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Effects of Common Pesticides on Prostaglandin D2 (PGD2) Inhibition in SC5 Mouse Sertoli Cells, Evidence of Binding at the COX-2 Active Site, and Implications for Endocrine Disruption.

Kugathas S, Audouze K, Ermler S, Orton F, Rosivatz E, Scholze M, Kortenkamp A - Environ. Health Perspect. (2015)

Bottom Line: Many endocrine-disrupting chemicals have been found to suppress prostaglandin synthesis, but to our knowledge, pesticides have never been tested for these effects.Supplementation with AA failed to reverse this effect, suggesting that the sites of action of these pesticides are COX enzymes.Kugathas S, Audouze K, Ermler S, Orton F, Rosivatz E, Scholze M, Kortenkamp A. 2016.

View Article: PubMed Central - PubMed

Affiliation: Institute of Environment, Health and Societies, Brunel University London, Uxbridge, United Kingdom.

ABSTRACT

Background: There are concerns that diminished prostaglandin action in fetal life could increase the risk of congenital malformations. Many endocrine-disrupting chemicals have been found to suppress prostaglandin synthesis, but to our knowledge, pesticides have never been tested for these effects.

Objectives: We assessed the ability of pesticides that are commonly used in the European Union to suppress prostaglandin D2 (PGD2) synthesis.

Methods: Changes in PGD2 secretion in juvenile mouse Sertoli cells (SC5 cells) were measured using an ELISA. Coincubation with arachidonic acid (AA) was conducted to determine the site of action in the PGD2 synthetic pathway. Molecular modeling studies were performed to assess whether pesticides identified as PGD2-active could serve as ligands of the cyclooxygenase-2 (COX-2) binding pocket.

Results: The pesticides boscalid, chlorpropham, cypermethrin, cyprodinil, fenhexamid, fludioxonil, imazalil (enilconazole), imidacloprid, iprodione, linuron, methiocarb, o-phenylphenol, pirimiphos-methyl, pyrimethanil, and tebuconazole suppressed PGD2 production. Strikingly, some of these substances-o-phenylphenol, cypermethrin, cyprodinil, linuron, and imazalil (enilconazole)-showed potencies (IC50) in the range between 175 and 1,500 nM, similar to those of analgesics intended to block COX enzymes. Supplementation with AA failed to reverse this effect, suggesting that the sites of action of these pesticides are COX enzymes. The molecular modeling studies revealed that the COX-2 binding pocket can accommodate most of the pesticides shown to suppress PGD2 synthesis. Some of these pesticides are also capable of antagonizing the androgen receptor.

Conclusions: Chemicals with structural features more varied than previously thought can suppress PGD2 synthesis. Our findings signal a need for in vivo studies to establish the extent of endocrine-disrupting effects that might arise from simultaneous interference with PGD2 signaling and androgen action.

Citation: Kugathas S, Audouze K, Ermler S, Orton F, Rosivatz E, Scholze M, Kortenkamp A. 2016. Effects of common pesticides on prostaglandin D2 (PGD2) inhibition in SC5 mouse Sertoli cells, evidence of binding at the COX-2 active site, and implications for endocrine disruption. Environ Health Perspect 124:452-459; http://dx.doi.org/10.1289/ehp.1409544.

No MeSH data available.


Related in: MedlinePlus

Suppression of prostaglandin D2 synthesis by pesticides in the mouse Sertoli cell assay. (A–C) Best-fitting regression models for suppression of prostaglandin D2 (PGD2) synthesis in SC5 (mouse Sertoli) cells after 24-hr exposure to selected pesticides (3 replicates). Pesticides are grouped according to their exposure in the European Union (Orton et al. 2011) in A, B, and C as high, medium, and low exposure, respectively. All data were normalized to the responses of solvent controls. Ibuprofen was chosen as the positive control (dashed line in A–C). (D)Responses (black dots) and best-fitting regression model with 95% confidence belts (dashed and solid red lines) for o-phenylphenol.
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f1: Suppression of prostaglandin D2 synthesis by pesticides in the mouse Sertoli cell assay. (A–C) Best-fitting regression models for suppression of prostaglandin D2 (PGD2) synthesis in SC5 (mouse Sertoli) cells after 24-hr exposure to selected pesticides (3 replicates). Pesticides are grouped according to their exposure in the European Union (Orton et al. 2011) in A, B, and C as high, medium, and low exposure, respectively. All data were normalized to the responses of solvent controls. Ibuprofen was chosen as the positive control (dashed line in A–C). (D)Responses (black dots) and best-fitting regression model with 95% confidence belts (dashed and solid red lines) for o-phenylphenol.

Mentions: Suppression of prostaglandin synthesis in the SC5 assay. We selected 24 pesticides (for chemical structures, see Supplemental Material, Figure S1) to be tested in the present study. After converting the PGD2 readings for the tested compounds on each EIA plate to percentages of the average values for solvents, 15 of the initial 24 [boscalid, chlorpropham, cypermethrin, cyprodinil, fenhexamid, fludioxonil, imazalil (enilconazole), imidacloprid, iprodione, linuron, methiocarb, OPP, pirimiphos-methyl, pyrimethanil, and tebuconazole] were found to inhibit PGD2 synthesis in a concentration-dependent manner in the SC5 assay, as shown in Figure 1A–C (data and regression models from three independent experiments for groups of pesticides and ibuprofen) and in Figure 1D (for OPP); see also Supplemental Material, Figure S2 (for the remaining compounds). The concentration–response relationship for the known nonsteroidal anti-inflammatory drug ibuprofen is also shown.


