Assessment of PCBs and hydroxylated PCBs as potential xenoestrogens: In vitro studies based on MCF-7 cell proliferation and induction of vitellogenin in primary culture of rainbow trout hepatocytes.

In the present study, four structurally diverse polychlorinated biphenyls (PCBs) were chosen from a set of 20 PCBs selected to represent the 154 tetra- through hepta-chlorinated biphenyls. The purpose was to determine estrogenic activities of the chosen PCBs and five of their hydroxylated derivatives (OH-PCBs). A human breast cancer cell line (MCF-7) and primary cultures of rainbow trout (Oncorhyncus mykiss) hepatocytes were used to determine estrogenic effects. The PCBs 2,2′,4,6,6′-pentachlorobiphenyl (104) and 2,2′,3, 4′, 5,6,6′-heptachlorobiphenyl (188), and the hydroxylated PCBs 2,2′, 4′,6′-tetrachloro-4-biphenylol (4′-50), 2′,4′, 6′-trichloro-4-biphenylol (4′-30), 2′,3,5, 5′-tetrachloro-4-biphenylol (4′-72), 2′,3,3′,5′, 6′-pentachloro-4-biphenylol (4′-112), and 2′,3,4′,5, 6′-pentachloro-4-biphenylol (4′-121) significantly increased MCF-7 cell proliferation. The coaddition of hydroxytamoxifen, an estrogen antagonist, inhibited increased cell proliferation. The activity of the hydroxylated PCBs 4′-50 and 4′-30 was significantly higher at all nominal concentrations tested as compared to the corresponding PCB, viz., PCB 104. The hydroxylated PCBs 4′-50, 4′-30, 4′-72 and 4′-112 induced vitellogenin synthesis in rainbow trout hepatocytes. Significant differences were found in the MCF-7 system between the parent PCB and its hydroxylated derivative, viz., for 4′-50/4′-30 and 104, and in the rainbow trout hepatocyte assay between 4′-112 and 112, respectively. No activity was observed for PCB 58 in any of the two assays in the present study. Even though cells from two different species (human and fish) are used in the present study, the results obtained by the two methods agree fairly well. In both studies the hydroxylated PCBs were more active than the PCBs, and 4′-30 was the most active compound second only to 17beta-estradiol. http://link.springer-ny. com/link/service/journals/00244/bibs/37n2p145.html

Assessment of hydroxylated metabolites of polychlorinated biphenyls as potential xenoestrogens: a QSAR comparative analysis∗.

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Alternative methods, including quantitative structure-activity relationships (QSAR), are being used increasingly when appropriate data for toxicity evaluation of chemicals are not available. Approximately 40 mono-hydroxylated polychlorinated biphenyls (OH-PCBs) have been identified in humans. They represent a health and environmental concern because some of them have been shown to have agonist or antagonist interactions with human hormone receptors. This could lead to modulation of steroid hormone receptor pathways and endocrine system disruption. We performed QSAR analyses using available estrogenic activity (human estrogen receptor ER alpha) data for 71 OH-PCBs. The modelling was performed using multiple molecular descriptors including electronic, molecular, constitutional, topological, and geometrical endpoints. Multiple linear regressions and recursive partitioning were used to best fit descriptors. The results show that the position of the hydroxyl substitution, polarizability, and meta adjacent un-substituted carbon pairs at the phenolic ring contribute towards greater estrogenic activity for these chemicals. These comparative QSAR models may be used for predictive toxicity, and identification of health consequences of PCB metabolites that lack empirical data. Such information will help prioritize such molecules for additional testing, guide future basic laboratory research studies, and help the health/risk assessment community understand the complex nature of chemical mixtures.

Hormonal action of plant derived and anthropogenic non-steroidal estrogenic compounds: phytoestrogens and xenoestrogens.

Herbivorous and omnivorous vertebrates have evolved in the presence of a variety of phytoestrogens, i.e., plant-derived compounds that can mimic, modulate or disrupt the actions of endogenous estrogens. Since the discovery of the estrus-inducing effects of some plant products in 1926, considerable effort has been devoted to the isolation and structural and pharmacological characterization of phytoestrogens. Recently, agricultural and industrial pollution has added anthropogenic estrogenic compounds to the list of environmental estrogens. Unlike phytoestrogens, these xenoestrogens tend to accumulate and persist in adipose tissue for decades and may cause long-lasting, adverse endocrine effects. Here we review the endocrine effects of known phytoestrogens and xenoestrogens with special emphasis on molecular structure-activity relationships. Phytoestrogens include flavonoids, isoflavonoids, chalcons, coumestans, stilbenes, lignans, ginsenosides and other saponins, as well as the recently discovered tetrahydrofurandiols. Fungal estrogenic compounds may enter the food chain via infested crops. Since some phytoestrogens have been shown to display organ-specific actions, pharmaceutical estrogen analogues with similar properties (selective estrogen receptor modulators, SERMs) are also discussed. Xenoestrogens include dichlorodiphenyltrichloroethane (DDT) and its metabolites, bisphenols, alkylphenols, dichlorophenols, methoxychlor, chlordecone,polychlorinated benzol derivatives (PCBs), and dioxins. While most of these compounds act through estrogen receptors alpha and beta, some of their effects may be mediated by other nuclear or membrane-bound receptors or receptor-independent mechanisms. Some might also interfere with the production and metabolism of ovarian estrogens. Better understanding of the molecular pharmacology of phyto- andxenoestrogens may result in the development of novel compounds with therapeutic utility and improved environmental protection.

