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PubMed2001

Diet and organochlorine contaminants in women of reproductive age under 40 years old.

The diet of the breast-feeding mother impacts on the quality and quantity of the milk that she feeds her child. Milk can be a vehicle for toxins, such as drugs and their metabolites, viruses, nicotine, caffeine, alcohol, and organochlorine molecules such as PCBs, DDT, HCB, HCH and dioxins, which can harm the health of the breast-feeding child. The 24-h recall diet was considered appropriate to adequately study the diet of breast-feeding mothers and was used in the present preliminary study to establish the possible relationship between the food items consumed and the presence of pesticides in her milk. Two groups of randomly selected healthy breast-feeding volunteers aged between 17 and 35 years from two different areas were recruited: 34 from intensive agriculture zone, El Ejido (Almeria), from the "Hospital de Poniente" and 21 urban zone, the city of Granada, from the "Clinico" University Hospital. Application of the Spearman Correlation Test to the results from Almeria showed a certain positive correlation between the total intake of fats and both the p,p'DDD (rho=0.53, p< or =0.05) and methoxychlor (rho=0.48, p< or =0.05) in mature milk, and between the energy supplied by vegetables and the endosulfan-lactone in mature milk (rho=0.50, p< or =0.05). Among the group of breast-feeding women from Granada, there was a strong correlation between the intake of fats and both the p,p'DDT in transition milk (rho=0.90, p< or =0.05) and the p,p'DDD in mature milk (rho=0.90, p< or =0.05). In conclusion, there is a statistically significant relationship between the consumption of fatty foods and some organochlorine molecules and between the consumption of vegetables and pesticides, and the latter relationship occurs in Almeria but not in Granada.

Adolescent↗
PubMedDate not supplied

Assessment of estrogenicity by using the delayed implanting rat model and examples.

Endocrine disrupting chemicals have recently drawn increased interest. The delayed implanting rat model is a method that can identify and quantify the estrogenic activity of a chemical. In rats hypophysectomized after breeding, the administration of progesterone delays embryo implantation, and exposure to one dose of an estrogenic substance initiates implantation. Although methoxychlor was ineffective at dosages below 400 mg/kg when given by injection, the administration of the chemical by gavage resulted in an increase in the percent of fertilized rats exhibiting implantation sites. These results were statistically significant at dosages of 50, 100, 200, and 300 mg methoxychlor/kg. When bisphenol A was administered, by subcutaneous injection, dosages of 50, 100, and 200 mg/kg induced implantation. Only the 400 mg/kg dose of 4-tert-octylphenol was effective. Doses of beta-sitosterol up to 30 mg/kg failed to initiate implantation. These data confirm previous evidence of the availability of this model for evaluating estrogenic activity and provide estimates of the estrogenic potencies of several environmentally important chemicals.

Administration, Oral↗
PubMedDate not supplied

Incorporation of S-9 activation into an ER-alpha transactivation assay.

We evaluated the feasibility of incorporating an exogenous metabolic activating system into an estrogen receptor-alpha transactivation assay. 17beta-estradiol (E2), and the proestrogenic pesticide methoxychlor (MXC) were evaluated for activity in the presence and absence of Aroclor-1254 induced rat liver S-9 fractions. Both E2 and MXC responded consistently in the assay with average EC(50) values of 9.6 x 10(-11) M and 1.2 x 10(-5) M, respectively. In the presence of a 0.1% S-9 fraction, the EC(50) for E2 was increased to 1.4 x 10(-9) M and that for MXC decreased to 4.9 x 10(-7) M, with both compounds demonstrating increased secondary metabolite formation as evidenced by HPLC analysis. Consistent with these data, metabolites of E2 and MXC exhibited decreased and increased potencies, respectively, in the assay system relative to the parent molecules. S-9 was compatible with the MCF-7 reporter assay and has the potential to enhance detection of proestrogenic materials.

Animals↗
PubMedDate not supplied

Influence of organochlorine pesticides on maturation and postfertilization development of bovine oocytes in vitro.

