Modeling endocrine control of the pituitary-ovarian axis: androgenic influence and chaotic dynamics.

Mathematical models of the hypothalamus-pituitary-ovarian axis in women were first developed by Schlosser and Selgrade in 1999, with subsequent models of Harris-Clark et al. (Bull. Math. Biol. 65(1):157-173, 2003) and Pasteur and Selgrade (Understanding the dynamics of biological systems: lessons learned from integrative systems biology, Springer, London, pp. 38-58, 2011). These models produce periodic in-silico representation of luteinizing hormone (LH), follicle stimulating hormone (FSH), estradiol (E2), progesterone (P4), inhibin A (InhA), and inhibin B (InhB). Polycystic ovarian syndrome (PCOS), a leading cause of cycle irregularities, is seen as primarily a hyper-androgenic disorder. Therefore, including androgens into the model is necessary to produce simulations relevant to women with PCOS. Because testosterone (T) is the dominant female androgen, we focus our efforts on modeling pituitary feedback and inter-ovarian follicular growth properties as functions of circulating total T levels. Optimized parameters simultaneously simulate LH, FSH, E2, P4, InhA, and InhB levels of Welt et al. (J. Clin. Endocrinol. Metab. 84(1):105-111, 1999) and total T levels of Sinha-Hikim et al. (J. Clin. Endocrinol. Metab. 83(4):1312-1318, 1998). The resulting model is a system of 16 ordinary differential equations, with at least one stable periodic solution. Maciel et al. (J. Clin. Endocrinol. Metab. 89(11):5321-5327, 2004) hypothesized that retarded early follicle growth resulting in "stockpiling" of preantral follicles contributes to PCOS etiology. We present our investigations of this hypothesis and show that varying a follicular growth parameter produces preantral stockpiling and a period-doubling cascade resulting in apparent chaotic menstrual cycle behavior. The new model may allow investigators to study possible interventions returning acyclic patients to regular cycles and guide developments of individualized treatments for PCOS patients.

Pre-birth acquisition of personhood: Incremental accrual of attributes as the framework for individualization by serial and concurrently acting developmental factors.

Discrete events and processes influence development of individual humans. Attribution of personhood to any individual human being cannot be disconnected from the underlying biological events and processes of early human development. Nonetheless, the philosophical, sociological and legal components that are integral to the meaning of the term as commonly used cannot be deduced from biology alone. The challenge for biomedical scientists to inform discussion in this arena then rests on profiling the key biological events and processes that must be assessed when considering how one might objectively reason about the task of superimposing the concept of personhood onto the developing biological entity of a potential human being. Endogenous genetic and epigenetic events and exogenous developmental milieu processes diversify developmental trajectories of potential individual humans prior to livebirth. First, fertilization and epigenetic resetting of each individual's organismic clock to time zero (t = 0) at the gastrulation/primitive streak stage (day 15 of embryogenesis), are two discrete unseen biological events that impact a potential individual human's attributes. Second, those two discrete unseen biological events are immersed in the continuous developmental process spanning pre-fertilization and gestation, further driving individualization of diverse attributes of each future human before the third discrete and blatant biological event of parturition and livebirth. Exposures of the gravida to multiple diverse exogenous exposures means that morphogenesis and physiogenesis of every embryo/fetus has individualized attributes for its future human lifespan. Our proposed framework based on the biological discrete events and processes spanning pre-fertilization and prenatal development, implies that personhood should be incrementally attributed, and societal protections should be graduated and applied progressively across the pre-birth timespan.

Alcohol, drugs, caffeine, tobacco, and environmental contaminant exposure: reproductive health consequences and clinical implications.

