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PubMedDate not supplied

Response of adult murine uterine epithelium to 50% methoxychlor.

This study was designed to assess the response of uterine epithelia of adult mice to a 4-week exposure of 50% methoxychlor (MXC) to ascertain whether significant changes were induced by 50% MXC that might compromise future implantation. Sexually mature virgin female mice were exposed to 0.1, 0.5, 1.0, 2.5, or 5.0 mg MXC via oral gavage for 5 consecutive days for 4 weeks. Controls received either sesame oil or 25 micrograms estradiol-17 beta (E-17 beta) also by gavage. At sacrifice, segments from each uterine horn were prepared for morphometric studies or for transmission electron microscopy. Results revealed a dose-dependent increase in the heights of uterine epithelial cells. Epithelial cell heights of the two groups treated with the highest doses of the pesticide were similar to that of the E-17 beta-treated group. Electron microscopy revealed increased vacuolization and swelling of mitochondria in cells of the 2.5 and 5.0 mg treated groups when compared to either of the control groups. In addition, there were effects on the number and size of microvilli in the uterine epithelial cells. The present study clearly demonstrates that a 4-week exposure of adult female mice to 50% MXC elicits significant estrogenic and toxic effects on the uterine epithelium.

Animals↗
PubMedDate not supplied

Neonatal exposures to technical methoxychlor alters ovaries in adult mice.

Technical grade methoxychlor (MXC) is an estrogenic pesticide currently used for pest control in the US. To determine the long-term effects of technical MXC on ovaries and estrous cycles, neonatal mice received 14 daily intraperitoneal injections of sesame oil only, 10.0 micrograms estradiol-17 beta, or 0.05 mg, 0.1 mg, 0.5 mg, or 1.0 mg of technical MXC. At 3, 6, and 12 months, vaginal smears were examined for 12 d and ovaries collected. All technical MXC doses and estradiol increased the duration of vaginal cornification but only estradiol, 0.5, or 1.0 mg technical MXC induced ovarian atrophy, relative ovarian weight loss, and depletion of corpora lutea. Technical MXC doses of 0.05 or 0.1 mg produced the opposite effects; the ovaries remained heavy, large, and filled with corpora lutea. On the other hand, follicular cysts were recorded in all groups, except the 1.0 mg MXC group. These augmentary and inhibitory effects of MXC at low and high doses mimic the estrogen effects at low and high doses, and were probably due to the altered hypothalamic-hypophyseal function.

Animals↗
PubMedDate not supplied

Estradiol or methoxychlor stimulates estrogen receptor (ER) expression in uteri.

The estrogenic pesticide methoxychlor (MXC) abnormally alters reproduction in rodents. The influence of MXC on expression of the estrogen receptor (ER) gene was investigated in the uterus of BALB/c mice and compared to the effect of estradiol. Uterine epithelium in control mice is devoid of ER until 5 d of life. Sesame oil, 10.0 micrograms estradiol 17 beta or 1.0 mg of base-washed 95% MXC were injected into neonates (days 1 to 4) and immature mice (days 10 to 14), after which they were sacrificed. By day 5, E or MXC induced production of nuclear ER mRNA and its translation in uterine epithelium. The mRNA was detected by in situ hybridization and ER protein by immunocytolocalization. In controls, ER was present only in stroma and myometrium. By day 15, the nuclei of uterine epithelium, stroma, and myometrium expressed the ER gene, with no apparent influence of E or MXC. Both E and MXC induce premature nuclear expression of the ER gene in neonatal uterine epithelium, without apparent change in ER gene expression between days 10 and 14 of life.

Animals↗
PubMedDate not supplied

Methoxychlor mimics the action of 17 beta-estradiol on induction of uterine epidermal growth factor receptors in immature female rats.

