Subject(s)
Endocrine Disruptors/toxicity , Gonadal Steroid Hormones/metabolism , Signal Transduction/drug effects , Acetates/toxicity , Animals , Diethylstilbestrol/toxicity , Estrogens, Non-Steroidal/toxicity , Genistein/toxicity , Humans , Lavandula , Oils, Volatile/toxicity , Phytoestrogens/toxicity , Plant Oils/toxicity , Risk Assessment , Tea Tree Oil/toxicityABSTRACT
BACKGROUND: Ethylene glycol monomethyl ether (EGME) exposure is associated with impaired reproductive function. The primary metabolite of EGME is methoxyacetic acid (MAA), a short-chain fatty acid that inhibits histone deacetylase activity and alters gene expression. OBJECTIVE: Because estrogen signaling is necessary for normal reproductive function and modulates gene expression, the estrogen-signaling pathway is a likely target for MAA; however, little is known about the effects of MAA in this regard. METHODS: We evaluated the mechanistic effects of MAA on estrogen receptor (ER) expression and estrogen signaling using in vitro and in vivo model systems. RESULTS: MAA potentiates 17beta-estradiol (E(2)) stimulation of an estrogen-responsive reporter plasmid in HeLa cells transiently transfected with either a human ERalpha or ERbeta expression vector containing a cytomegalovirus (CMV) promoter. This result is attributed to increased exogenous ER expression due to MAA-mediated activation of the CMV promoter. In contrast to its effects on exogenous ER, MAA decreases endogenous ERalpha expression and attenuates E(2)-stimulated endogenous gene expression in both MCF-7 cells and the mouse uterus. CONCLUSIONS: These results illustrate the importance of careful experimental design and analysis when assessing the potential endocrine-disrupting properties of a compound to ensure biological responses are in concordance with in vitro analyses. Given the established role of the ER in normal reproductive function, the effects of MAA on the endogenous ER reported here are consistent with the reproductive abnormalities observed after EGME exposure and suggest that these toxicities may be due, at least in part, to attenuation of endogenous ER-mediated signaling.
Subject(s)
Acetates/toxicity , Estrogen Receptor alpha/drug effects , Estrogen Receptor beta/drug effects , Gene Expression Regulation/drug effects , Animals , Cell Line, Tumor , Cytomegalovirus/genetics , Endocrine Disruptors/toxicity , Estradiol/pharmacology , Estrogen Receptor alpha/genetics , Estrogen Receptor beta/genetics , Female , HeLa Cells , Humans , Mice , Mice, Inbred C57BL , Promoter Regions, Genetic , Research Design , Signal Transduction/drug effects , Uterus/drug effects , Uterus/metabolismABSTRACT
Most cases of male prepubertal gynecomastia are classified as idiopathic. We investigated possible causes of gynecomastia in three prepubertal boys who were otherwise healthy and had normal serum concentrations of endogenous steroids. In all three boys, gynecomastia coincided with the topical application of products that contained lavender and tea tree oils. Gynecomastia resolved in each patient shortly after the use of products containing these oils was discontinued. Furthermore, studies in human cell lines indicated that the two oils had estrogenic and antiandrogenic activities. We conclude that repeated topical exposure to lavender and tea tree oils probably caused prepubertal gynecomastia in these boys.
Subject(s)
Androgen Antagonists/pharmacology , Gynecomastia/chemically induced , Oils, Volatile/adverse effects , Plant Oils/adverse effects , Tea Tree Oil/adverse effects , Breast Neoplasms , Cathepsin D/biosynthesis , Cathepsin D/genetics , Cells, Cultured/drug effects , Child , Child, Preschool , Dose-Response Relationship, Drug , Genes, myc/drug effects , Humans , Insulin-Like Growth Factor Binding Protein 3 , Insulin-Like Growth Factor Binding Proteins/biosynthesis , Insulin-Like Growth Factor Binding Proteins/genetics , Lavandula , Male , Oils, Volatile/pharmacology , Plant Oils/pharmacology , RNA, Messenger/biosynthesis , Receptors, Estrogen/drug effects , Tea Tree Oil/pharmacologyABSTRACT
The term endocrine-disrupting chemicals is used to define a structurally diverse class of synthetic and natural compounds that possess the ability to alter various components of the endocrine system and potentially induce adverse health effects in exposed individuals and populations. Research on these compounds has revealed that they use a variety of both nuclear receptor-mediated and non-receptor-mediated mechanisms to modulate different components of the endocrine system. This review will describe in vitro and in vivo studies that highlight the spectrum of unique mechanisms of action and biological effects of four endocrine-disrupting chemicals--diethylstilbestrol, genistein, di(n-butyl)phthalate, and methoxyacetic acid--to illustrate the diverse and complex nature of this class of compounds.