The aim of this study was to perform a dose-response test to determine whether bovine oocytes exposed to dichlorodiphenyltrichloroethane (DDT), hexachlorocyclohexane (gammaHCH), or methoxychlor (MXC) in vitro would exhibit changes in maturation rates, cleavage rates at Day 2, or blastocyst rates at Day 7 to 8 after fertilization in vitro (IVF). All three pesticides affected maturation and degeneration rates in a dose-dependent manner, but to different extents. Higher concentrations of pesticides were associated with higher rates of chromatin degeneration. Because the maturation of bovine oocytes was depressed in a dose-dependent manner, the fertilizability and further embryonic development of in vitro matured oocytes was studied at the lowest previously tested concentration (7.25 microg/mL) only. No significant difference in fertilization rates was seen between unexposed control and treated groups. The cleavage rates did not differ among groups 48 h after IVF. The number of morulae and blastocysts on Day 7 to 8 after IVF, which is commonly used as a parameter for normal development, was significantly different between control and DDT- and gammaHCH-treated groups, but not between the control and MXC groups. The pesticides did not differ significantly among themselves. These results show that the tested pesticides decrease the rate of normal oocyte maturation in vitro in a dose-dependent manner. The effect of the lowest concentration of pesticides is seen only after Day 7 of embryo development.

Animals↗
PubMedDate not supplied

Inhibitory effects of organochlorine pesticides on intercellular transfer of Lucifer Yellow in cultured bovine oviductal cells.

The present study investigated the effects of dichlorodiphenyltrichloroethane (DDT), methoxychlor (MXC), and gamma-hexachlorocyclohexane (gammaHCH, lindane) on gap junctional intercellular communication (GJIC) in cultured bovine oviductal cells. GJIC was evaluated by microinjecting fluorescent dye Lucifer Yellow and observing the inhibition of the spreading of dye into adjacent cells. After incubation for 1 h at 37 degrees C, a dose-dependent inhibition of GJIC was observed over a concentration range of 16 to 128 microM DDT, MXC, or gammaHCH compared with nonexposed controls. A significant inhibition began at 32 microM DDT, MXC, or gammaHCH. After incubation for 5 h, a dose-dependent inhibition of GJIC was obtained in the concentration range from 8 to 64 microM of the pesticides. The first significant inhibitory effect on GJIC was caused by 8 microM DDT, 16 microM MXC, and 32 microM gammaHCH. The 128 microM concentration of the pesticides was toxic. At pesticide concentration of 64 microM, the decrease in dye-coupling observed was not due to lethal cell injury, as is indicated by the use of trypan blue dye exclusion. After removal of 64 microM DDT from the culture medium, intercellular communication was reestablished within 3 h. Measurement of cytosolic free Ca2+ concentration [Ca2+]i in fura-2/AM-loaded oviductal cells showed that the inhibition of GJIC by addition of DDT, MXC, or gammaHCH was not associated with a detectable increase in [Ca2+]i. Coincubation of the DDT with dibutyryl-cAMP prevented the 64 microM DDT-induced inhibition of intercellular communication in adherent oviduct cells. It is suggested that organochlorine pesticides can influence cells responsible for reproduction.

Animals↗
PubMed2000

Differential estrogen receptor binding of estrogenic substances: a species comparison.