Epidermal growth factor (EGF) and its receptor (EGF-R) have been implicated as mediators for estrogen induced cellular growth. This study examines whether the action of the estrogenic pesticide methoxychlor (MXC) parallels the action of 17 beta-estradiol (E2) on uterine EGF-R. Administration of 20 micrograms E2/sexually immature female rat increased 125I-EGF binding to membranes extracted from whole uteri 175% over endogenous levels, while 500 mg MXC/kg led to a 156% increase. E2 in both 20 and 40 micrograms/rat doses and 500 mg MXC/kg led to maximal stimulation over endogenous levels, 12-h posttreatment. Rats were treated with E2, MXC, or vehicle plus 100 micrograms actinomycin-D (ACT-D) or 100 micrograms cycloheximide (CYCLO) per rat to determine if mRNA transcription and translation are involved in the increased EGF-R binding following estrogenic treatment. Only ACT-D inhibited the estrogenic stimulation of EGF-R binding, resulting in a 44% decrease when given concurrently with E2 or MXC, suggesting transcription is required. Additionally, ACT-D decreased endogenous receptor levels by 55%. No other differences were detected. When EGF-R binding data were analyzed by the method of Scatchard, both E2 and MXC, at maximal dosages, elevated uterine EGF-R binding sites by over 200% after 12 h as measured by maximal binding (Bmax) with no significant difference in dissociation constant (Kd) values. These results demonstrate that both E2 and MXC can stimulate the number of EGF-R binding sites without significantly altering the receptor binding affinity (Kd). Further, this stimulation is time dependent and is affected by dose.

Analysis of Variance↗
PubMed2004

Effects of methoxychlor, dieldrin and lindane on sea urchin fertilization and early development.

We have studied the effects of methoxychlor (MXC), dieldrin, and lindane on fertilization and early development of sea urchin egg. These organochlorine pesticides have often been found in polluted ground and water near agricultural sites, and have therefore been detected from time to time in the food chain and in drinking water. They have been reported to alter various reproduction functions in various animals including marine populations. We observed that the rate of fertilization decreased when the sperm was incubated with dieldrin or lindane. Treatment of eggs with each pesticide did not prevent fertilization, but increased the rate in polyspermy, delayed or blocked the first mitotic divisions, and altered early embryonic development. Moreover, all pesticides could alter several intracellular biochemical pathways that control first mitotic divisions and early development, including intracellular calcium homeostasis, MPF (mitosis promoting factor) activity and formation of the bipolar mitotic spindle. We found that lindane was the most potent of the three pesticides to alter all biochemical events. All these effects were observed at relatively high concentrations. However, bio-accumulation in sediments and aquatic organisms have been reported. Sea urchin eggs may then be in contact with very high concentrations of these pesticides in areas where these pesticides are not handled or stocked properly, and then develop into abnormal embryos.

Animals↗
PubMed2005

Methoxychlor-induced inducible nitric oxide synthase and proinflammatory cytokines expression in macrophages via NF-kappaB, ERK, and p38 mitogen-activated protein kinases.

Methoxychlor (MXC) is a pesticide that was developed as a replacement for dichlorodiphenyltrichloroethane. The influence of MXC on cytokine production or the functions of macrophages is unclear. This study examined the effects of MXC on the production of nitric oxide (NO) and the proinflammatory cytokines (IL-1beta, IL-6, and TNF-alpha), and analyzed the molecular mechanism in mouse macrophages. The addition of MXC to macrophages induced the production of NO and proinflammatory cytokines and expression levels of these genes in a dose-dependent manner. The NF-kappaB sites were identified in the promoter of the iNOS and proinflammatory cytokines genes. The transient expression and electrophoretic mobility shift assays revealed that the NF-kappaB transcription factor mediated the MXC-induced increase in the iNOS and proinflammatory cytokines expression levels. In addition, MXC induced the rapid phosphorylation of the ERK1/2 and p38 MAPK. This demonstrates that MXC stimulates the production of NO and proinflammatory cytokines and can up-regulate the expression levels of these genes via NF-kappaB transactivation and ERK1/2 and p38 MAPK phosphorylation. Overall, this study provides evidence showing that MXC has inflammatory potential that is previously unrecognized immunomodulating activity.

Animals↗
PubMed2004

Assessing the consequences of the pesticide methoxychlor: neuroendocrine and behavioral measures as indicators of biological impact of an estrogenic environmental chemical.

