16 Molecular Modeling Method Applications …
317
triBBPA
Tribromobisphenol A
UNEP
United Nations Environment Programme
US EPA
United States Environmental Protection Agency
WHO
World Health Organization
16.1 Introduction
Since the 1990s, the scientific community, regulators, and the public have been
increasingly concerned by the harmful effects of endocrine-disrupting chemicals
(EDCs) on humans and wildlife [1]. The observed adverse effects include suppression of gene expression or enzyme activities, alteration of protein concentrations or hormones homeostasis, disruption of brain or immune system development,
reproductive dysfunction and/or hormone-dependent cancers, feminization effects or
demasculinization problems, and so on [2–6]. In response to this pressing issue, several EDCs screening programs and national/international actions have been launched
and implemented in USA [7], European Union [8], China [9], Japan [10], Organization for Economic Co-operation and Development (OECD) [11], World Health
Organization (WHO) [12], and United Nations Environment Programme (UNEP)
[13, 14] since 1996. Clarification of the endocrine-linked toxic mechanism of action
(MOA) is needed to implement EDC screening programs and actions [15, 16].
To date, there are various mechanisms through which EDCs can exert their effects
on the endocrine system [17–20]: (a) impacting macromolecule regulatory function
in the hypothalamic-pituitary-gonad/thyroid/adrenal axis, (b) inhibiting hormone
synthesis-related enzymes, (c) disrupting hormone transport proteins, (d) activating/inhibiting hormone receptors, and/or (e) inhibiting hormone metabolism-related
enzymes. Thus, the endocrine-linked MOA of EDCs causing endocrine-related diseases and endocrine dysfunction can be summarized as the interactions between
small molecules (toxicant) and biomacromolecule (target) [21, 22]. Furthermore,
the interaction between EDCs and biological targets was also the critical molecularinitiating event (MIEs) of the endocrine-specific adverse outcome pathway (AOP)
[23, 24]. Thus, studying the interaction of EDCs with endocrine system targets (hormone receptors, synthesis, and metabolism-related enzymes of hormones, hormone
transport proteins, and so on) will pave the way for developing screening methods,
prioritizing, and elucidating the endocrine-related AOP.
A variety of bioassays have been developed and used to test if a given EDC activates, inhibits, or binds to a target up to now [11, 18, 25]. However, current experimental methods poorly probe the underlying molecular mechanisms. For example,
it is thought that compounds with common structural features exhibit and elicit
similar toxicological effects as well as share similar interaction mechanisms. As
shown in Fig. 16.1, the 4
-HO-2,3
,4,5
,6-pentabrominated diphenyl ether (4
-HOBDE 121) and 3,3
,5,5
-tetrabromobisphenol A (TBBPA) are structurally similar to
tetraiodothyronine (T4). In contrast, the structure of pentabromophenol, perfluoroheptanoic acid (PFHpA), perfluorooctane sulfonic acid (PFOS) is greatly different
317
triBBPA
Tribromobisphenol A
UNEP
United Nations Environment Programme
US EPA
United States Environmental Protection Agency
WHO
World Health Organization
16.1 Introduction
Since the 1990s, the scientific community, regulators, and the public have been
increasingly concerned by the harmful effects of endocrine-disrupting chemicals
(EDCs) on humans and wildlife [1]. The observed adverse effects include suppression of gene expression or enzyme activities, alteration of protein concentrations or hormones homeostasis, disruption of brain or immune system development,
reproductive dysfunction and/or hormone-dependent cancers, feminization effects or
demasculinization problems, and so on [2–6]. In response to this pressing issue, several EDCs screening programs and national/international actions have been launched
and implemented in USA [7], European Union [8], China [9], Japan [10], Organization for Economic Co-operation and Development (OECD) [11], World Health
Organization (WHO) [12], and United Nations Environment Programme (UNEP)
[13, 14] since 1996. Clarification of the endocrine-linked toxic mechanism of action
(MOA) is needed to implement EDC screening programs and actions [15, 16].
To date, there are various mechanisms through which EDCs can exert their effects
on the endocrine system [17–20]: (a) impacting macromolecule regulatory function
in the hypothalamic-pituitary-gonad/thyroid/adrenal axis, (b) inhibiting hormone
synthesis-related enzymes, (c) disrupting hormone transport proteins, (d) activating/inhibiting hormone receptors, and/or (e) inhibiting hormone metabolism-related
enzymes. Thus, the endocrine-linked MOA of EDCs causing endocrine-related diseases and endocrine dysfunction can be summarized as the interactions between
small molecules (toxicant) and biomacromolecule (target) [21, 22]. Furthermore,
the interaction between EDCs and biological targets was also the critical molecularinitiating event (MIEs) of the endocrine-specific adverse outcome pathway (AOP)
[23, 24]. Thus, studying the interaction of EDCs with endocrine system targets (hormone receptors, synthesis, and metabolism-related enzymes of hormones, hormone
transport proteins, and so on) will pave the way for developing screening methods,
prioritizing, and elucidating the endocrine-related AOP.
A variety of bioassays have been developed and used to test if a given EDC activates, inhibits, or binds to a target up to now [11, 18, 25]. However, current experimental methods poorly probe the underlying molecular mechanisms. For example,
it is thought that compounds with common structural features exhibit and elicit
similar toxicological effects as well as share similar interaction mechanisms. As
shown in Fig. 16.1, the 4
-HO-2,3
,4,5
,6-pentabrominated diphenyl ether (4
-HOBDE 121) and 3,3
,5,5
-tetrabromobisphenol A (TBBPA) are structurally similar to
tetraiodothyronine (T4). In contrast, the structure of pentabromophenol, perfluoroheptanoic acid (PFHpA), perfluorooctane sulfonic acid (PFOS) is greatly different