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Biomedical subjects

Ana M Soto

Publications and source records attributed to Ana M Soto.

At least 19 recordsLinked to original sources
PubMed2006

Induction of mammary gland ductal hyperplasias and carcinoma in situ following fetal bisphenol A exposure.

Exposure of the fetus to excess estrogen is believed to increase the risk of developing breast cancer during adult life. Fetal exposure to low doses of the xenoestrogen bisphenol A resulted in long-lasting effects in the mouse mammary gland that were manifested during adult life. It enhanced sensitivity to estradiol, decreased apoptosis, increased the number of progesterone receptor-positive epithelial cells at puberty and increased lateral branching at 4 months of age. We now report that fetal exposure to 2.5, 25, 250 and 1000 microg bisphenol A/kg body weight/day induces the development of ductal hyperplasias and carcinoma in situ at postnatal day 50 and 95 in rats. These highly proliferative lesions have an increased number of estrogen receptor-alpha positive cells. Thus, fetal bisphenol A exposure is sufficient to induce the development of preneoplastic and neoplastic lesions in the mammary gland in the absence of any additional treatment aimed at increasing tumor development.

Animals↗
PubMed2006

Exposure to environmentally relevant doses of the xenoestrogen bisphenol-A alters development of the fetal mouse mammary gland.

Humans are routinely exposed to bisphenol-A (BPA), an estrogenic compound that leaches from dental materials, food and beverage containers, and other plastic consumer products. Effects of perinatal BPA exposure on the mouse mammary gland have been observed in puberty and adulthood, long after the period of exposure has ended. The aim of this study was to examine fetal mammary gland development at embryonic day (E)18 and assess changes in the tissue organization and histoarchitecture after exposure to an environmentally relevant dose of BPA. In unexposed fetuses, the relative position of the fetus with respect to its female and male siblings in the uterus influenced growth of the ductal tree, which was more developed in females placed between two males than in females placed between two females. Exposure of dams to 250 ng BPA per kilogram body weight per day from E8 to E18 significantly increased ductal area and ductal extension in exposed fetuses and obliterated positional differences. In the stroma, BPA exposure promoted maturation of the fat pad and altered the localization of collagen. Within the epithelium, BPA exposure led to a decrease in cell size and delayed lumen formation. Because mammary gland development is dependent on reciprocal interactions between these compartments, the advanced maturation of the fat pad and changes in the extracellular matrix may be responsible for the altered growth, cell size, and lumen formation observed in the epithelium. These results suggest that alterations in mammary gland phenotypes observed at puberty and adulthood in perinatally exposed mice have their origins in fetal development.

Adipose Tissue↗
PubMed2006

The mammary gland response to estradiol: monotonic at the cellular level, non-monotonic at the tissue-level of organization?

The role of hormones in mammary gland development has been studied in detail using surgical and genetic models. These studies have indicated roles for estrogen in ductal elongation and terminal end bud formation. However, no comprehensive study has quantified how different doses of estrogen affect morphological parameters of mammary gland development. Additionally, comparisons between the estrogen-responsiveness of the mammary gland and uterus, the model organ for estrogen action are incomplete. In this study, immature mice were ovariectomized and implanted with osmotic pumps releasing one of eight doses of 17beta-estradiol for 10 days. As expected from the classical uterotrophic assay, the uterus showed a monotonic dose-response curve for all measured endpoints. In contrast, the mammary gland showed a non-monotonic, inverted-U shaped response to estrogen with regard to morphometric parameters, and a monotonic response with regard to gene expression parameters. These results indicate that estrogen has opposing effects in mammary gland morphogenesis depending on estrogen dose, i.e. low to moderate doses induce terminal end bud formation and ductal elongation while higher doses inhibit these processes. This non-monotonic dose-response in the mammary gland may reflect complex interactions, where estrogen can act on multiple targets either as an agonist or antagonist.

Animals↗
PubMed2006

Importance of dosage standardization for interpreting transcriptomal signature profiles: evidence from studies of xenoestrogens.