Japanese quail provide an advantageous avian model for assessing long-term biological consequences of endocrine disrupting chemicals (EDCs). These studies examined route of exposure and vulnerability to biological impact of EDCs over the life cycle in a precocial avian model, the Japanese quail. Embryonic exposure occurs with maternal deposition and methoxychlor (MXC) accumulated with maternal exposure. Egg injections of MXC or estradiol at selected stages of development impacted hypothalamic neuroendocrine systems in hatchlings and affected sexual maturation, with evidence for long-term effects on neurotransmitters and male behavior. Two-generation dietary studies were conducted to examine transgenerational effects of EDCs. Adult quail (P1) were exposed to dietary MXC (0, 0.5 and 5 ppm), with continued exposure in their offspring (F1), and control diet for all F2 chicks. Toxicological end points, including fertility, hatching success, and 14-day viability were unaffected. F1 and F2 male offspring from MXC-treated pairs MXC had impaired mating behavior and altered plasma hormones. These studies confirm neuroendocrine and behavioral measures as reliable indices of exposure to an estrogenic EDC. Moreover, maternal deposition remains a primary route of EDC exposure, with potential deleterious consequences for field birds, especially precocial species that appear to be particularly sensitive to embryonic EDC exposure.

Animals↗
PubMedDate not supplied

Preimplantation exposures of murine embryos to estradiol or methoxychlor change postnatal development.

Long-term effects of in vivo exposures to proestrogen methoxychlor (MXC) or estradiol-17beta (E) were studied during early pregnancy (preimplantation) in ICR mice. Pregnant dams received either subcutaneous injections of 1 microg of E on Day 2 of pregnancy only (vaginal plug = Day 1), or 5.0mg of MXC on Days 2-4 of pregnancy in sesame oil. Pregnant control mice were treated with the vehicle only. Litter size, postnatal survival, sex ratio at birth, and anogenital distance (AGD) in offspring of both sexes were examined, as well as vaginal opening in female offspring. High mortality rate was recorded in MXC-exposed offspring due to infanticide. Exposures to either E or MXC did not change sex ratio at birth, but the litter size was smaller in the former group. On postnatal Day 21, male pups exposed to either E or MXC at preimplantation stage exhibited shorter AGD than the controls, with the change most pronounced after MXC treatments. AGD in female offspring was unaffected after MXC exposures, but E treatments produced longer AGD in the females than that recorded in the controls. Preimplantation exposures to E or MXC also accelerated sexual maturation as significantly more females exhibited precocious vaginal opening at weaning. Our study shows that exposures to MXC or E at preimplantation stages cause long term alteration of sexual development during weaning in offspring of both sexes. Also, MXC treatments retarded both growth and weight of both sexes of offspring, in comparison to controls.

Animals↗
PubMed2004

The effects of the reported active metabolite of methoxychlor, 2,2-bis(p-hydroxyphenyl)-1,1,1-trichloroethane, on testosterone formation by cultured Leydig cells from young adult rats.

Methoxychlor (MC) is an insecticide that is currently used on a variety of agricultural crops, especially following the ban of 2,2-bis(p-chlorophenyl)-1,1,1-trichloroethane (DDT) use in the United States. Following in vivo administration, MC is converted to 2,2-bis(p-hydroxyphenyl)-1,1,1-trichloroethane (HPTE), which is proposed to be the active agent. Both MC and HPTE have been demonstrated to exhibit weak estrogenic and antiandrogenic activities, and they are thought to exert their effects through estrogen or androgen receptors, respectively. A recent study reported that HPTE inhibited both basal and hCG-stimulated testosterone formation by immature and adult cultured rat Leydig cells and that this effect was mediated through the estrogen receptor. In the current studies, we examined the effects of HPTE on basal and hCG-stimulated testosterone formation by cultured Leydig cells from young adult rats. In addition, we evaluated whether the effects of HPTE on rat Leydig cell testosterone biosynthesis were mediated through the estrogen receptor as an estrogen agonist or the androgen receptor as an antiandrogen. The current studies demonstrated that HPTE inhibited both basal and hCG-stimulated testosterone formation in a dose-dependent manner with significant declines in testosterone being observed at approximately 100 nM. The effects of HPTE were localized to the cholesterol side-chain cleavage step; however, these effects were not mediated through the classic estrogen receptor or by its acting as an antiandrogen, the currently recognized modes of action of MC and HPTE.