The study investigated the ability of 34 natural and synthetic chemicals to compete with [3H]17beta-estradiol (E2) for binding to bacterially expressed glutathione-S-transferase (GST)-estrogen receptors (ER) fusion proteins from five different species. Fusion proteins consisted of the ER D, E and F domains of human alpha (GST-hERalphadef), mouse alpha (GST-mERalphadef), chicken (GST-cERdef), green anole (GST-aERdef) and rainbow trout ERs (GST-rtERdef). All five fusion proteins displayed high affinity for E2 with dissociation constants (K(d)) ranging from 0.3 to 0.9 nM. Although, the fusion proteins exhibited similar binding preferences and binding affinities for many of the chemicals, several differences were observed. For example, alpha-zearalenol bound with greater affinity to GST-rtERdef than E2, which was in contrast to other GST-ERdef fusion proteins examined. Coumestrol, genistein and naringenin bound with higher affinity to the GST-aERdef, than to the other GST-ERdef fusion proteins. Many of the industrial chemicals examined preferentially bound to GST-rtERdef. Bisphenol A, 4-t-octylphenol and o,p' DDT bound with approximately a ten-fold greater affinity to GST-rtERdef than to other GST-ERdefs. Methoxychlor, p,p'-DDT, o,p'-DDE, p,p'-DDE, alpha-endosulfan and dieldrin weakly bound to the ERs from the human, mouse, chicken and green anole. In contrast, these compounds completely displaced [3H]E2 from GST-rtERdef. These results demonstrate that ERs from different species exhibit differential ligand preferences and relative binding affinities for estrogenic compounds and that these differences may be due to the variability in the amino acid sequence within their respective ER ligand binding domains.

Amino Acid Sequence↗
PubMed2001

Assessing the biological potency of binary mixtures of environmental estrogens using vitellogenin induction in juvenile rainbow trout (Oncorhynchus mykiss).

Experiments were conducted to assess the in vivo potency of binary mixtures of estrogenic chemicals using plasma vitellogenin (VTG) concentrations in juvenile rainbow trout (Oncorhynchus mykiss) as the endpoint. The estrogenic potencies of estradiol-17beta (E2), 4-tertnonylphenol (NP), and methoxychlor (MXC) were determined following 14 day exposures to the individual chemicals and binary mixtures of these chemicals. E2, NP, and MXC all induced concentration dependent increases in plasma VTG, with lowest observed effect concentrations of 4.7 and 7.9 ng L(-1) for E2, 6.1 and 6.4 microg L(-1) for NP, and 4.4 and 6.5 microg L(-1) for MXC. Concentration-response curves for fixed ratio binary mixtures of E2 and NP (1:1000), E2 and MXC (1:1000), and NP and MXC (1:1) were compared to those obtained for the individual chemicals, using the model of concentration addition. Mixtures of E2 and NP were additive at the concentrations tested, but mixtures of E2 and MXC were less than additive. This suggests that while NP probably acts via the same mechanism as E2 in inducing VTG synthesis, MXC may be acting via a different mechanism(s), possibly as a result of its conversion to HPTE which is an estrogen receptor alpha agonist and an estrogen receptor beta antagonist. It was not possible to determine whether mixtures of MXC and NP were additive using VTG induction, because the toxicity of MXC restricted the effect range forwhich the expected response curve forthe binary mixture could be calculated. The data presented illustrate that the model of concentration addition can accurately predict effects on VTG induction, where we know that both chemicals act via the same mechanism in mediating a vitellogenic response.

Animals↗
PubMed2006

David Kupfer, Ph.D. A mentor and a scientist.

I worked with the late Dr. David Kupfer for nearly nine years at the Worcester Foundation/University of Massachusetts Medical School, Worcester, MA. I was involved in the metabolism of methoxychlor and tamoxifen, the areas of research close to David's heart. We demonstrated the metabolic pathways of these compounds in rats and humans, and the covalent binding to microsomal proteins that could result in long-term toxic manifestations. I learned a lot from David, who was a mentor and friend/colleague. His death has left a void in my heart and he will be sorely missed.

Animals↗
PubMed2005

Validation study of OECD rodent uterotrophic assay for the assessment of estrogenic activity in Sprague-Dawley immature female rats.