Reproductive function and fertility are thought to be compromised by behaviors such as cigarette smoking, substance abuse, and alcohol consumption; however, the strength of these associations are uncertain. Furthermore, the reproductive system is thought to be under attack from exposure to environmental contaminants, particularly those chemicals shown to affect endocrine homeostasis. The relationship between exposure to environmental contaminants and adverse effects on human reproductive health are frequently debated in the scientific literature and these controversies have spread into the lay press drawing increased public and regulatory attention. Therefore, the objective of the present review was to critically evaluate the literature concerning the relationship between lifestyle exposures and adverse effects on fertility as well as examining the evidence for a role of environmental contaminants in the purported decline of semen quality and the pathophysiology of subfertility, polycystic ovarian syndrome, and endometriosis. The authors conclude that whereas cigarette smoking is strongly associated with adverse reproductive outcomes, high-level exposures to other lifestyle factors are only weakly linked with negative fertility impacts. Finally, there is no compelling evidence that environmental contaminants, at concentrations representative of the levels measured in contemporary biomonitoring studies, have any effect, positive or negative, on reproductive health in the general population. Further research using prospective study designs with robust sample sizes are needed to evaluate testable hypotheses that address the relationship between exposure and adverse reproductive health effects.

Interrelationships between ovarian and pituitary hormones in ovulatory menstrual cycles across reproductive age.

CONTEXT: Ovarian hormones regulate pituitary gonadotropin secretion across the menstrual cycle via negative and positive feedback mechanisms. The contribution of individual hormones is complex and is a continuing area of research. OBJECTIVE: The aim of the study was to identify relationships between LH/FSH and estradiol, progesterone, inhibin A, inhibin B, and anti-Mullerian hormone (AMH) in ovulatory menstrual cycles across reproductive age. DESIGN: Serum ovarian and pituitary hormones were studied in a group of young (<35 yr; n = 21) and older (>45 yr; n = 55) women. The slopes of the regression lines relating the ovarian and pituitary hormones were determined by multiple linear regression analysis and expressed with 95% confidence intervals for each ovarian hormone, with FSH and LH as independent variables. Both simultaneous and delayed (time lagged) relationships were examined. RESULTS: Clear associations were evident for the lagged prediction of FSH, with significant negative associations being evident with inhibin B and AMH in the follicular phase and with estradiol, inhibin B, progesterone, and AMH in the luteal phase. For the lagged prediction of LH, significant positive and negative associations were observed with estradiol and inhibin B, respectively, in the follicular phase and a negative association with progesterone and inhibin B in the luteal phase. CONCLUSIONS: It is concluded that in the follicular phase, inhibin B is a major feedback regulator of FSH and may also be a negative feedback regulator of LH. AMH may be indirectly involved in FSH regulation.

Endocrine features of menstrual cycles in middle and late reproductive age and the menopausal transition classified according to the Staging of Reproductive Aging Workshop (STRAW) staging system.

CONTEXT: Female reproductive aging based on changes in menstrual cycle length and frequency progresses through a number of stages as defined by the Stages of Reproductive Aging Workshop (STRAW) staging criteria. OBJECTIVE: This paper provides a comprehensive description of the endocrine features associated with the STRAW stages. DESIGN: Healthy women aged 21-35 and 45-55 yr submitted three blood samples a week over a single menstrual cycle. They were classified as mid-reproductive age (n = 21), late-reproductive age (n = 16), early menopause transition (n = 16), and late menopause transition (n = 23). RESULTS: There were nine, one, zero, and two anovulatory cycles identified in the late menopause transition, early menopause transition, late-reproductive age, and mid-reproductive age groups, respectively. Ovulatory cycle FSH, LH, and estradiol levels increased with progression of STRAW stage (P = 0.001, P < 0.01, and P < 0.05, respectively), and mean luteal phase serum progesterone decreased (P < 0.01). Early cycle (ovulatory and anovulatory) inhibin B decreased steadily across the STRAW stages (P < 0.01) and was largely undetectable during elongated ovulatory and anovulatory cycles in the menopause transition. Anti-Mullerian hormone decreased markedly (10- to 15-fold) and progressively across the STRAW stages (P < 0.01 and P < 0.001, respectively). CONCLUSIONS: Progression through the STRAW stages is associated with elevations in serum FSH, LH, and estradiol and decreases in luteal phase progesterone. The marked fall in inhibin B and particularly anti-Mullerian hormone indicate that they may be useful in predicting STRAW stage but future analyses of early cycle measurements on larger cohorts are needed to draw predictive conclusions.

Effect of the isoflavone genistein against galactose-induced cataracts in rats.