8-Bromo Cyclic Adenosine Monophosphate↗
PubMedDate not supplied

The reported active metabolite of methoxychlor, 2,2-bis(p-hydroxyphenyl)-1,1,1-trichloroethane, inhibits testosterone formation by cultured Leydig cells from neonatal rats.

Methoxychlor (MC) is an insecticide that is presently used on agricultural crops, especially after the ban on the use of 2,2-bis(p-chlorophenyl)-1,1,1-trichloroethane (DDT) in the United States. Following administration in vivo, MC is converted to 2,2-bis(p-hydroxyphenyl)-1,1,1-trichloroethane (HPTE), which is thought to be the active agent. However, both MC and HPTE have been reported to have weak estrogenic and antiandrogenic activities, and they are thought to exert their potential adverse (endocrine disruptive) effects through the estrogen and androgen receptors, respectively. In a recent study, HPTE was shown to inhibit both basal and hCG-stimulated testosterone production by cultured Leydig cells from immature and adult rats, and these effects were reported to be mediated through the estrogen receptor. Because fetal Leydig cells represent a separate population from adult Leydig cells and many of the reported adverse actions of endocrine disruptors are thought to have their effects during gestational exposure, the present studies examined the effects of HPTE on testosterone formation by cultured fetal Leydig cells from neonatal rats to determine whether these cells are sensitive to HPTE. Our studies demonstrated that HPTE inhibited both basal and hCG-stimulated testosterone formation in a dose-dependent manner. Significant declines in testosterone were observed at about 100nM HPTE, and this effect was detected as early as 1h after exposure. The main effects of HPTE appeared to be localized to the cholesterol side-chain cleavage step which converts cholesterol to pregnenolone. In addition, this effect did not appear to be mediated through the estrogen receptor as a weak estrogen or the androgen receptor as an antiandrogen, which are the currently proposed modes of action of MC and HPTE.

8-Bromo Cyclic Adenosine Monophosphate↗
PubMed2005

Reproductive abnormalities in adult male mice following preimplantation exposures to estradiol or pesticide methoxychlor.

Adult females of ICR strain of mice were bred, separated into different experimental groups, and treated as follows. On Days 2-4 of pregnancy, the mice received daily subcutaneous injections of either 0.05 ml sesame oil (vehicle) or same volume of 5.0mg of purified methoxychlor (MXC) suspended in the vehicle. Another group received a single subcutaneous injection of 1.0 microg of estradiol-17beta (E) on Day 2 of pregnancy only. Male offspring were tested at 3 and 6 months of age. At 3 months, E or MXC did not alter the weights of seminal vesicles, preputial glands, or testes, although after exposure for 30 min to a female in estrus behind a partition, testosterone levels were significantly reduced in treated males in comparison to control males exposed to the same partition test. At 6 months, the preputial glands and testes weight remained unchanged, while the seminal vesicles were significantly heavier in E- and MXC-treated males. Same partition tests again revealed that in E and MXC groups, testosterone levels remained significantly lower in comparison to control males. MXC or E exposures during preimplantation appear to induce long-term effects on the sexual development in 3 and 6 month-old-males by compromising their sexual arousal and altering seminal vesicles weights in the older group.

Animals↗
PubMed2005

In vivo exposure of young adult male rats to methoxychlor reduces serum testosterone levels and ex vivo Leydig cell testosterone formation and cholesterol side-chain cleavage activity.

Methoxychlor (MC) was developed as a replacement for the banned pesticide DDT. After in vivo administration, it is metabolized in the liver to 2,2-bis(p-hydroxyphenyl)-1,1,1-trichloroethane (HPTE), which is proposed to be the active agent. Both MC and HPTE have been shown to exhibit weak estrogenic and antiandrogenic activities, and they are thought to exert their effects through estrogen and androgen receptors, respectively. Although in vitro studies using cultured rat Leydig cells have reported that HPTE inhibits both basal and hCG-stimulated testosterone formation, the response of circulating testosterone levels to in vivo MC has been more variable. Therefore, the current studies evaluated whether the daily in vivo administration of MC (0, 5, 40 and 200 mg/kg body weight) for a short duration (days 54-60 of age) by gavage altered serum testosterone levels and ex vivo Leydig cell testosterone formation in young adult male rats. These results demonstrate that both fluid-retained and fluid-expressed seminal vesicle weights declined to 44 and 60% of control, respectively, in the 200 mg/kg MC-exposed animals. Similarly, serum testosterone and dehydroepiandrosterone levels declined to 41 and 45% of control, respectively, in the 200 mg/kg MC-exposed animals; however, serum LH and FSH levels were unaffected. Ex vivo Leydig cell basal testosterone formation over 4h declined to 49% of control in animals exposed to 200 mg/kg MC, and ex vivo Leydig cell P450 cholesterol side-chain cleavage activity declined to 79 and 50% of control in animals exposed to 40 and 200 mg/kg of MC, respectively, supporting previous in vitro studies which demonstrated the sensitivity of this step to MC.