Effects of Common Pesticides on Prostaglandin D2 (PGD2) Inhibition in SC5 Mouse Sertoli Cells, Evidence of Binding at the COX-2 Active Site, and Implications for Endocrine Disruption.

Kugathas S, Audouze K, Ermler S, Orton F, Rosivatz E, Scholze M, Kortenkamp A - Environ. Health Perspect. (2015)

Suppression of prostaglandin D2 synthesis by pesticides in the mouse Sertoli cell assay. (A–C) Best-fitting regression models for suppression of prostaglandin D2 (PGD2) synthesis in SC5 (mouse Sertoli) cells after 24-hr exposure to selected pesticides (3 replicates). Pesticides are grouped according to their exposure in the European Union (Orton et al. 2011) in A, B, and C as high, medium, and low exposure, respectively. All data were normalized to the responses of solvent controls. Ibuprofen was chosen as the positive control (dashed line in A–C). (D)Responses (black dots) and best-fitting regression model with 95% confidence belts (dashed and solid red lines) for o-phenylphenol.
© Copyright Policy - public-domain
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4829986&req=5

f1: Suppression of prostaglandin D2 synthesis by pesticides in the mouse Sertoli cell assay. (A–C) Best-fitting regression models for suppression of prostaglandin D2 (PGD2) synthesis in SC5 (mouse Sertoli) cells after 24-hr exposure to selected pesticides (3 replicates). Pesticides are grouped according to their exposure in the European Union (Orton et al. 2011) in A, B, and C as high, medium, and low exposure, respectively. All data were normalized to the responses of solvent controls. Ibuprofen was chosen as the positive control (dashed line in A–C). (D)Responses (black dots) and best-fitting regression model with 95% confidence belts (dashed and solid red lines) for o-phenylphenol.
Mentions: Suppression of prostaglandin synthesis in the SC5 assay. We selected 24 pesticides (for chemical structures, see Supplemental Material, Figure S1) to be tested in the present study. After converting the PGD2 readings for the tested compounds on each EIA plate to percentages of the average values for solvents, 15 of the initial 24 [boscalid, chlorpropham, cypermethrin, cyprodinil, fenhexamid, fludioxonil, imazalil (enilconazole), imidacloprid, iprodione, linuron, methiocarb, OPP, pirimiphos-methyl, pyrimethanil, and tebuconazole] were found to inhibit PGD2 synthesis in a concentration-dependent manner in the SC5 assay, as shown in Figure 1A–C (data and regression models from three independent experiments for groups of pesticides and ibuprofen) and in Figure 1D (for OPP); see also Supplemental Material, Figure S2 (for the remaining compounds). The concentration–response relationship for the known nonsteroidal anti-inflammatory drug ibuprofen is also shown.

Bottom Line: Many endocrine-disrupting chemicals have been found to suppress prostaglandin synthesis, but to our knowledge, pesticides have never been tested for these effects.Supplementation with AA failed to reverse this effect, suggesting that the sites of action of these pesticides are COX enzymes.Kugathas S, Audouze K, Ermler S, Orton F, Rosivatz E, Scholze M, Kortenkamp A. 2016.

View Article: PubMed Central - PubMed

Affiliation: Institute of Environment, Health and Societies, Brunel University London, Uxbridge, United Kingdom.

ABSTRACT

Background: There are concerns that diminished prostaglandin action in fetal life could increase the risk of congenital malformations. Many endocrine-disrupting chemicals have been found to suppress prostaglandin synthesis, but to our knowledge, pesticides have never been tested for these effects.

Objectives: We assessed the ability of pesticides that are commonly used in the European Union to suppress prostaglandin D2 (PGD2) synthesis.

Methods: Changes in PGD2 secretion in juvenile mouse Sertoli cells (SC5 cells) were measured using an ELISA. Coincubation with arachidonic acid (AA) was conducted to determine the site of action in the PGD2 synthetic pathway. Molecular modeling studies were performed to assess whether pesticides identified as PGD2-active could serve as ligands of the cyclooxygenase-2 (COX-2) binding pocket.

Results: The pesticides boscalid, chlorpropham, cypermethrin, cyprodinil, fenhexamid, fludioxonil, imazalil (enilconazole), imidacloprid, iprodione, linuron, methiocarb, o-phenylphenol, pirimiphos-methyl, pyrimethanil, and tebuconazole suppressed PGD2 production. Strikingly, some of these substances-o-phenylphenol, cypermethrin, cyprodinil, linuron, and imazalil (enilconazole)-showed potencies (IC50) in the range between 175 and 1,500 nM, similar to those of analgesics intended to block COX enzymes. Supplementation with AA failed to reverse this effect, suggesting that the sites of action of these pesticides are COX enzymes. The molecular modeling studies revealed that the COX-2 binding pocket can accommodate most of the pesticides shown to suppress PGD2 synthesis. Some of these pesticides are also capable of antagonizing the androgen receptor.

Conclusions: Chemicals with structural features more varied than previously thought can suppress PGD2 synthesis. Our findings signal a need for in vivo studies to establish the extent of endocrine-disrupting effects that might arise from simultaneous interference with PGD2 signaling and androgen action.

Citation: Kugathas S, Audouze K, Ermler S, Orton F, Rosivatz E, Scholze M, Kortenkamp A. 2016. Effects of common pesticides on prostaglandin D2 (PGD2) inhibition in SC5 mouse Sertoli cells, evidence of binding at the COX-2 active site, and implications for endocrine disruption. Environ Health Perspect 124:452-459; http://dx.doi.org/10.1289/ehp.1409544.

No MeSH data available.


Related in: MedlinePlus