To obtain insights into similarities and differences in the biological actions of related drugs or toxic agents, their transcriptomal signature profiles (TSPs) have been examined in a large number of studies. However, many such reports did not provide proper justification for the dosage criteria of each agent. Using a well characterized cell culture model of estrogen-dependent proliferation of MCF7 human breast cancer cells, we demonstrate how different approaches to dosage standardization exert critical influences on TSPs, leading to different and even conflicting conclusions. Using quantitative cellular response (QCR)-based dosage criteria, TSPs were determined by Affymetrix microarray when cells were proliferating at comparable rates in the presence of various estrogens. We observed that TSPs of the xenoestrogens (e.g., genistein or bisphenol A) were clearly different from the TSP of 17beta-estradiol; namely, the former strongly enhanced expression of genes involved in mitochondrial oxidative phosphorylation, whereas the latter showed minimal effects. In contrast, TSPs for genistein and 17beta-estradiol were indistinguishable by using the marker gene expression-based dosage criteria, conditions in which there was comparable expression of the mRNA transcripts for the estrogen-inducible WISP2 gene. Our findings indicate that determination and interpretation of TSPs in pharmacogenomic and toxicogenomic studies that examine the transcriptomal actions of related agents by microarray require a clear rationale for the dosage standardization method to be used. We suggest that future studies involving TSP analyses use quantitative and objective dosage standardization methods, such as those with quantitative cellular response or marker gene expression-based dosage criteria.

Cell Line, Tumor↗
PubMed2006

Endocrine disruptors and reproductive health: the case of bisphenol-A.

Epidemiological studies have reported that during the last 60 years the quantity and quality of human sperm has decreased and the incidence of male genital tract defects, testicular, prostate and breast cancer has increased. During the same time period, developmental, reproductive and endocrine effects have also been documented in wildlife species. The last six decades have witnessed a massive introduction of hormonally active synthetic chemicals into the environment leading some to postulate that the diverse outcomes documented in human and wildlife populations might be the result of extemporaneous exposure to xenoestrogens during development. The estrogen-mimic bisphenol-A (BPA) is used as a model agent for endocrine disruption. BPA is used in the manufacture of polycarbonate plastics and epoxy resins from which food and beverage containers and dental materials are made. Perinatal exposure to environmentally relevant BPA doses results in morphological and functional alterations of the male and female genital tract and mammary glands that may predispose the tissue to earlier onset of disease, reduced fertility and mammary and prostate cancer.

Animals↗
PubMed2006

Evidence of altered brain sexual differentiation in mice exposed perinatally to low, environmentally relevant levels of bisphenol A.

Humans are routinely exposed to bisphenol A (BPA), an estrogenic chemical present in food and beverage containers, dental composites, and many products in the home and workplace. BPA binds both classical nuclear estrogen receptors and facilitates membrane-initiated estrogenic effects. Here we explore the ability of environmentally relevant exposure to BPA to affect anatomical and functional measures of brain development and sexual differentiation. Anatomical evidence of alterations in brain sexual differentiation were examined in male and female offspring born to mouse dams exposed to 0, 25, or 250 ng BPA/kg body weight per day from the evening of d 8 of gestation through d 16 of lactation. These studies examined the sexually dimorphic population of tyrosine hydroxylase (TH) neurons in the rostral periventricular preoptic area, an important brain region for estrous cyclicity and estrogen-positive feedback. The significant sex differences in TH neuron number observed in control offspring were diminished or obliterated in offspring exposed to BPA primarily because of a decline in TH neuron number in BPA-exposed females. As a functional endpoint of BPA action on brain sexual differentiation, we examined the effects of perinatal BPA exposure on sexually dimorphic behaviors in the open field. Data from these studies revealed significant sex differences in the vehicle-exposed offspring that were not observed in the BPA-exposed offspring. These data indicate that BPA may be capable of altering important events during critical periods of brain development.

Animals↗
PubMed2006

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

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

Air Pollution, Indoor↗
PubMed2006

Strengths and weaknesses of in vitro assays for estrogenic and androgenic activity.