Animals↗
PubMed2006

The methoxychlor metabolite, 2,2-bis-(p-hydroxyphenyl)-1,1,1-trichloroethane, inhibits steroidogenesis in rat ovarian granulosa cells in vitro.

The exquisitely balanced hormonal mechanisms that control female fertility can be affected by several internal and external factors including pathogens, genetic maladies, and environmental agents. In the latter group are natural and synthetic agents known as endocrine disruptors. One such compound, 2,2-bis-(p-hydroxyphenyl)-1,1,1-trichloroethane (HPTE), is the predominant metabolite of the pesticide methoxychlor. The effects of HPTE on ovarian steroidogenesis have not been previously reported and were investigated in the present study. Granulosa cells harvested from immature rats were treated with follicle-stimulating hormone (FSH) or N(6),2'-O-dibutyryladenosine 3',5'-cyclic monophosphate (db-cAMP) in the presence or absence of HPTE. After 48h, progesterone (P4) and estradiol-17beta (E2) concentrations were measured in the culture media. Steady-state levels of the mRNAs encoding steroidogenic acute regulatory protein (StAR), P450 side-chain cleavage (P450scc), 3beta-hydroxysteroid dehydrogenase type 1 (3beta-HSD), and P450 aromatase (P450arom) were examined using real-time PCR. Both FSH- and db-cAMP-stimulated P(4) accumulation were impaired by HPTE. In contrast, FSH-, but not db-cAMP-stimulated, E2 content was suppressed by HPTE. The FSH-dependent increase in the abundance of P450scc, 3beta-HSD, and P450arom mRNAs was blocked by HPTE; however, StAR expression was not altered. Although db-cAMP-dependent P450arom was moderately reduced by HPTE, the levels of db-cAMP-dependent StAR, P450scc, and 3beta-HSD mRNAs were increased in the presence of HPTE. These data collectively show that HPTE can disrupt P4 and E2 production in granulosa cells, with implications for sites of action both preceding and following the generation of cAMP. The steroid-modulatory effects of HPTE in granulosa cells appear to involve the general suppression of the FSH-dependent expression of mRNAs encoding steroid pathway proteins, whereas the disparate effects of HPTE on cAMP-dependent mRNA content in this regard suggest a broader and more complex mechanism of action.

3-Hydroxysteroid Dehydrogenases↗
PubMed2006

Methoxychlor causes mitochondrial dysfunction and oxidative damage in the mouse ovary.

Methoxychlor (MXC) is an organochlorine pesticide that reduces fertility in female rodents by causing ovarian atrophy, persistent estrous cyclicity, and antral follicle atresia (apoptotic cell death). Oxidative damage resulting from reactive oxygen species (ROS) generation has been demonstrated to lead to toxicant-induced cell death. Thus, this work tested the hypothesis that MXC causes oxidative damage to the mouse ovary and affects mitochondrial respiration in a manner that stimulates ROS production. For the in vitro experiments, mitochondria were collected from adult cycling mouse ovaries, treated with vehicle (dimethyl sulfoxide; DMSO) or MXC, and subjected to polarographic measurements of respiration. For the in vivo experiments, adult cycling CD-1 mice were dosed with either vehicle (sesame oil) or MXC for 20 days. After treatment, ovarian mitochondria were isolated and subjected to measurements of respiration and fluorimetric measurements of H2O2 production. Some ovaries were also fixed and processed for immunohistochemistry using antibodies for ROS production markers: nitrotyrosine and 8-hydroxy-2'-deoxyguanosine (8-OHG). Ovaries from in vivo experiments were also used to measure the mRNA expression and activity of antioxidants such as Cu/Zn superoxide dismutase (SOD1), glutathione peroxidase (GPX), and catalase (CAT). The results indicate that MXC significantly impairs mitochondrial respiration, increases production of H2O2, causes more staining for nitrotyrosine and 8-OHG in antral follicles, and decreases the expression and activity of SOD1, GPX, and CAT as compared to controls. Collectively, these data indicate that MXC inhibits mitochondrial respiration, causes ROS production, and decreases antioxidant expression and activity in the ovary, specifically in the antral follicles. Therefore, it is possible that MXC causes atresia of ovarian antral follicles by inducing oxidative stress through mitochondrial production of ROS.