The Organization for Economic Cooperation and Development (OECD) is developing a screening and testing method to identify estrogenic/antiestrogenic compounds. Based on these demands, phase 1 study for OECD uterotrophic assay was undertaken. The OECD is in the process of validating the assay results from international participating laboratories, which carried out this study with established environmental estrogenic compounds using designed protocols. The aim of this study was to provide data for validating the OECD uterotrophic assay using Sprague-Dawley immature female rats when testing with weak or partial estrogenic compounds. Ethinyl estradiol (EE) at 0.3 or 1 microg/kg/d, a positive control used in the present study, significantly increased both uterine wet and blotted weights. In the case of weak estrogenic compounds, the uterine wet weights were significantly increased by bisphenol A (BPA) at 300 mg/kg/d, nonylphenol (NP) at 80 mg/kg/d, genistein (GN) at 35 mg/kg/d, and methoxychlor (MXC) at 500 mg/kg/d. In addition, the increase in uterine blotted weights also showed a similar pattern to that of uterine wet weights. However, both 1,1,1-trichloro-2,2-bis(p-chlorphenyl)ethane (o,p-DDT) and dibutyl phthalate (DBP) did not affect uterus (wet and blotted) weights at doses of 100 and 500 mg/kg/d. These results suggest that the increase in uterine weights should be considered useful as a sensitive endpoint for detecting weak estrogenic compounds in 3-d rodent uterotrophic assay. However, further combination studies using surrogate biomarkers may be needed to improve the sensitivity of this assay for the detection of weak estrogenic compounds, such as o,p-DDT.

Animals↗
PubMed2002

Effects of primary exposure to environmental and natural estrogens on vitellogenin production in carp (Cyprinus carpio) hepatocytes.

Vitellogenin (vtg) is a precursor of the yolk proteins lipovitelline and phosvitin and is synthesized as a consequence of estrogen-dependent gene expression in female and male hepatocytes of egg-laying vertebrates. Freshly isolated carp hepatocytes of a genetically uniform strain of adult male carp (Cyprinus carpio) were used to investigate the effects of primary exposure to estrogenic compounds on the vitellogenic response to xenoestrogens. Isolated carp hepatocytes were first exposed (primary exposure) to 50 or 100 microM of either methoxychlor (MXCL) or bisphenol A (BPA), different concentrations of estrone (E1; 1 or 10 nM) or 17beta-estradiol (E2; 0.1 or 1 nM) for 2 days. Hepatocytes were exposed to xenoestrogens (secondary exposure) at both 2 and 5 days after isolation. Hepatocytes were cultured for a total period of 8 days. A competitive indirect ELISA was used to determine the level of vtg after 8 days. The concentration of chemicals used for the primary exposure induced vtg to a level that was less than 10% of the response elicited by E2 (1000 nM). A cytotoxic response, measured by MTT, was not observed after primary exposure to any of the xenoestrogens. After primary exposure to MXCL, vtg production in response to E2 was increased by 4-fold, and vitellogenesis in response to E1 treatment was doubled compared with vitellogenesis without pretreatment. No significant differences were observed between primary exposure to 50 and 100 microM MXCL. Primary exposure to 50 and 100 microM BPA increased the maximum vtg production in response to secondary E2 exposure by about 5- and 7-fold, respectively. Primary exposure to BPA (50 and 100 microM) followed by secondary exposure to E1 showed a 4- and 5-fold increase of the vtg synthesis in comparison to E1 exposure alone. Primary exposure to the endogenous estrogens had no significant influence on the vtg synthesis in response to secondary exposure to E1 or E2. Compared to hepatocytes exposed only to MXCL or BPA, primary exposure to E2 increased the vtg synthesis in hepatocytes induced by MXCL or BPA by almost a factor of 2. Primary exposure to E1 increased vitellogenesis after secondary exposure to MXCL only marginally. The present results indicate that weakly estrogenic environmental chemicals such as MXCL and BPA can increase the sensitivity of carp hepatocytes towards endogenous estrogens with respect to VTG synthesis.

Animals↗
PubMed2003

Effect of organochlorine pesticides on maturation of starfish and mouse oocytes.

