Effect of Substituent Size and Dimensionality on Potency of Phenolic Xenoestrogens Evaluated With a Recombinant Yeast Assay

Schultz, T.W.; Sinks, Glendon D.; Cronin, Mark

doi:10.1897/1551-5028(2000)019<2637:eossad>2.0.co;2

Cited by 9 publications

(17 citation statements)

References 15 publications

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“…1). Similar patterns have been found with phenolic compounds [6][7][8][9], with alkyl hydroxy benzoates [38], and with flavonoids [39]. Increasing, statistically nonsignificant absorbance values were detected at higher o-DCB concentration (1.7 ϫ 10 Ϫ4 to 6.8 ϫ 10 Ϫ4 M).…”

Section: Resultssupporting

confidence: 79%

IN VITRO AND IN VIVO ESTROGENICITY AND TOXICITY OF o-, m-, AND p-DICHLOROBENZENE

Versonnen¹,

Arijs²,

Verslycke³

et al. 2003

Environ Toxicol Chem

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The estrogenicity of o-, m-, and p-dichlorobenzene (DCB) was evaluated with a yeast estrogen screen (YES) and zebrafish (Danio rerio) vitellogenin (VTG) assays. With the YES, p-DCB and m-DCB were found to be estrogenic in a concentration-responsive manner. The relative potency measured with the YES (relative to 17beta-estradiol) was 2.2 x 10(-7) for p-DCB and 1.04 x 10(-8) for m-DCB. Following acute toxicity tests with the zebrafish, plasma VTG production was measured to examine the in vivo estrogenic activity of the three compounds after a 14-d exposure. Adult zebrafish were exposed to different concentrations of o-, m- and p-DCB, ranging from 0.1 to 32 mg/L; ethynylestradiol ([EE2]; 5 ng/L, 10 ng/L, 50 ng/L, and 100 ng/L) was used as a positive control. After exposure, blood samples were taken and protein electrophoresis was performed to determine the relative VTG content. Gonadosomatic indices (GSI) and condition factors (CF) were also calculated. Elevated VTG levels and decreased female GSIs were found in fish exposed to > or = 5 ng EE2/L and in fish exposed to > or = 10 mg p-DCB/L. Low GSIs coincided with high levels of VTG in the blood of female zebrafish. This relation was not only found in fish exposed to EE2 but also in controls and fish exposed to DCB. Therefore, a direct or indirect effect of VTG on the GSI is suggested rather than a direct toxic effect of the tested compounds on the gonads.

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Section: Resultssupporting

confidence: 79%

IN VITRO AND IN VIVO ESTROGENICITY AND TOXICITY OF o-, m-, AND p-DICHLOROBENZENE

Versonnen¹,

Arijs²,

Verslycke³

et al. 2003

Environ Toxicol Chem

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“…While the uptake of molecules into the cell is critical to reaching the site of action (i.e., the cytosolic receptor protein), this is rarely the rate-limiting step in gene expression studies. Thus, physicochemical properties, especially hydrophobicity, are not good predictors of receptor-mediated activities (Schultz et al, 2000a). Moreover, when physicochemical properties have been shown to be related to activity, they are often collinear with descriptors of size and shape, or hydrogen-bonding capacity.…”

Section: Discussionmentioning

confidence: 99%

“…Plates were wrapped in parafilm to prevent evaporation. Earlier experiments determined that pH, cell number (determined by absorbance at 540 nm), and cell viability (determined by reculturing) were not altered over 5 days of exposure (Schultz et al, 2000a). Moreover, negative controls revealed only a very slight color change (tan), which occurred on the 5th day of incubation.…”

Section: Biological Testingmentioning

confidence: 95%

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Structure–activity relationships for gene activation oestrogenicity: Evaluation of a diverse set of aromatic chemicals