8-Hydroxy-2'-Deoxyguanosine↗
PubMed2005

Myelotoxicity in genistein-, nonylphenol-, methoxychlor-, vinclozolin- or ethinyl estradiol-exposed F1 generations of Sprague-Dawley rats following developmental and adult exposures.

The myelotoxicity of five endocrine active chemicals was evaluated in F1 generation of Sprague-Dawley rats following developmental and adult exposures at three concentration levels. Rats were exposed to genistein (GEN: 25, 250 and 1250 ppm), nonylphenol (NPH: 25, 500 and 2000 ppm), methoxychlor (MXC: 10, 100 and 1000 ppm), vinclozolin (VCZ: 10, 150 and 750 ppm) and ethinyl estradiol (EE2: 5, 25 and 200 ppb) gestationally and lactationally through dams from day 7 of gestation and through feed after weaning on postnatal day (PND) 22 to PND 64. The parameters examined included the number of recovered bone marrow cells, DNA synthesis, and colony forming units (CFU) in the presence of granulocyte macrophage-colony stimulating factor (GM-CSF), macrophage colony-stimulating factor (M-CSF) and erythropoietin. Except for the EE2, the concentrations of other individual chemicals in the diet were in an approximate range that allowed for a comparison to be made in terms of myelotoxic potency. Decreases in the DNA synthesis, CFU-GM and CFU-M seemed to be the common findings among the alterations induced by these compounds. Using the numbers of alterations induced by each chemical in the parameters examined as criteria for comparison, the order of myelotoxic potency in F(1) males was: GEN>MXC>NPH>VCZ; the order in females: GEN>NPH>VCZ. Additionally, some of the functional changes induced by these compounds were gender-specific or dimorphic. Overall, the results demonstrated that developmental and adult exposures of F1 rats to these endocrine active chemicals at the concentrations tested had varied degrees of myelotoxicity with GEN being the most potent. Furthermore, the sex-specific effects of these chemicals in F1 male and female rats suggest that there may be interactions between these compounds and sex hormone in modulating these responses.

Animals↗
PubMed2003

Inhibition of gonadotropin-induced oviposition and ovarian steroidogenesis in the African clawed frog (Xenopus laevis) by the pesticide methoxychlor.

Concern over the role of environmental toxicants in amphibian population declines has highlighted the need to develop more comprehensive ecotoxicological test methods for this at-risk group. With continued interest in environmental endocrine disrupters (EDs), and the paucity of data pertaining to endocrine disrupting effects in amphibia, such tests should incorporate reproductive and endocrine endpoints. We investigated the effects of in vivo exposure to the pesticide methoxychlor (MXC) on reproductive and endocrine function in adult female African clawed frogs, (Xenopus laevis). Frogs were exposed to MXC (0.5-500 microg/l) in tank water throughout a cycle of oogenesis stimulated by exogenous gonadotropins. Gonadotropin-induced oviposition was delayed, and reduced numbers of unfertilizable eggs of increased size were oviposited by frogs exposed to 500 microg/l MXC. Reduced egg output was mirrored by increased gonado-somatic index in MXC-treated frogs. Post-oviposition, plasma sex steroid profiles were altered in MXC-exposed frogs as estradiol/progesterone and estradiol/testosterone ratios were elevated. Ex vivo synthesis of progesterone by ovarian explants was significantly reduced for frogs exposed to MXC> or = 0.5 microg/l. Additionally, plasma vitellogenin concentrations were significantly depressed in frogs exposed to 500 microg/l MXC. These data indicate that reproductive and endocrine dysfunction can occur in adult amphibia exposed to high concentrations of an environmental toxin with endocrine disrupting activity. Such effects may be indicative of the potential for adverse effects on amphibian wildlife exposed to environmental EDs.