High levels of xenoestrogens in patients with low-grade endometrial stromal sarcoma–report of two cases.

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Endometrial stromal sarcomas (ESS) are rare uterine tumors with unknown etiological risk factors, but estrogen-dependent growth promotion.


We present two patients with advanced ESS, who had increased levels of p,p-DDE; hexachlorobenzene; PCB 28; PCB 52; PCB 101; PCB 138; PCB 153 and PCB 180 in abdominal adipose tissue. Other xenoestrogens were within expected limits for the non-exposed European population.


Increased levels of xenoestrogens in patients with ESS may be involved in the pathogenesis of ESS. Chronic exposure toxenoestrogens may be a risk factor for tumor progression.

Estrogenic effects of polychlorinated biphenyls and relation to cytochrome P4501A activity in the endangered goodeid fish Ameca splendens.

The present study examines the relationships between cytochrome P4501A (CYP1A) activity and vitellogenin (VTG) induction in Ameca splendens elicited by a polychlorinated biphenyl (PCB) mixture. Ethoxyresorufin-O-deethylase (EROD) activity, mRNA levels of VTG, and VTG induction were evaluated in male and female fish exposed for 1, 2, 4, 8, and 16 d to a commercial PCB mixture. Polychlorinated biphenyls induced higher EROD in both sexes and this induction was higher in females than in males. Maximum EROD and VTG induction occurred on day 1 in females, while in males these maxima occurred on days 8 and 16. A correlation between EROD and VTG induction was found only in males (p<0.001), and VTG induction was also higher in males than in females (p<0.01). Exposure to PCBs elicited increases in VTG expression and induction over time in males, while in females these decreased at the end of the exposure period. Deficiencies in the feedback mechanisms of male A. splendens exposed in the wild to xenoestrogens such as PCBs have probably contributed to alter the sex ratio of wild populations of this species.

[Effects of environmental pollutants on hormone disturbances].

[Article in French]

There is an increasing scientific concern that organochlorine compounds, recognized as environmental pollutants, may cause estrogen-related disorders. One of the main hypotheses is that organochlorines can act through their estrogenic or anti-estrogenic properties. Many endocrine diseases can be concerned by the pathogenic role on environmental residues in their promotion. The carcinogenic potential of environmental xenoestrogens on breast cancer is a matter of controversy. In Europe, despite their prohibition since the 70’s, residues persist in soil and rivers, resulting in a widespread contamination of the general population. Our results suggest that environmental exposure to p,p’-DDE, HCB or PCBS may contribute to multifactorial pathogenesis of breast cancer. Male infertility is also a matter of concern. Our data suggest that male infertility can be associated with exposure of the mothers to p,p’-DDE, and that deleterious effects are probably restricted to intra-uterine life. Early or precocious puberty in children adopted from developing countries where organochlorines are still used is frequently reported. A possible relationship with exposure to DDT is suggested. There are two possible pathways to account for precocious puberty following chronic exposure to estrogenic related compounds: weak stimulation of estrogen sensitive tissues or removal in Belgium of the suppressing effects of estrogens on gonadotrophins, suppressing effect that was due to exposure in the origin country.

Estrogenic activity of polychlorinated biphenyls present in human tissue and the environment.

This study evaluated the estrogenicity of polychlorinated biphenyls (PCBs) present in environmental media and human tissue and assessed exposure pathways for PCB-derived estrogenic potency in air, soil, and dust from New Bedford, MA, an area with a PCB-contaminated Superfund site. Thirty-four PCB congeners were assayed for estrogenic potency using E-SCREEN, an assay based on the estrogen-dependent proliferation of MCF-7 cells in vitro. Childhood exposure to estradiol-equivalents via PCBs in environmental media was estimated byweighting previously reported New Bedford congener-specific concentrations by their relative estrogenic potency and published inhalation and soil ingestion rates. Thirteen congeners were weakly estrogenic in E-SCREEN: PCBs 17, 18, 30, 44, 49, 66, 74, 82, 99, 103, 110, 128, and 179. These PCBs were typically 6 orders of magnitude less potent than 17beta-estradiol, with proliferative potencies ranging from 0.0007% to 0.0040%. Of the environmental media assessed, air (inhalation) had the highest PCB-derived estradiol-equivalent exposure. PCB estrogenic potency information from this study provides an important resource both for preliminary estimation of routes of human exposure to xenoestrogens and for application to human health studies focused on estrogen-responsive health outcomes, such as reproductive development and related malignancies.