Worldwide, ocular cataracts are a major cause of human blindness. A key goal of cataract-related research is to identify simple, cost-efficient but effective ways to prevent cataract formation or progression. Genistein is a naturally occurring dietary isoflavone with well-documented estrogenic, antioxidant, and protein tyrosine kinase inhibitor activity, which in turn modulates the activity of several enzymes involved in cell signaling and proliferation. Furthermore, many isoflavones have been shown to be potent inhibitors of aldose reductase, which is an important rate-limiting enzyme in the process of cataract induction in the metabolic disease galactosemia. In order to assess the potential for genistein to mitigate cataract formation, we have studied its effects in the animal model of dietary galactose-induced cataracts in adult male rats. Our experimental hypothesis was that dietary genistein would prevent or delay the progression of cataracts induced by high dietary intake of galactose. Our results show that the isoflavone genistein was not able to completely prevent galactose-induced cataract formation, but genistein did delay the progression of cataracts induced by dietary galactose. In addition, we found that dietary galactose decreased concentrations of serum somatostatin, while adding genistein decreased the serum glucose level but increased the serum testosterone level. As an initial inquiry into the mechanisms by which the partial protective effect of genistein could be mediated, we found that genistein increased the expression of connexin (Cx) 43 in the lens but did not affect the expression of soluble guanylyl cyclase (sGC) subunits. This finding suggests that the partial protective effect of genistein on cataract induction appears to be unrelated to sGC but may be mediated by enhanced expression of Cx43 and changed metabolic state.

Dietary galactose inhibits GDF-9 mediated follicular development in the rat ovary.

Clinical evidence suggests an association between galactosemia and premature ovarian failure, but the mechanism is still not fully understood. Growth differentiation factor-9 (GDF-9) is thought to be an obligatory growth factor during the gonadotropin-independent phase of folliculogenesis. The objective of this study was to examine the effects of galactose on initiation of folliculogenesis in the peripubertal interval and the connection between galactose toxicity and GDF-9 expression in the ovary. After immature Long-Evans rats (n = 10) were fed a diet consisting of 20% galactose for 19 days, whole body, ovary and uterine weights were measured. Serum estradiol and progesterone concentrations were measured by radioimmunoassay. Ovarian follicles were counted by morphometric analysis and GDF-9 expression was investigated by immunohistochemistry and immunoblot assay. Galactose treatment did not affect the onset of puberty as marked by the time of vaginal opening. The galactose diet significantly decreased the number of healthy growing follicles. The results of immunoblot assay showed that both bands corresponding to propeptide and mature forms of GDF-9 decreased with the galactose diet about 90 and 70%, respectively. The results of immunohistochemical staining showed that the GDF-9 positive follicle number and the ratio of GDF-9 positive to GDF negative (primordial/non-growing) follicles significantly decreased with this high galactose diet. The present study suggests that a high galactose diet inhibits follicular development, possibly through down-regulation of GDF-9 in the rat ovary, implying that GDF-9 may be involved in galactose-related ovarian toxicity.

Progestin-induced apoptosis in the Macaque ovarian epithelium: differential regulation of transforming growth factor-beta.

BACKGROUND: Oral contraceptive (OC) use is associated with a reduced risk of ovarian cancer. An OC component, progestin, induces apoptosis in the primate ovarian epithelium. One regulator of apoptosis is transforming growth factor-beta (TGF-beta). We determined the effect of progestin on TGF-beta expression in the primate ovarian epithelium and examined the relationship between TGF-beta expression and apoptosis. METHODS: Female cynomolgus macaques were randomly assigned to receive a diet for 35 months containing no hormones (n = 20); the OC Triphasil (n = 17); or each of its constituents, ethinyl estradiol (estrogen, n = 20) or levonorgestrel (progestin, n = 18 ), alone. Ovarian sections were immunostained with monoclonal antibodies against TGF-beta1 or TGF-beta2 plus TGF-beta3 (TGF-beta2/3) isoforms. The expression of TGF-beta isoforms in four ovarian compartments (epithelium, oocytes, granulosa cells, and hilar vascular endothelium) was compared among treatment groups. The association between TGF-beta expression and apoptosis, as determined by morphology and histochemistry, was examined in ovarian epithelium. All statistical tests were two-sided. RESULTS: Compared with ovaries from the control and estrogen-only-treated monkeys, the ovaries of progestin-treated monkeys showed 1) a marked decrease in the expression of TGF-beta1 and a concomitant increase in the expression of the TGF-beta2/3 isoforms in the ovarian epithelium (P<.001), 2) an increase in the expression of TGF-beta2/3 in the hilar vascular endothelium (P<.001), and 3) a marked decrease in TGF-beta2/3 expression in granulosa cells (P<.001). The apoptotic index of the ovarian epithelium was highly associated with the change in expression from TGF-beta1 (P<.001) to TGF-beta2/3 (P

Dioxin-like activity and maternal thyroid hormone levels in second trimester maternal serum.