Subject(s)
Endocrine Disruptors/pharmacology , Endocrine System/drug effects , Acetates/pharmacology , Acetates/toxicity , Animals , Dibutyl Phthalate/pharmacology , Dibutyl Phthalate/toxicity , Diethylstilbestrol/pharmacology , Diethylstilbestrol/toxicity , Female , Genistein/pharmacology , Genistein/toxicity , Genitalia, Female/drug effects , Genitalia, Male/drug effects , Humans , Male , Receptors, Cytoplasmic and Nuclear/drug effects , Receptors, Cytoplasmic and Nuclear/physiology , Receptors, Estrogen/drug effectsABSTRACT
The signaling pathways that modulate IL-1beta expression in human keratinocytes have not been well defined. We have previously shown that TCDD-stimulated AhR-dependent IL-1beta expression in human keratinocytes is due to posttranscriptional regulation involving mRNA stabilization. Since TCDD activates a variety of cellular signaling pathways such as PKC, JNK, and ERK, we investigated these pathways to determine their roles in TCDD-stimulated IL-1beta expression in the human keratinocyte cell line SCC-12F. In this study, we used specific signaling inhibitors to show that ERK and JNK, but not transglutaminase, PKC, or p38, signaling modulate IL-1beta expression. In addition, we show that ERK is constitutively active and unaffected by TCDD treatment and differentiation, while the JNK signaling pathway is modulated by TCDD in an AhR-dependent manner. Thus, both the ERK and JNK MAPK pathways are necessary for IL-1beta expression in TCDD-stimulated human keratinocytes, however, they act at different levels to modulate IL-1beta expression.
Subject(s)
Interleukin-1/biosynthesis , Keratinocytes/metabolism , MAP Kinase Signaling System/physiology , Mitogen-Activated Protein Kinases/metabolism , Cell Line, Transformed , Enzyme Activation/drug effects , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Humans , JNK Mitogen-Activated Protein Kinases , Keratinocytes/enzymology , MAP Kinase Signaling System/drug effects , Mitogen-Activated Protein Kinases/antagonists & inhibitors , Polychlorinated Dibenzodioxins/metabolism , Polychlorinated Dibenzodioxins/toxicity , Protein Kinase C/metabolism , RNA, Messenger/biosynthesis , Receptors, Aryl Hydrocarbon/drug effects , Receptors, Aryl Hydrocarbon/metabolismABSTRACT
TCDD stimulated IL-1beta gene expression in differentiating human keratinocyte cell lines in a time- and dose-dependent manner. Increases in prointerleukin-1beta (pIL-1beta) protein and IL-1beta steady state mRNA levels were observed in both SCC-12F and HaCaT cells following TCDD treatment. When pretreated with alpha-naphthoflavone, an AhR antagonist, TCDD-mediated increases in IL-1beta gene expression were attenuated, demonstrating for the first time that the environmental toxin, TCDD, can stimulate cytokine (IL-1beta) gene expression in an AhR-dependent manner. Nuclear run-on experiments were performed in SCC-12 cells to determine if the AhR-dependent increases in IL-1beta expression were due to transcriptional activation of the IL-1beta gene. Results showed high constitutive levels of IL-1beta transcriptional activity, however, TCDD treatment, which stimulated IL-1beta steady state mRNA levels, failed to potentiate IL-1beta transcription. Taken together, these results demonstrate that AhR-mediated IL-1beta regulation is occurring posttranscriptionally.