Methoxychlor, lindane, and dieldrin are organochlorine pesticides that have been described as altering different reproductive functions in mammals and in invertebrates. However, few data have been published concerning the effects these pesticides have on oocyte maturation and fertilization. The aim of this study was to determine whether these compounds could affect maturation of mouse and starfish oocytes. We observed that germinal vesicle breakdown (GVBD) in starfish oocytes was significantly inhibited by the pesticides. Furthermore, formation of the first meiotic spindle and extrusion of the first polar body were also altered in mouse as well as in starfish. Our results suggest that the three pesticides act on common intracellular targets in invertebrates as well as in vertebrates.

Animals↗
PubMed2003

Effects of exogenous estrogenic agents on pubertal growth and reproductive system maturation in female rhesus monkeys.

Concern has been raised that environmental contaminants with estrogenic properties can alter normal sexual maturation. Monkeys, like humans, undergo a long and complex period of development during adolescence, which makes them important models for understanding exogenous estrogen effects during this period. This study examined the consequences of treatment with estrogenic agents (methoxychlor, MXC, 25 and 50 mg/kg/day; diethylstilbestrol, DES, 0.5 mg/kg/day) given in the peripubertal period (6 months before and after the expected age at menarche) to female rhesus monkeys. These treatments increased estrogen activity of serum as determined with an in vitro estrogen receptor alpha (ERa) transcription assay. DES completely suppressed adolescent growth (weight and height) and menses in a reversible manner; smaller effects of MXC on the timing of growth and menarche were also detected. Both DES and MXC led to premature emergence of a secondary sex characteristic, reddening and swelling of skin, but retarded growth of the nipple. As evaluated by ultrasound after an 8-month recovery period, uterine size was not affected by exogenous estrogen, but there was some indication of increased incidence of ovarian cysts/masses in MXC- and DES-treated groups. Ovarian cyclicity, as reflected in urinary hormone metabolites, demonstrated shorter follicular stages in the MXC-treated monkeys. In conclusion, the data indicate that DES had a striking effect on adolescent maturation and that the estrogenic pesticide MXC also altered development during this period. The pattern of effects across agents and doses may be based on specifics of estrogenic action, such as relative ERalpha and ERbeta binding and activation. Long-term consequences of this disruption of pubertal development are being studied in this cohort of monkeys as adults.

Aging↗
PubMed2004

Endocrine disruption in adolescence: immunologic, hematologic, and bone effects in monkeys.

Environmental contaminants with estrogenic properties have the potential to alter pubertal development. In addition to the reproductive system, other systems that mature under the influence of estrogen could be affected. This study examined the effect on immune, hematologic, and bone mass parameters of treatment with estrogenic agents (methoxychlor, MXC, 25 and 50 mg/kg/day; diethylstilbestrol, DES, 0.5 mg/kg/day) given in the peripubertal period to female rhesus monkeys. DES had striking effects on several parameters assessed measures CBC and clinical chemistry including hematocrit, hemoglobin, serum albumin, liver transaminases, and lipids. Circulating lymphocytes, particularly B cells, were depressed by DES, and a maturational shift in a memory T-cell population was altered. Bone mass and length, as measured after a 9-month recovery period, were significantly lower in the DES group and bone mass tended to be reduced in the femur of the MXC50 group relative to controls. In conclusion, the data indicate that DES had a clear effect on immunohematology and bone growth, while MXC influenced fewer parameters. Disruption in these systems during puberty could alter adolescent risk for anemia and infectious disease and subsequent adult risk for diseases such as osteoporosis, heart disease, and autoimmune disease.

Absorptiometry, Photon↗
PubMed2006

A proteomic (SELDI-TOF-MS) approach to estrogen agonist screening.