Animals↗
PubMed2002

Genistein and methoxychlor modulate the activity of natural killer cells and the expression of phenotypic markers by thymocytes and splenocytes in F0 and F1 generations of Sprague-Dawley rats.

The isoflavone genistein (GE) and methoxychlor (MXC) have been shown to be estrogenic in both in vitro and in vivo experimental systems. The objective of the present study was to evaluate the effects of GE and MXC on the immune system in adult and developing rats and the potential interaction between these compounds in their immunomodulatory actions. Timely pregnant Sprague-Dawley rats were exposed to GE (300 or 800 ppm), MXC (800 ppm), or their combinations in feed starting on day 1 of gestation. The offspring were exposed to these chemicals gestationally and lactationally. Immunological evaluation was performed on postnatal day 22. In F0 females, exposure to GE had no effect on the percentages of thymocyte subsets, but caused a significant decrease in the absolute thymus weight at the 800-ppm dose level. In the spleen, GE did not affect the activity of natural killer cells but induced changes in the percentages of splenic T lymphocyte subsets. Exposure to MXC produced no effect on the immune parameters examined except for a decrease in the percentage of CD4+CD8- thymocytes. Additionally, minimal interaction between GE and MXC was observed. In F(1) males, both GE and MXC decreased the percentage of CD4+CD8- thymocytes, but only GE increased spleen natural killer cell activity. MXC in combination with 300 ppm-GE, but not separately, produced significant decreases in the absolute weights of thymus and spleen. In F1 females, GE decreased the percentage of CD4+CD8- thymocytes, increased the percentage of CD4+CD8+ thymocytes, and decreased the activity of spleen natural killer cells. In contrast, MXC increased the percentages of spleen natural killer cells and CD8+ T cells. Overall, the results demonstrate that both GE and MXC can modulate the immune system with greater effects observed in developing rats. Moreover, male and female rats have differential responses to these compounds. A lack of interaction between these two estrogenic chemicals in modulating these immune parameters indicates that their effects on the immune system might involve other mechanisms in addition to the estrogen receptors.

Animals↗
PubMed2003

Impact of dietary exposure to methoxychlor, genistein, or diisononyl phthalate during the perinatal period on the development of the rat endocrine/reproductive systems in later life.

To evaluate the impact of dietary exposure to endocrine disrupting chemicals (EDCs) during the sensitive period of brain sexual differentiation, maternal Sprague-Dawley rats were fed three representative chemicals, methoxychlor (MXC; 24, 240, and 1200 ppm), genistein (GEN; 20, 200, and 1000 ppm), or diisononyl phthalate (DINP; 400, 4000, and 20,000 ppm), from gestational day 15 to postnatal day 10. Soy-free diet was used as a basal diet to eliminate possible estrogenic effects from the standard diet. Offspring were examined in terms of anogenital distances, prepubertal organ weights, onset of puberty, estrous cyclicity, and organ weights and histopathology of endocrine organs at adult stage (week 11) as well as the volumes of sexually dimorphic nucleus of preoptic area (SDN-POA). All chemicals caused signs of maternal toxicity at high doses. MXC, at 1200 ppm, facilitated and delayed the onset of puberty in females and males, respectively, females also showing endocrine disrupting effects thereafter, such as irregular estrous cyclicity and histopathological alterations in the reproductive tract and anterior pituitary. GEN, at all doses, reduced body weight (BW) at week 11, but did not affect endocrine parameters. Treatment with DINP at 20,000 ppm resulted in degeneration of meiotic spermatocytes and Sertoli cells in the testis and decrease of corpora lutea in the ovary at week 11, although changes remained minimal or slight. The SDN-POA volume remained unchanged with all three chemicals. The results demonstrated that perinatal dietary exposure to EDCs for a limited period causes endocrine disruption in offspring only at high doses.

Administration, Oral↗