Endocrine disrupting alkylphenols: structural requirements for their adverse effects on Ca2+ pumps, Ca2+ homeostasis & Sertoli TM4 cell viability

Alkylphenols such as nonylphenol are pollutants that are widely dispersed within our environment. They bio-accumulate within man, with levels in the muM concentration range reported in human tissues. These chemicals act as endocrine disruptors, having xenoestrogenic activity. More recently alkylphen...

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Bibliographic Details
Published in:Chemico-biological interactions 2008-11, Vol.176 (2-3), p.220-226
Main Authors: Michelangeli, Francesco, Ogunbayo, Oluseye A, Wootton, Laura L, Lai, Pei F, Al-Mousa, Fawaz, Harris, Robert M, Waring, Rosemary H, Kirk, Christopher J
Format: Article
Language:English
Subjects:
Alkylation
Animals
Calcium - metabolism
Cell Survival - drug effects
Dose-Response Relationship, Drug
Endocrine Disruptors - chemistry
Endocrine Disruptors - pharmacology
Homeostasis - drug effects
Male
Mice
Mitochondria - drug effects
Mitochondria - metabolism
Phenols - chemistry
Phenols - pharmacology
Sarcoplasmic Reticulum Calcium-Transporting ATPases - antagonists & inhibitors
Sarcoplasmic Reticulum Calcium-Transporting ATPases - metabolism
Sertoli Cells - cytology
Sertoli Cells - drug effects
Sertoli Cells - metabolism
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Summary:Alkylphenols such as nonylphenol are pollutants that are widely dispersed within our environment. They bio-accumulate within man, with levels in the muM concentration range reported in human tissues. These chemicals act as endocrine disruptors, having xenoestrogenic activity. More recently alkylphenols have also been shown to affect Ca2+ signalling pathways. Here we show that alkylphenols are potent inhibitors of sarcoplasmic-endoplasmic reticulum Ca2+-ATPase (SERCA) activity. For linear chain alkylphenols the potency of inhibition is related to chain length, with the IC50 values for inhibition ranging from 8 microM for 4-n-nonylphenol (C9) to 1.3 mM for 4-n-propylphenol (C3). Branched chain alkylphenols generally had lower potencies than their linear chain counterparts, however, good correlations for all alkylphenols were observed between their Ca2+ pump inhibition and hydrophobicity, molecular volume and flexibility, indicating that these parameters are all important factors. Alkylphenols cause abnormal elevations of intracellular [Ca2+] within TM4 Sertoli cells (cells involved in sperm maturation) depolarise their mitochondria and induce cell death in these cells, in an alkyl chain size-dependent manner.
ISSN:0009-2797
1872-7786
DOI:10.1016/j.cbi.2008.08.005