OBJECTIVE: Developmental exposure to dioxin-like compounds has been associated with cognitive and motor impairments in children. These toxicants have been shown to be thyroid toxicants in animal studies. Therefore, the objective of this study was to quantify the overall dioxin-like activity in maternal serum and determine the association between dioxin-like activity and thyroid hormone levels. STUDY DESIGN: Cross-sectional examination of serum from pregnant women (n = 150) attending a prenatal diagnosis clinic between January 2002 and December 2003. RESULTS: Serum dioxin-like activity was measured in 145 of 150 (96.7%) maternal serum samples. The mean (+/- SEM) serum lipid-adjusted dioxin-like activity was 0.34 +/- 0.01 pg/g. Multiple regression analysis failed to demonstrate a relationship between maternal serum dioxin-like activity and serum thyroid hormone levels. CONCLUSION: Dioxin-like activity is quantifiable in an overwhelming majority of second-trimester maternal serum samples but there was no relationship between dioxin-like activity and thyroid hormone levels in our study population.

Application of the estrogen threshold hypothesis to the physiologic hypoestrogenemia of lactation.

OBJECTIVE: This study determined the impact of breastfeeding on hypoestrogenic symptoms among women in the postpartum period and correlated these findings with the Estrogen Threshold Hypothesis, which postulates that the hypoestrogenic symptoms experienced are related to circulating estrogen levels. STUDY DESIGN: Using a survey instrument that combined previously validated assessments of postpartum mood changes and menopausal symptoms, women were evaluated in the immediate postpartum period, prior to hospital discharge, and at 3 and 6 weeks postpartum. Each time period was analyzed independently, in a cross-sectional design, where women were categorized as "breastfeeding" or "bottle feeding." RESULTS: Of 236 women recruited, 171 (72.5%) intended to breastfeed, and 62 (26.3%) intended to bottle feed. At both the 3- and 6-week postpartum evaluations, a similar percentage of women in the breastfeeding and bottle-feeding groups reported hot flashes. However, breastfeeding women were more likely to report vaginal dryness than those who did not breastfeed: 20/150 (13.3%) versus 3/80 (3.8%) at 3 weeks, p<0.05; 25/143 (17.5%) versus 2/87 (2.3%) at 6 weeks, p<0.001. CONCLUSIONS: The Estrogen Threshold Hypothesis accurately predicts the findings of increased reported vaginal dryness but not hot flashes during lactation.

Mammary gland morphology in Sprague-Dawley rats following treatment with an organochlorine mixture in utero and neonatal genistein.

In a related reproductive toxicology study designed to investigate the effects of in utero exposure to environmental toxicants and potential interaction with postnatal genistein, gross enlargement of thoracic mammary glands was observed in female offspring at 200 days of age. Therefore, the objective of this study was to analyze the effect of in utero exposure to a mixture of toxicants on mammary gland morphology. Time-mated Sprague-Dawley rats were treated on days 9-16 of gestation with vehicle or a mixture of environmental toxicants at 1x the acceptable daily intake. Furthermore, it is unclear whether postnatal exposure to phytoestrogens in soy formulas poses breast cancer benefit or risk, and potential interactions with environmental toxicants are unknown. Therefore, half the female pups from each treatment group received either subcutaneous vehicle or genistein (10 microg/g body weight [bw]/day) on postnatal days 2-8. Following necropsy at 200 days of age, a pathologist, blinded to treatment groups, examined mammary gland histopathology. Only mild histological changes were found in mammary glands of rats exposed to the mixture in utero while pronounced ductal hyperplasia, lactational changes, and fibrosis were observed in mammary glands from the genistein group and were more prominent in the mixture + genistein group. Mammary glands of the control group were histologically normal. Collectively, our results reveal that postnatal exposure to pharmacological levels of genistein induces profound morphological changes in the mammary glands of adult female rats, and that high levels of phytoestrogens possess the potential to modulate the toxicological effects of toxicant mixtures.

