Unequivocal estrogen receptor-binding affinity of phthalate esters featured with ring hydroxylation and proper alkyl chain size

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Phthalate esters (PEs) are plasticizers used in many plastic products, food packaging materials, and medical bags. The widespread use of PEs has led to ubiquitous environmental contamination and human-exposure. Several epidemiological studies have indicated that exposure to PEs, especially during the prenatal period, induces adverse effects, including developmental and behavioral abnormalities, suggesting that PEs are endocrine-disrupters. Although the endocrine-disrupting effect of PEs is thought to be estrogen receptor (ER)-mediated, the ER-binding affinity of PEs is quite low, indicating that other mechanisms should be considered. In this review, we demonstrate that alkyl chain length and hydroxylation of PEs have a significant impact on binding to ERs and peroxisome proliferator-activated receptors. In addition, we discuss recent results from our laboratory that suggest additional risks may arise from environmental and metabolic processing of PEs through microbial transformation, microsomal metabolism, and sunlight exposure.

Section: Er-mediated Effects Of Hydroxylated Phthalate Estersmentioning

confidence: 99%

Section: Microbial Biotransformationmentioning

confidence: 99%

Potential Risks of Phthalate Esters: Acquisition of Endocrine-disrupting Activity during Environmental and Metabolic Processing

Okamoto

Ueda

Kojima

2011

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“…For example, differences in alkyl chain lengths and branching are associated with drastic differences in the estrogen receptor (ER)-mediated effects of ring-hydroxylated PEs, which are active metabolites/photo-oxidation products of PEs and are bound to ERs. [7][8][9][10] The ER-binding potential of ring-hydroxylated PEs increases with increasing alkyl chain length and branching. A yeast reporter gene assay revealed that PEs with short alkyl chains (e.g., ethyl or propyl esters) promoted ERdependent reporter gene expression, whereas PEs with long alkyl chains (e.g., octyl or 2-ethylhexyl esters) did not, even though the latter exhibited extremely high ER-binding affinities.…”

Section: Introductionmentioning

confidence: 99%

Transesterification in the Microbial Degradation of Phthalate Esters

Okamoto

Toda

Ueda

et al. 2011

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Our previous study revealed that phthalate esters (PEs), a group of suspected endocrine-disrupting chemicals, acquire estrogenic activities by ring 4-hydroxylation. In addition, the estrogenic activities are modified depending on alkyl chain structures (chain length and branching), which can be altered in the environmental conditions such as microbial degradation. Therefore, it is important to determine the environmental fate of these alkyl chains to evaluate the biological impact of PEs on humans and wildlife. PEs are known to undergo biodegradation via sequential hydrolysis, resulting in the formation of monoester and dicarboxylic acid forms. In this study, dipropyl phthalate chosen as one of PEs was cultivated with Acinetobacter lwoffii, a known PE-degrading bacterium, in the presence of a limited amount of CH 3 OH as a PE-solvent. As a result, several unknown biotransformation products were detected. The products were characterized as methyl propyl phthalate, dimethyl phthalate, and monomethyl phthalate, suggesting that environmental PEs are processed through novel biotransformation pathways. The products can be produced both by esterification of monoester forms and transesterification of diester forms. However, when monobutyl phthalate-a monoester of dibutyl phthalate-was used as a substrate, esterified products were not detected, indicating phthalate methyl esters were formed via transesterification. A stable-isotope tracer experiment using CD 3 OH instead of CH 3 OH revealed the production of phthalate methyl esters, the molecular ions of which shifted by 3 or 6 atomic mass units. These results revealed that PE was bacterially trans- * To whom correspondence should be addressed: Faculty of Pharmacy, Meijo University, 150 Yagotoyama, Tempaku-ku, Nagoya 468-8503, Japan. Tel.: +81-52-839-2676; Fax: +81-52-834-8090; E-mail: kojiman@meijo-u.ac.jp formed via transesterification in the presence of alcohol. We demonstrated that PEs are transformed in the environment via more diverse ways than expected, although the environmental concentration of alcohols is very low. It would be worthwhile to perform a systematic assessment on the possibility that transesterification products may be associated with the potential adverse effects of PEs in the environment.

“…Some insecticides and medicines are also possible proestrogens. Hydroxylated derivatives of sunscreen, 88) and phthalate esters 89) show positive in estrogenicity tests. Thus, the parent compounds may be proestrogens.…”

Section: Activation Of Other Proestrogens In Environments By the Cytomentioning

confidence: 99%

Metabolic Activation of Proestrogens in the Environment by Cytochrome P450 System

Kawa

Sugihara

Sanoh

et al. 2008

Liver microsome-mediated activation of proestrogens in the environment is reviewed here. Proestrogens such as methoxychlor, trans-stilbene, diphenyl, diphenylmethane, 2,2-diphenylpropane, benzo[a]pyrene, benzophenone, 2-nitrofluorene (NF), chalcone, trans-4-phenyl-3-buten-2-one and styrene oligomers are negative in in vitro estrogen screening tests. However, those proestrogens exhibit estrogenic activity after metabolic activation by the microsomal cytochrome P450 system. In these cases, hydroxylated derivatives of the compounds are formed as major metabolites, and these metabolites exhibit significant estrogenic activities. Thus, the estrogenic activities of proestrogenic compounds are a consequence of metabolism of the parent compounds. Various candidates for proestrogens among medicines and insecticides are also discussed.