression of the intracellular sulfatase(s) catalyzing the hydrolysis of EDC-sulfates. Finally, results from these investigations must always be placed in the context of other regulatory pathways for the specific endocrine hormone involved and be incorporated into an overall mechanistic understanding of the resulting toxicological outcomes.

• Mammalian cytosolic sulfotransferases catalyze the sulfation of endocrine hormones as well as many EDCs. These enzymes exhibit distinct but overlapping specificities for substrates and inhibitors, are distributed among many human tissues, and utilize various transcription factors to regulate their cell-specific expression.

• Some EDCs inhibit the SULT-catalyzed sulfation of an endocrine hormone, and this inhibition can alter localized concentrations of the active hormone.

• Sulfation may either aid in detoxication of an EDC or assist in its delivery to remote tissues. Efflux of an EDC-sulfate into systemic circulation can lead to its retention through reversible binding to serum proteins. Subsequent active transport of the EDC-sulfate into a cell may be followed by sulfatase-catalyzed hydrolysis to regenerate the original EDC and initiate its effects on hormonal signaling.

• Some EDC-sulfates interact with endocrine hormone receptors, and complex nonlinear dose–response relationships have been observed.

The author declares that there are no competing interests associated with this manuscript.

This work was supported by the National Institute of Environmental Health Sciences, National Institutes of Health [grant numbers NIH P42 ES013661 and P30 ES005605]. The contents of this review are solely the responsibility of the author and do not necessarily represent the official views of the National Institutes of Health.

3,3′T2

3,3′-diiodothyronine

AhR

aryl hydrocarbon receptor

BPA

bisphenol A

DHEA

dehydroepiandrosterone

DHEAS

dehydroepiandrosterone sulfate

E2

estradiol

E2-sulfate

estradiol-3-sulfate

EDC

endocrine disrupting chemical

EDC-OH

general representation of an EDC that either initially contains a hydroxy group or obtains it through metabolism

EDC-OSO₃⁻ or EDC-sulfate

sulfate ester derived from an endocrine disrupting chemical

ERR

estrogen-related orphan receptor

FXR

farnesoid X receptor

HNF

hepatocyte nuclear family receptor

HSA

human serum albumin

K_m

Michaelis constant

LXR

liver X receptor

OATP

organic anion-transporting polypeptide

OAT

organic anion-transporter

OH-PBDE

hydroxylated polybrominated diphenyl ether

OH-PCB

hydroxylated polychlorinated biphenyl

OH-PCDD

hydroxylated polychlorinated dibenzo-p-dioxin

OH-PCDF

hydroxylated polychlorinated dibenzofuran

PAP

3′-5′-adenosine diphosphate

PAPS

3′-phosphoadenosine-5′-phosphosulfate

PCB

polychlorinated biphenyl

PCB-sulfate

sulfate ester of a hydroxylated polychlorinated biphenyl

PPARα

peroxisome proliferator receptor α

PPARγ

peroxisome proliferator receptor γ

ROR

retinoid-related orphan receptor

SO₃

sulfuryl group

SOAT

sodium-dependent organic anion transporter

STS

steroid sulfatase (arylsulfatase C)

SULT

mammalian cytosolic sulfotransferase

T3

3,3′5-triiodothyronine

T4

thyroxine

TBBPA

tetrabromobisphenol A

TCBPA

tetrachlorobisphenol A

TRα

thyroid hormone receptor alpha

TTR

transthyretin

VDR

vitamin D receptor