Effects of subchronic exposure to a complex mixture of persistent contaminants in male rats: systemic, immune, and reproductive effects.

Human populations throughout the world are exposed daily to low levels of environmental contaminants. The consequences of potential interactions of these compounds to human endocrine, reproductive, and immune function remain unknown. The current study examines the effects of subchronic oral exposure to a complex mixture of ubiquitous persistent environmental contaminants that have been quantified in human reproductive tissues. The dosing solution used in this study contained organochlorines (2,3,7,8-tetrachlorodibenzo-p-dioxin [TCDD], polychlorinated biphenyls [PCBs],p,p'-dichlorodiphenoxydichloroethylene [p,p'-DDE],p,p-dichlorodiphenoxytrichloroethane [p,p'-DDT], dieldrin, endosulfan, methoxychlor, hexachlorobenzene, and other chlorinated benzenes, hexachlorocyclohexane, mirex and heptachlor) as well as metals (lead and cadmium). Each chemical was included in the mixture at the minimum risk level (MRL) or tolerable daily intake (TDI) as determined by the U.S. EPA or ATSDR or, for TCDD, at the no observable effect level (NOEL) used to calculate the TDI. Sexually mature male rats were exposed to this complex mixture at 1, 10, 100, and 1000 times the estimated safe levels daily for 70 days. On day 71, all animals were sacrificed and a variety of physiological systems assessed for toxic effects. Evidence of hepatotoxicity was seen in the significant enlargement of the liver in the 1000x group, reduced serum LDH activity (100x), and increased serum cholesterol and protein levels (both 1000x). Hepatic EROD activities were elevated in animals exposed to10x and above. The mixture caused decreased proliferation of splenic T cells at the highest dose and had a biphasic effect on natural killer cell lytic activity with an initial increase in activity at 1x followed by a decrease to below control levels in response to 1000x. No treatment-related effects were seen on bone marrow micronuclei, daily sperm production, serum LH, FSH, or prolactin levels or weights of most organs of the reproductive tract. The weights of the whole epididymis and of the caput epididymis were significantly decreased at 10x and higher doses, although no effect was seen on cauda epididymal weight. The sperm content of the cauda epididymis was increased at the 1x level but not significantly different from control at higher dose levels. A slight, but significant, increase in the relative numbers of spermatids was seen in the animals from the 1000x group with a trend towards reduced proportion of diploid cells at the same dose. Only minor, nondose related changes were seen in parameters related to condensation of chromatin, as determined by flow cytometry, in epididymal sperm. We conclude that the mixture induced effects on the liver and kidney and on general metabolism at high doses but caused only minor effects on immune function, reproductive hormone levels, or general indices of reproductive function measures. These data suggest that additive or synergistic effects of exposure to contaminants resulting in residue levels representative of contemporary human tissue levels are unlikely to result in adverse effects on immune function or reproductive physiology in male rats.

Effects of genistein or soy milk during late gestation and lactation on adult uterine organization in the rat.

In utero and lactational exposure to estrogenic agents has been shown to influence morphological and functional development of reproductive tissues. Thus, consumption of dietary phytoestrogens, such as isoflavones, during pregnancy and lactation could influence important periods of development, when the fetus and neonate are more sensitive to estrogen exposure. In this study, reproductive outcomes after developmental exposure to isoflavones were examined in Long-Evans rats maternally exposed to isoflavones via a commercial soy beverage or as the isolated isoflavone, genistein. Most reproductive endpoints examined at birth, weaning, and 2 months of age were not significantly modified in pups of either sex after lactational exposure to soy milk (provided to the dams in place of drinking water) from birth until weaning. However, soy milk exposure induced a significant increase in progesterone receptor (PR) in the uterine glandular epithelium of the 2-month-old pups. In pregnant dams treated with genistein (GEN; 15 mg/kg body weight) by gavage, from Gestational Day 14 through weaning, PR expression in the uterine glandular epithelium from 2-month-old GEN-treated females (postexposure) was also significantly increased. Diethylstilbesterol (DES) also stimulated uterine PR expression only in the glandular but not luminal epithelial cells. However, unlike DES, in utero/lactational exposure to GEN did not increase expression of the proliferation marker, proliferating cell nuclear antigen (PCNA), in the luminal epithelial cells of the 2-month-old rat uteri. These experiments demonstrate that developmental exposure to dietary isoflavones, at levels comparable to the ranges of human exposure, modify expression of the estrogen-regulated PR in the uterus of sexually mature rats weeks after exposure ended. Since the PR is essential for regulating key female reproductive processes, such as uterine proliferation, implantation, and maintenance of pregnancy, its increased expression suggests that soy phytoestrogen exposure during reproductive development may have long-term reproductive health consequences.

