Clinical and reproductive effects of clophen A50 (PCB) administered during gestation on pregnant guinea pigs and their offspring

Recent research has suggested that con ants in the environment may influence sdifferentation and reproductive endocrine fimction in wildlie. Concentrations oforganochlorine contaminants (total polychlorinated biphenyls, pesticides) were higher in the blood plasma of snapping turtles from contaminated sites than in those from reference sites. The ratio of the precloacal length to the posterior lobe of the plastron (PPR) is sually dimorphic in snapp turdes. There were significant reductions in the PPR at three conm ted site versus two reference sites. The magnitude of the response was such that a sigificnty higher proportion of PPRs of males from a contaminated site (Cootes Paradise) overlapped with those of females than PPRs of males from a reference site (Lae Sasajewun). Observers can incorrety idenify the sex ofturtes at the contaminated site based on secondary sexual characteristics alone. Unlike the changs to the morphology, there were few changes in 17J-estradiol or testosterone levels, and where differences occurred, therewas more varnation among reference sites than between the reference and contaminated sites. Our results suggest that environmental CO minants may afiect sexually dimorphic morphology in snapping turles without affecting circulating testosterone or estrogen levls in the adults. &y words biomonitoring femintion, morphology, organochlorines, pesticides, snapping turtes, testosterone.

Section: Discussionmentioning

confidence: 54%

Impact of Organochlorine Contamination on Levels of Sex Hormones and External Morphology of Common Snapping Turtles (Chelydra serpentina serpentina) in Ontario, Canada

Solla¹,

Bishop²,

Kraak³

et al. 1998

“…Three PCB derivatives (8,9, and 12) in the training set possess chlorine substituents adjacent to the para-hydroxyl group. The plA of the hydroxyl group in these compounds is calculated by manufacturer (CompuDrug Chemistry Ltd, Budapest) to be lower (6.7, 6.2, and 5.8, respectively) than the pH of the assay medium (7.6).…”

Section: Resultsmentioning

confidence: 99%

“…However, these products have been banned in the United States since the 1970s (6X7). The highly chlorinated and lipophilic nature of these compounds underlie their persistence as environmental contaminants, and they are known to cause adverse reproductive effects in males (8) and females (8, M. Modified mixtures of PCBs, which are lower in overall chlorine content yet rich in ortho-chlorinated biphenyls, have been proposed as alternatives to the highly chlorinated PCB mixtures. The lower chlorine content favors increased metabolism in biological systems.…”

mentioning

confidence: 99%

Using Three-Dimensional Quantitative Structure-Activity Relationships to Examine Estrogen Receptor Binding Affinities of Polychlorinated Hydroxybiphenyls

Waller¹,

Minor²,

McKinney³

1995

Certain phenyl-substituted hyd ns of environmental concen have the potential to disrupt the endocrine system of animals, apparently in association with their estrogenic properties. Competition with natural estrogens for the estrogen receptor isaa possible mechanism by which such effects could occur. We used comp molecular field analysis (CoMFA), a three-dimensional quantitative structure-activity relationship (QSAR) (11).In addition to the PCB family of chemicals, other phenyl-substituted hydrocarbons such as the biphenyl ethanes and ethylenes related to diethylstilbestrol (DES) (12) and triphenylethanes (13), including tamoxifen and nafoxidine, have been shown to be ligands of the estrogen receptor. A common substructure of many of these chemicals is a phenolic ring system, with an obvious relationship to the phenolic A ring in estradiol (Fig. 1). However, it is not clear if in all cases the hydroxyl group has unique properties as a substituent or if any similar-sized (isosteric) group, such as chlorine, could replace it. Such a substructure serves as a unique way to align the molecules for comparing the overall structures of otherwise structurally diverse chemicals. In this way it may be possible to determine their estradiol equivalency (14) in a manner analogous to determining the dioxin equivalency (15) of structurally related chlorinated aromatic hydrocarbons of environmental health concern. We used comparative molecular field analysis (CoMFA) (16), a three-dimensional quantiative structure-activity relationship (QSAR) paradigm, to examine the unique physicochemical properties of polychlorinated hydroxybiphenyls (Table 1) underlying their estrogen receptor binding affinities and thus their potential estradiol equivalency. MethodsThe SYBYL molecular modeling software package (version 6.0, Tripos Associates, Inc., St. Louis, Missouri) was used to do all molecular modeling. The coordinates for estradiol and DES were retrieved from the Cambridge Structural Database. The remaining molecules were constructed in SYBYL using the sketch option. All molecules were minimized using the standard Tripos force field (17) to an energy change convergence criterion of 0.001 kcal/mol. The SYBYL geometries were used as starting coordinates for full-geometry optimization using MOPAC 5.0 (Quantum Chemistry Program Exchange, Indiana University, Bloomington, Indiana) with the AMI (18) model Hamiltonian.For each biphenyl molecule (including DES), using the MOPAC/AMI optimized structure as a starting point, the conformational space about the twist bond(s) connecting the two ring systems was explored. This bond was systematically searched at 50 increments. The lowest energy conformer obtained from the search was then subjected to full MOPAC/AM1 optimization. This structure was then aligned relative to estradiol by root-mean-squares (RMS) fit of the hydroxyphenyl ring (A) carbons and the corresponding carbons of the para-substituted ring of the molecule to be fitted. Due to structural symmetry of the biphenyls, several alignments w...

“…Mixtures exhibit properties consistent with their multiple components. Thus, while the estrogenic PCB mixture Aroclor 1221 causes precocious puberty (12), another mixture (Clophen A-50, which contains many antiestrogenic congeners) delays onset of puberty in female rats (17). Similarly estrogenic organochlorines support implantation and pregnancy, while TCDD inhibits implantation (18).…”

Section: Pcbs and Breast Cancer Riskmentioning

confidence: 99%

Environmental Organochlorine Exposure as a Potential Etiologic Factor in Breast Cancer

Wolff¹,

Toniolo²

1995

Known risk factors for breast cancer do not account for a significant proportion of the overall incidence. Reproductive factors and endogenous hormones are thought to be responsible for a large component of risk. An environmental contribution has been sought in the past to explain the international trends in breast cancer rates and changes in risk among migrating populations. Recently, environmental research has turned to investigation of exogenous chemical exposures, including environmental contamination, as potential risk factors that may arise from the hormonal activity or from the carcinogenicity of many of these chemicals. Several reports since 1991 suggest that organochlorines may be a risk factor for breast cancer. The data are strongest for DDT. For PCBs, the results to date have been equivocal if not entirely negative. However, different groups of polychlorinated biphenyl (PCB) congeners are known to provoke biological responses that are structure specific. A wide divergence of estrogenic response, cytochrome P450 activity, and biological half-life exists within these groups of PCB congeners. Therefore, understanding breast-cancer risk from PCB exposure requires attention to congener structures in complex mixtures and to temporal changes in exposure. Investigation of environmental contributions to breast cancer risk offers the potential for understanding more about the etiology of this complex disease and may also provide opportunities for prevention of the most common cancer among women in the United States. -Environ Health Perspect 103(Suppl 7): 141-145 (1995)