A small fish model and surface-enhanced laser desorption/ionization time-of-flight mass spectrometry were used to investigate plasma protein expression as a means to screen chemicals for estrogenic activity. Adult male sheepshead minnows (Cyprinodon variegatus) were placed into aquaria for seawater control, solvent control, and treatments of 17beta-estradiol (E2), methoxychlor (MXC), bisphenol-A (BPA), 4-tert-pentylphenol (TPP), endosulfan (ES), and chlorpyriphos (CP). Fish plasma was applied to weak cation exchange (CM10) ProteinChip arrays, processed, and analyzed. The array produced approximately 42 peaks for E2 plasma and 30 peaks for solvent control plasma. Estrogen-responsive mass spectral biomarker peaks were identified by comparison of E2-treated and control plasma spectra. Thirteen potential protein biomarkers with a range from 1 to 13 kDa were up- or downregulated in E2-treated fish and their performance as estrogenic effects markers was evaluated by comparing spectra from control, estrogen agonist, and nonagonist stressor-treated males and normal female fish plasma. One of the biomarkers, mass-to-charge ratio 3025.5, was identified by high-resolution tandem mass spectrometry as C. variegatus zona radiata protein, fragment 2. The weak environmental estrogens MXC, BPA, and TPP elicited protein expression profiles consistent with the estrogen expression model. Estrogen-responsive peaks were not detected in plasma from fish in the seawater, vehicle, ES, or CP treatments. No difference was found between plasma protein expression of seawater control and solvent control fish. We show that water exposure of fish to estrogen agonists produces distinct plasma protein biomarkers that can be reproducibly detected at low levels using protein chips and mass spectrometry.

Animals↗
PubMed1987

Base-line susceptibility of Phlebotomus papatasi to insecticides.

Susceptibility of the leishmaniasis vector sandfly Phlebotomus papatasi (Scopoli) to three insecticides was assessed on a colony originating in the Jordan Valley, Israel. Results are considered to show susceptibility to DDT and permethrin. The results for methoxychlor indicated the possibility of heterogeneity in the population and tolerance towards this compound.

Animals↗
PubMed1976

Evaluation of insecticide smears for the control of screw-worm fly, Chrysomya bezziana, in Papua New Guinea.

Three new insecticide smear preparations for the control of Chrysomya bezziana larvae infesting wounds of cattle have been tested under field and laboratory conditions and compared with an established preparation EQ 335 which is based on 3% lindane. Two preparations based on 3% coumaphos proved comparable to EQ 335 in the field trials and exhibited more prolonged residual effectiveness in laboratory tests. A smear preparation based on 2.5% methoxychlor was only effective in controlling 1 and 2 day-old larvae in wounds and was generally inferior to other smears tested in the laboratory.

Animals↗
PubMed2005

Epigenetic transgenerational actions of endocrine disruptors and male fertility.

Transgenerational effects of environmental toxins require either a chromosomal or epigenetic alteration in the germ line. Transient exposure of a gestating female rat during the period of gonadal sex determination to the endocrine disruptors vinclozolin (an antiandrogenic compound) or methoxychlor (an estrogenic compound) induced an adult phenotype in the F1 generation of decreased spermatogenic capacity (cell number and viability) and increased incidence of male infertility. These effects were transferred through the male germ line to nearly all males of all subsequent generations examined (that is, F1 to F4). The effects on reproduction correlate with altered DNA methylation patterns in the germ line. The ability of an environmental factor (for example, endocrine disruptor) to reprogram the germ line and to promote a transgenerational disease state has significant implications for evolutionary biology and disease etiology.

Androgen Antagonists↗
PubMed2001

Response of MCF-7 human breast cancer cells to some binary mixtures of oestrogenic compounds in-vitro.

The effects of simultaneous administration of some binary mixtures of seven natural and synthetic oestrogenic substances (17beta-estradiol, estrone, bisphenol A, butylbenzyl phthalate, endosulfan, methoxychlor and pentachlorophenol) on the cellular proliferation of human breast cancer MCF-7 cells in-vitro (a modified E-screen assay) have been measured. To assess the presence or absence of interactions of the two agents, the data were analysed on the basis of a graphical method in which the types and extents of interactions were described by response-surface diagrams. Of the nine combinations of the agents examined, synergistic interaction was evident for the combination of 17beta-estradiol and bisphenol A, whereas the remaining eight combinations were weakly synergistic, additive and/or weakly antagonistic in the dose-range tested.

Benzhydryl Compounds↗