Endocrine-disrupting Chemicals: Review of Toxicological Mechanisms Using Molecular Pathway Analysis

Abstract

Endocrine disruptors are known to cause harmful effects to human through various exposure routes. These chemicals mainly appear to interfere with the endocrine or hormone systems. As importantly, numerous studies have demonstrated that the accumulation of endocrine disruptors can induce fatal disorders including obesity and cancer. Using diverse biological tools, the potential molecular mechanisms related with these diseases by exposure of endocrine disruptors. Recently, pathway analysis, a bioinformatics tool, is being widely used to predict the potential mechanism or biological network of certain chemicals. In this review, we initially summarize the major molecular mechanisms involved in the induction of the above mentioned diseases by endocrine disruptors. Additionally, we provide the potential markers and signaling mechanisms discovered via pathway analysis under exposure to representative endocrine disruptors, bisphenol, diethylhexylphthalate, and nonylphenol. The review emphasizes the importance of pathway analysis using bioinformatics to finding the specific mechanisms of toxic chemicals, including endocrine disruptors.

Keywords: Endocrine disruptors; Molecular mechanism; Obesogen; Pathway analysis.

Figure 1.

Exposure sources and routes of endocrine disruptors in human. (A) Humans are exposed to endocrine disruptors directly or indirectly. Direct is through raw substance such as pharmaceutical including endocrine disruptors and phytoestrogens in plants. Indirect is exposure from foods treated with endocrine disruptors like pesticides and fungicides. (B) The major routes of human exposure. The fetus can be exposed by endocrine disruptors from the mother through the blood and breast milk. Cited from the article of Sharpe and Irvine (BMJ 2004;328:447–51) with original copyright holder’s permission.

Figure 2.

Common molecular mechanisms of endocrine disruptors. (A) Endocrine disruptors act as receptors (especially endocrine receptor) binding inhibitors. Most harmful effects are initiated by this inhibition and is shown by most endocrine disruptors mechanism. (B) When the targets of endocrine disruptors were adipocyte, endocrine disruptors can be obesogens. In this case, peroxisome proliferator activated receptor (PPAR) on mesenchymal cells or progenitor cells are the targets. (C) In the case of cancer, endocrine disruptors act on the cell cycle. Cyclin protein and p21 protein were known to regulate cancer cells when exposed to endocrine disruptors. ER, estrogen receptor; MSC, mesenchymal stem cell. Cited from the article of Celik et al. (Chem Res Toxicol 2008;21:2195–206), Masuno et al. (Toxicol Sci 2005;84:319–27), and Ohtsubo et al. (Mol Cell Biol 1995;15:2612–24).–

Figure 3.

The related pathway of molecular/cellular process and disease/ disorder. (A) Bisphenol A. Included molecular/cellular process and diseases/disorders were collected from the relevant papers.– (B) Phthalate. Included molecular/cellular process and diseases/disorders were collected from the relevant papers.– (C) Nonylphenol. Included molecular/ cellular process and diseases/disorders were collected from the relevant papers.,– Each pathway was discovered using pathway analysis. Researchers can find the significant molecular and cellular pathway and compare and infer the correlation between the endocrine disruptors and the disease in terms of gene ontology. The pathway analysis can open up the possibility for more study. LEF1, lymphoid enhancer-binding factor 1; PPAR, proliferator activated receptor; ICF3, immunodeficiency-centromeric instability-facial anomalies syndrome 1.