Detection of phytoestrogens in samples of second trimester human amniotic fluid.

There is widespread concern that fetal exposure to hormonally active chemicals may adversely affect development of the reproductive tract. Therefore, the present study was performed to develop the necessary analytical methods and test the hypothesis that dietary phytoestrogens can be quantified in second trimester human amniotic fluid. Amniotic fluid samples (n=59) from women (n=53) undergoing routine amniocentesis between 15 and 23 weeks of gestation were analyzed by gas chromatography/mass spectrometric (GC/MS). Analytes included the phytoestrogens daidzein, genistein, formononetin, biochanin A, and coumestrol. Dietary phytoestrogens were quantified in 96.2% of second trimester amniotic fluid samples tested. The mean (+/- standard deviation (S.D.)) concentration of daidzein and genistein in amniotic fluid was 1.44 +/- 1.34 and 1.69 +/- 1.48 ng/ml with maximum levels of 5.52 and 6.54 ng/ml, respectively. Second trimester amniotic fluid contains quantifiable levels of dietary phytoestrogens and thus is a marker of mid pregnancy fetal exposure.

Dietary compounds in relation to dietary diversity and human health.

The human diet contains numerous endocrine-active compounds that influence mammalian physiology. The effects of these dietary compounds may be mediated by interaction with well-characterized intracellular hormone receptors or by other effects on patterns of endogenous hormone production, metabolism, target tissue signaling, growth, or differentiation. Because humans evolved as omnivores, the spectrum of dietary compounds that can be tolerated at modest levels of intake without frank toxicity is broad. Modest intake of these diverse nonnutritive endocrine-active compounds offers potential human health benefits through modulation of metabolic and hormonal responses, especially in sedentary individuals consuming a highly refined diet.

Human developmental exposure to endocrine active compounds.

Quantification of exposure to environmental contaminants such as endocrine active chemicals (EACs) during critical periods of development, particularly in utero, remains largely unexplored. Therefore, we tested the hypothesis that EACs can be detected and quantified in second trimester human amniotic fluid. Amniotic fluid was obtained from women (n=175) undergoing routine amniocentesis between 14 and 21 weeks gestation. Samples were assayed by gas chromatography/mass spectrometry (GC/MS) for common organochlorine contaminants and dietary phytoestrogens. The DDT metabolite p,p'-DDE was found in approximately 25% of amniotic fluid samples (mean±S.D., 0.15±0.06 ng/ml) whereas the dietary phytoestrogens, genistein and or daidzein were found in 96.2% of samples tested (0.94±0.91 and 1.08±0.91 ng/ml, respectively). Our results demonstrate that: (1) human amniotic fluid is a suitable biological medium to evaluate developmental exposure to EACs, and (2) fetuses are exposed to biologically active levels of EACs in mid pregnancy.

Accelerated mammary tumor onset in a HER2/Neu mouse model exposed to DDT metabolites locally delivered to the mammary gland.