Schultz

Sinks

Cronin

2002

Environmental Toxicology

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Structure-activity relationships for oestrogenicity were developed based on 120 aromatic chemicals evaluated in the Saccharomyces cerevisiae-based Lac-Z reporter assay. Relative gene activation was compared to 17 beta-estradiol and varied over eight orders of magnitude. Analysis of the data compared to 17 beta-estradiol identified three structural criteria that were related to xenoestrogen activity and potency: (1) the hydrogen-bonding ability of the phenolic ring mimicking the A-ring, (2) a hydrophobic centre similar in size and shape to the B- and C-rings, and (3) a hydrogen-bond donor mimicking the 17 beta-hydroxyl moiety of the D-ring, especially with an oxygen-to-oxygen distance similar to that between the 3- and 17 beta-hydroxyl groups of 17 beta-estradiol. Binding data were segregated into activity clusters including strong, moderate, weak, and detectable gene expression, and those compounds that were inactive. The hydrogen-bonding ability of hydroxy group in the 3-position on 17 beta-estradiol was observed to be essential for gene activation. Compounds with a 4-hydroxyl substituted benzene ring and a hydrophobic moiety of size and shape equivalent to the B-ring of 17 beta-estradiol were generally observed to be weakly active compounds. Moderately active compounds have a 4-hydroxyl substituted benzene ring with a hydrophobic moiety equivalent in size and shape to the B- and C-ring of 17 beta-estradiol, or have a high hydrogen-bond donor capacity owing to the presence of halogens on a nonphenolic ring. Strongly active compounds, similar to 4,4'-diethylethylene bisphenol (DES), possess the same hydrophobic ring structure as described for moderately active compounds and an additional hydroxyl group with an oxygen-to-oxygen distance close to that exhibited by the 3- and 17-hydroxyl groups of 17 beta-estradiol.

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“…Estrogenicity assays were performed following the protocol of Schultz et al [12]. The compounds evaluated, a series of 29 PAHs (Table 1), were purchased from Aldrich Chemical (Milwaukee, WI, USA) or Lancaster Synthesis (Windham, NH, USA).…”

Section: Methodsmentioning

confidence: 99%

Xenoestrogenic gene exression: Structural features of active polycyclic aromatic hydrocarbons

Schultz

Sinks

2002

Enviro Toxic and Chemistry

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Estrogenicity was assessed using the Saccharomyces cerevisiae-based Lac-Z reporter assay and was reported as the logarithm of the inverse of the 50% molar beta-galactosidase activity (log[EC50(-1)]). In an effort to quantify the relationship between molecular structure of polycyclic aromatic hydrocarbons (PAHs) and estrogenic gene expression, a series of PAHs were evaluated. With noted exceptions, the results of these studies indicate that the initial two-dimensional structural warning for estrogenicity, the superpositioning of a hydroxylated aromatic system on the phenolic A-ring of 17-beta-estradiol, can be extended to the PAHs. This two-dimensional-alignment criterion correctly identified estrogenicity of 22 of the 29 PAHs evaluated. Moreover, the estrogenic potency of these compounds was directly related to the size of the hydrophobic backbone. The seven compounds classified incorrectly by this structural feature were either dihydroxylated naphthalenes or aromatic nitrogen-heterocyclic compounds; all such compounds were false positives. Results with dihydroxylated naphthalenes reveal derivatives that were nonestrogenic when superimposed on the phenolic A-ring of 17-beta-estradiol had the second hydroxyl group in the position of the C-ring or were catechol-like in structure. Structural alerts for nitrogen-heterocyclic compounds must take into account the position of the hydroxyl group and the in-ring nitrogen atom; compounds with the hydroxyl group and nitrogen atom involved with the same ring were observed to be nonactive.

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Effect of Substituent Size and Dimensionality on Potency of Phenolic Xenoestrogens Evaluated With a Recombinant Yeast Assay

Cited by 9 publications

References 15 publications

IN VITRO AND IN VIVO ESTROGENICITY AND TOXICITY OF o-, m-, AND p-DICHLOROBENZENE

IN VITRO AND IN VIVO ESTROGENICITY AND TOXICITY OF o-, m-, AND p-DICHLOROBENZENE

Structure–activity relationships for gene activation oestrogenicity: Evaluation of a diverse set of aromatic chemicals

Xenoestrogenic gene exression: Structural features of active polycyclic aromatic hydrocarbons

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