The endocrine and reproductive effects of xenobiotics are believed to be due to (1) their mimicking the effects of endogenous hormones; (2) their antagonizing the effects of endogenous hormones; (3) their altering the pattern of synthesis and metabolism of natural hormones; and (4) their modifying hormone receptor levels. It has been suggested that endocrine disruptors may play a role in the decrease in human semen quantity and quality, an increase in the anomalies of male genital tract, and an increase in the testicular and breast cancer incidence during the last 50 years. Testing these hypotheses will require: (1) identifying estrogen and androgen agonists and antagonists among the chemicals present in the environment; (2) assessing the interactions among the endocrine disruptors to which humans are exposed; and (3) finding markers of estrogen (and androgen) exposure. The development of fast and sensitive bioassays is central to the achievement of these three goals.

Androgen Antagonists↗
PubMed2005

Perinatal exposure to bisphenol-A alters peripubertal mammary gland development in mice.

Developmental exposure to estrogenic chemicals induces morphological, functional, and behavioral anomalies associated with reproduction. Humans are exposed to bisphenol-A (BPA), an estrogenic compound that leaches from dental materials and plastic food and beverage containers. The aim of the present study was to determine the effects of perinatal exposure to low, environmentally relevant doses of BPA [25 and 250 ng BPA/kg body weight (bw).d] on the peripubertal development of the mammary gland. BPA exposure enhanced the mammary glands' sensitivity to estradiol in ovariectomized CD-1 mice. In their intact 30-d-old littermates, the area and numbers of terminal end buds relative to the gland ductal area increased whereas their apoptotic activity decreased. There was a positive correlation between ductal length and the age at first proestrus; that was reduced as the BPA dose increased, suggesting that BPA exposure slows down ductal invasion of the stroma. There was also a significant increase of progesterone receptor-positive ductal epithelial cells that were localized in clusters, suggesting future branching points. Indeed, lateral branching was significantly enhanced at 4 months of age in mice exposed to 25 ng BPA /kg bw.d. In conclusion, perinatal exposure to environmentally relevant BPA doses results in persistent alterations in mammary gland morphogenesis. Of special concern is the increased terminal end bud density at puberty as well as the increased number of terminal ends reported previously in adult animals, as these two structures are the sites at which cancer arises in humans and rodents.

Age Factors↗
PubMed2005

Long-term effects of fetal exposure to low doses of the xenoestrogen bisphenol-A in the female mouse genital tract.

Developmental exposure to estrogenic chemicals induces morphological, functional, and behavioral anomalies associated with reproduction. Humans are routinely exposed to bisphenol-A (BPA), an estrogenic compound that leaches from dental materials and plastic food and beverage containers. The aim of the present study was to determine the effects of in utero exposure to low, environmentally relevant doses of BPA on the development of female reproductive tissues in CD-1 mice. In previous publications, we have shown that this treatment alters the morphology of the mammary gland and affects estrous cyclicity. Here we report that in utero exposure to 25 and 250 ng BPA/ kg of body weight per day via osmotic pumps implanted into pregnant dams at Gestational Day 9 induces alterations in the genital tract of female offspring that are revealed during adulthood. They include decreased wet weight of the vagina, decreased volume of the endometrial lamina propria, increased incorporation of bromodeoxyuridine into the DNA of endometrial gland epithelial cells, and increased expression of estrogen receptor-alpha (ERalpha) and progesterone receptor in the luminal epithelium of the endometrium and subepithelial stroma. Because ERalpha is known to be expressed in these estrogen-target organs at the time of BPA exposure, it is plausible that BPA may directly affect the expression of ER-controlled genes involved in the morphogenesis of these organs. In addition, BPA-induced alterations that specifically affect hypothalamic-pituitary-gonadal axis function may further contribute to the anomalies observed at 3 mo of age, long after the cessation of BPA exposure.

Animals↗
PubMed2005

Emergentism as a default: cancer as a problem of tissue organization.

