Environmental Endocrine-Disrupting Chemicals (Endocrine Disrupters)

15 November, 1998

Environmental Endocrine-Disrupting Chemicals (Endocrine Disrupters)

Endocrine-disrupting chemicals are of considerable public concern and interest. Developmental abnormalities observed in natural environments are alleged to arise from pollutants with estrogenic and other hormonal activities. Some chemicals in pollutants and/or eluted from products for human use are suspected to affect normal development and differentiation to result in deformity and deficient sex characteristics. These claims are supported to a certain extent by recent clinical observations that suggest an increasing incidence of human male genital tract malformations, male infertility, and female breast cancer upon exposure to chemicals with antiandrogenic activity. It is not always clear, however, how these chemicals arise in the environment and are deleterious to embryonic development. Methodologies for screening endocrine disrupters and assaying their hormonal activities still remain to be explored to assess the level of their danger.
In early 1995 the Committee on the Environment and Natural Resources (CENR) of the National Science and Technology Council (USA) identified the endocrine disrupter issue as a major research initiative and subsequently established an ad hoc Working Group on Endocrine Disrupters. The main objectives at that time were 1) to develop a framework for research related to human and ecological health effects of endocrine disrupting chemicals, 2) to conduct an inventory of relevant ongoing research programs, and 3) to identify research gaps for the development of a coordinated plan to address priority research needs. As it turned out (Reiter LW et al. 1998: uid=9443998), studies on reproductive development and carcinogenesis were more prevalent among researchers than studies on neurotoxicity and immunotoxicity; mammals (mostly laboratory animals) were the main species under study; chlorinated dibenzodioxins and polychlorinated biphenyls were the most commonly studied chemical classes.ﾊThis is the status quo of the study on endocrine disrupters.

Recently bisphenols have also become of public concern. The chemical structure of hydroxylated diphenylalkanes (bisphenols) consists of two phenolic rings joined together through a bridging carbon. This class of endocrine disrupters that mimic estrogens is widely used in industry, particularly in plastics. Bisphenol F, bisphenol A, fluorine-containing bisphenol A (bisphenol AF), and other diphenylalkanes were found to be estrogenic in a bioassay with MCF7 human breast cancer cells in culture (E-SCREEN assay). Bisphenols promoted cell proliferation and increased the synthesis and secretion of cell type-specific proteins. When ranked by proliferative potency, the longer the alkyl substituent at the bridging carbon, the lower the concentration needed for maximal cell yield; the most active compound contained two propyl chains at the bridging carbon. Bisphenols with two hydroxyl groups in the para position and an angular configuration are suitable for appropriate hydrogen bonding to the acceptor site of the estrogen receptor. These data suggest that estrogenicity is influenced not only by the length of the substituents at the bridging carbon but also by their structural nature (Perez P et al. 1998: uid=9449681). As bisphenol A and octylphenol are used in the manufacture of plastics and other products, and have been detected in food and water consumed by animals and people, female mice were fed an average concentration (dissolved in oil) of bisphenol A or octylphenol of 2 ng/g body weight (2 ppb) and 20 ng/g (20 ppb). The 2 ppb dose of bisphenol A is lower than the amount reported to be swallowed during the first hour after application of a plastic dental sealant in the dentistry (that is, up to 931 micrograms; 13.3 ppb in a 70 kg adult). The 2 ng/g dose of bisphenol A was found to increase the size of the preputial glands, but reduced the size of the epididymides (These organs develop from different embryonic tissues). At 20 ng/g, bisphenol A significantly decreased the efficiency of sperm production (daily sperm production per g testis) by 20% relative to control males (vom Saal FS et al. 1998: uid=98121480). The only significant effect of octylphenol was a reduction in daily sperm production at the 2 ng/g dose.

Excessive publicity may easily distort the real significance of environmental endocrine-disrupting chemicals described in an increasing number of reports. There are a variety of natural endrogenic chemicals. For example, phytoestrogens (coumestans, isoflavonoids, flavonoids, and lignans) present in numerous edible plants are quantitatively the most important environmental estrogens when their hormonal potency is assessed in vitro. They exert in vitro their estrogenic activity by interacting with estrogen receptors (ERs). In fact they may also act as antiestrogens by competing for the binding sites of estrogen receptors, or for the active sites of the estrogen-biosynthesizing and -metabolizing enzymes, such as aromatase and estrogen-specific 17 beta-hydroxysteroid oxidoreductase (type 1). Estrogenic effects in wildlife have been described but the evidence for the role of phytoestrogens is indirect and seen under conditions of excessive exposure. Since agents that could influence endocrine systems pervade the environment, their full implications for public health and environmental integrity may not be captured simply by labelling estrogenic chemicals as disrupters. Therefore,the risk assessment might well be a difficult endeavor , particularly as the endpoints of endocrine disruption (that is, toxicity leading to infertility?) may not be determined easily.ﾊ

US Environment Protection Agency, OECD and other government and private organizations plan to establish systems for screening and assaying endocrine-disrupting activities. Molecular mechanisms related to the expression of endocrine-disrupting activities are essential to devise such systems. Some of the more relevant and interesting findings are described here. Mammalian cells possess specific receptors for aryl hydrocarbons (AHR). AHR is a ligand-inducible transcription factor that may be activated by environmental pollutants such as 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and benzo[a]pyrene, and mediates the carcinogenic, teratogenic, hepatotoxic and immunotoxic effects of these compounds. Unliganded AHR resides in the cytoplasm in a complex with the 90-kDa heat shock protein (HSP90) and the immunophilin homolog ARA9. Upon binding ligand, AHR translocates to the nucleus, dissociates from HSP90 and complexes with another transcription factor "AHR nuclear translocator" (ARNT). Both AHR and ARNT are members of a family of regulatory proteins that contain an N-terminal basic helix-loop-helix DNA-binding motif and a domain termed PAS. The PAS mediates interaction with HSP90, binding to the ligand and heterodimeization with ARNT. The AHR/ARNT heterodimer binds a specific DNA sequence termed either xenobiotic response element (XRE), dioxin response element or AhRE, to regulate the transcription of target genes.

There are a least 2 classes of AHR agonists (ligands). In the first class, certain polycyclic aromatic hydrocarbons such as b-naphthoflavone (bNF) and carcigngen benzo[a]pyrene produced by cigarette smoking and other combustion processes initiate induction of at least 3 enzymes of the cytochrome P450 pathway and other drug metabolizing enzymes that metabolize the inducing ligands. Some of the resultant intermediates can mutate DNA (Denissenko MF et al. 1996: uid=96436568). The second class of ligands, including halogenated aromatic hydrocarbons such as TCDD, are poorly metabolized and do not interact directly with DNA. However, these agonists initiate a broader pleiotropic response that includes induction of both those genes mentioned above and other less well characterized genes that are considered to be responsible for the toxic, teratogenic and carcinogenic effects of these compounds. An endogenous ligand for AHR is not yet described but it is most likely from embryonic expression of AHR that AHR and its presumptive endogenous ligand play a role in embryonic development and homeostasis. Disruption of murine Ahr gene resulted in defects in the liver development, and in decreased constitutive expression of xenobiotic metabolizing enzymes such as CYP1A2 (Schmidt JV et al. 1996: uid=96270611).

The elucidation of molecular mechanisms of endocrine disrupters should make for the reasonable risk assessment and for defining the endpoints of endocrine disruption. This would help classify which compounds be removed from the environment.

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