BACKGROUND: The association of DDT (dichlorodiphenyltrichloroethane) with breast cancer is controversial, but animal studies directly linking DDT to risk are lacking. Concerns with DDT reside in its environmental persistence, bioaccumulation in breast adipose tissue, and endocrine-disrupting actions. Whereas most attention has been focused on estrogenic congeners, we tested the cancer-inducing potential of the antiandrogen, p,p´-DDE [1,1-dichloro-2,2-bis(p-chlorophenyl) ethylene], the most prevalent and persistent DDT metabolite. OBJECTIVES: We aimed to determine whether developmental exposure to p,p´-DDE stored in adipose tissue surrounding the cancer-prone mammary epithelium of MMTV-Neu mice influences tumor development. METHODS: For localized delivery, Elvax 40P pellets containing p,p´-DDE were implanted into the mammary fat pads of prepubertal female mice. We compared mammary tumor development with p,p´-DDE with development in response to its estrogenic isomer, o,p´-DDE [1,1-dichloro-2-(o-chlorophenyl)-2-(p-chlorophenyl) ethylene], and a mixture of both isomers. RESULTS: p,p´-DDE implants significantly accelerated mammary tumor onset compared with vehicle Elvax implants. o,p´-DDE had similar results, but only at ≤ 10 months of age. Lipid-adjusted levels of p,p´-DDE in mammary adipose tissue and serum in young mice were within the ranges of human exposure, whereas concentrations in aged mice were low to undetectable. Exposure to a 2:1 ratio of p,p´-DDE:o,p´-DDE did not result in the younger latency observed with the individual isomers. CONCLUSIONS: p,p´-DDE exposure at concentrations relevant to human exposure accelerates mammary carcinogenesis in mice, possibly through hormonal and/or other actions. These data suggest that DDE exposure would promote, but not cause, mammary tumorigenesis. Developmental exposure in immature mammary tissue continues to affect tumor onset even after p,p´-DDE levels have declined. Future studies are needed to determine whether early exposure to p,p´-DDE correspondingly predisposes women to early-onset breast cancer.

Inhibition of Neu-induced mammary carcinogenesis in transgenic mice expressing ERΔ3, a dominant negative estrogen receptor α variant.

The estrogen receptor α (ERα) splicing variant with an in-frame deletion of exon 3 (ERΔ3) is frequently expressed in the normal breast, but its influence on tumorigenesis has not been explored. In vitro, ERΔ3 has dominant negative activity, suggesting it may suppress estrogen stimulation in the breast. ERΔ3 may inhibit classical signaling on estrogen response element (ERE)-regulated genes as well as activate non-classical pathways at Sp1 and AP-1 sites. Transgenic mice were developed that express mouse ERΔ3 in all tissues examined, including the mammary gland. To investigate if ERΔ3 expression affects tumorigenesis, ERΔ3 mice were crossbred with MMTV-Neu mice. Mammary tumor onset was significantly delayed in ERΔ3/Neu versus MMTV-Neu females and metastatic incidence and burden was significantly reduced. Consequently, ERΔ3 expression suppressed tumor development and metastasis in this aggressive model of HER2/Neu-positive breast cancer. To determine if ER ligands with anticancer activity may augment ERΔ3 protection, the bitransgenic mice were treated with tamoxifen and soy isoflavones starting at age 2 months. Soy protein with isoflavones (181 mg/1,800 kcal) did not affect tumor development in MMTV-Neu or ERΔ3/Neu mice; however, metastatic progression was not inhibited in soy-treated ERΔ3/Neu mice, as it was in untreated ERΔ3/Neu mice. In contrast, tamoxifen (20 mg/1,800 kcal) significantly enhanced tumor prevention in ERΔ3/Neu versus MMTV-Neu mice (98% vs. 81% tumor free). The results in ERΔ3/Neu mice demonstrate that ERΔ3 influences estrogen-dependent mammary carcinogenesis and, thus, may be protective in women expressing ERΔ3 in the breast. However, exposure to different estrogens may augment or block its beneficial effects.

Interactions between life stress factors and carrying the APOE4 allele adversely impact self-reported health in old adults.

Based on the multiple logistic regression analysis of data from a random sample of 1,023 old adults collected in Taiwan in 2000, we found that interactions between carrying the APOE4 allele and one of four life stress factors (relocated mainlander, living in a crowded household with six or more persons, living in an earthquake-damaged house, and monthly financial difficulty) significantly increased the odds ratio of poor self-reported health. Correlations between carrying the APOE4 allele and the life stress factors were ruled out by statistical tests. These life stress factors had a substantially larger adverse impact on self-reported health in APOE4 allele carriers than in noncarriers. This study provides evidence that interaction between carrying APOE4 allele and chronic life stressors has significant impacts on self-reported health while controlling for various sociodemographic and health behavior factors. Further studies with richer biomarkers are warranted for deeper understanding of the biological mechanisms.