During the last fifty years the dominant stance in experimental biology has been reductionism. For the most part, research programs were based on the notion that genes were in 'the driver's seat' controlling the developmental program and determining normalcy and disease (genetic reductionism and genetic determinism). Philosophers were the first to realize that the belief that the Mendelian genes were reduced to DNA molecules was questionable. Soon after these pronouncements, experimental data confirmed their misgivings. The optimism of molecular biologists, fueled by early success in tackling relatively simple problems, has now been tempered by the difficulties found when attempting to understand complex biological problems. Here, we analyse experimental data that illustrate the shortcomings of this sort of reductionism. We also examine the prevailing paradigm in cancer research, the somatic mutation theory (SMT), the premises of which are: (i) cancer is derived from a single somatic cell that has accumulated multiple DNA mutations; (ii) the default state of cell proliferation in metazoa is quiescence; and (iii) cancer is a disease of cell proliferation caused by mutations in genes that control proliferation and the cell cycle. We challenge the notion that cancer is a cellular problem caused by mutated genes by assessing data gathered both from within the reductionist paradigm and from an alternative view that regards carcinogenesis as a developmental process gone awry. This alternative view, explored under the name of the tissue organization field theory (TOFT), is based on premises that place cancer in a different hierarchical level of complexity from that proposed by the SMT, namely: (i) carcinogenesis represents a problem of tissue organization comparable to organogenesis, and (ii) proliferation is the default state of all cells. We propose that the organicist view, in which the TOFT is based, is a good starting point from which to explore emergent phenomena. However, new theoretical concepts are needed in order to grapple with the apparent circular causality of complex biological phenomena in development and carcinogenesis.

Animals↗
PubMed2005

Stromal regulation of neoplastic development: age-dependent normalization of neoplastic mammary cells by mammary stroma.

There is mounting evidence that the stroma plays a crucial role in mammary gland carcinogenesis. Here, we report that mammary gland stroma from mature and multiparous rats prevents neoplastic development and encourages normal ductal growth of grafted epithelial cancer cells. Fifty thousand epithelial cancer cells were injected into the cleared fat pads of virgin hosts at 24, 52, 80, and 150 days of age and of hosts that had undergone two cycles of pregnancy, lactation, and involution. Six months after inoculation, tumor incidence was 75%, 100%, 50%, and 18.2% in 24-, 52-, 80-, and 150-day-old virgin rats, respectively, and 0% in the twice-parous animals. Most remarkably, these neoplastic cells appeared to form normal ducts in all hosts-Ha-ras-1 mutation served as a marker to identify the tumor origin of the outgrowths. The tumor development pattern suggests a parallel to the phenomenon of age- and reproductive state-dependent susceptibility and resistance to chemical carcinogens. As susceptibility to carcinogenesis decreases, the ability of the stroma to reprogram neoplastic epithelial cells increases. Thus, the neoplastic phenotype is context-dependent, and it therefore offers the intriguing possibility that the process of carcinogenesis is amenable to normalization or cure once the mechanisms of stroma-mediated normalization are elucidated and manipulated.

Aging↗
PubMed2005

Hormone replacement therapy, cancer, controversies, and women's health: historical, epidemiological, biological, clinical, and advocacy perspectives.

Routine acceptance of use of hormone replacement therapy (HRT) was shattered in 2002 when results of the largest HRT randomised clinical trial, the women's health initiative, indicated that long term use of oestrogen plus progestin HRT not only was associated with increased risk of cancer but, contrary to expectations, did not decrease, and may have increased, risk of cardiovascular disease. In June 2004 a group of historians, epidemiologists, biologists, clinicians, and women's health advocates met to discuss the scientific and social context of and response to these findings. It was found that understanding the evolving and contending knowledge on hormones and health requires: (1) considering its societal context, including the impact of the pharmaceutical industry, the biomedical emphasis on individualised risk and preventive medicine, and the gendering of hormones; and (2) asking why, for four decades, since the mid-1960s, were millions of women prescribed powerful pharmacological agents already demonstrated, three decades earlier, to be carcinogenic? Answering this question requires engaging with core issues of accountability, complexity, fear of mortality, and the conduct of socially responsible science.

Cardiovascular Diseases↗