Paternal DDT exposure induces sex-specific programming of fetal growth, placenta development and offspring's health phenotypes in a mouse model.

Mounting evidence suggests that environmentally induced epigenetic inheritance occurs in mammals and that traits in the progeny can be shaped by parental environmental experiences. Epidemiological studies link parental exposure to environmental toxicants, such as the pesticide DDT, to health phenotypes in the progeny, including low birth and increased risk of chronic diseases later in life. Here, we show that the progeny of male mice exposed to DDT in the pre-conception period are born smaller and exhibit sexual dimorphism in metabolic function, with male, but not female, offspring developing severe glucose intolerance compared to controls. These phenotypes in DDT offspring were linked to reduced fetal growth and placenta size as well as placenta-specific reduction of glycogen levels and the nutrient sensor and epigenetic regulator OGT, with more pronounced phenotypes observed in male placentas. However, placenta-specific genetic reduction of OGT only partially replicates the metabolic phenotype observed in offspring of DDT-exposed males. Our findings reveal a role for paternal pre-conception environmental experiences in shaping placenta development and in fetal growth restriction. While many questions remain, our data raise the tantalizing possibility that placenta programming could be a mediator of environmentally induced intergenerational epigenetic inheritance of phenotypes and needs to be further evaluated.

Environmentally Induced Sperm RNAs Transmit Cancer Susceptibility to Offspring in a Mouse Model.

DNA sequence accounts for the majority of disease heritability, including cancer. Yet, not all familial cancer cases can be explained by genetic factors. It is becoming clear that environmentally induced epigenetic inheritance occurs and that the progeny's traits can be shaped by parental environmental experiences. In humans, epidemiological studies have implicated environmental toxicants, such as the pesticide DDT, in intergenerational cancer development, including breast and childhood tumors. Here, we show that the female progeny of males exposed to DDT in the pre-conception period have higher susceptibility to developing aggressive tumors in mouse models of breast cancer. Sperm of DDT-exposed males exhibited distinct patterns of small non-coding RNAs, with an increase in miRNAs and a specific surge in miRNA-10b levels. Remarkably, embryonic injection of the entire sperm RNA load of DDT-exposed males, or synthetic miRNA-10b, recapitulated the tumor phenotypes observed in DDT offspring. Mechanistically, miR-10b injection altered the transcriptional profile in early embryos with enrichment of genes associated with cell differentiation, tissue and immune system development. In adult DDT-derived progeny, transcriptional and protein analysis of mammary tumors revealed alterations in stromal and in immune system compartments. Our findings reveal a causal role for sperm RNAs in environmentally induced inheritance of cancer predisposition and, if confirmed in humans, this could help partially explain some of the "missing heritability" of breast, and other, malignancies.

Diets Differently Regulate Tumorigenesis in Young E0771 Syngeneic Breast Cancer Mouse Model.

Breast cancer (BC) is the most diagnosed cancer type, accounting for one in eight cancer diagnoses worldwide. Epidemiological studies have shown that obesity is associated with increased risk of BC in post-menopausal women, whereas adiposity reduces the risk of BC in premenopausal women. The mechanistic link between obesity and BC has been examined by combining murine BC models with high-fat diet (HFD) induced obesity. However, the effect of adiposity (not obesity) induced by a short period of HFD consumption on BC pathogenesis is not well understood. In the current study, we examined the effects of different diet compositions on BC pathogenesis using a young E0771 syngeneic BC mouse model fed on either an HFD or regular diet (RD: a low-fat high-carbohydrate diet) for a short period (4 weeks) before implanting mammary tumors in mice. We analyzed the effect of diet composition on the onset of tumor growth, metastasis, and metabolic and immune status in the tumor microenvironment (TME) using various methods including in vivo bioluminescence imaging and immunoblotting analyses. We showed for the first time that a short-term HFD delays the onset of tumorigenesis by altering the immune and metabolic signaling and energy mechanism in the TME. However, RD may increase the risk of tumorigenesis and metastasis by increasing pro-inflammatory factors in the TME in young mice. Our data suggest that diet composition, adipogenesis, and loss of body fat likely regulate the pathogenesis of BC in a manner that differs between young and post-menopausal subjects.

Epigenetic Inheritance: Intergenerational Effects of Pesticides and Other Endocrine Disruptors on Cancer Development.

Parental environmental experiences affect disease susceptibility in the progeny through epigenetic inheritance. Pesticides are substances or mixtures of chemicals-some of which are persistent environmental pollutants-that are used to control pests. This review explores the evidence linking parental exposure to pesticides and endocrine disruptors to intergenerational and transgenerational susceptibility of cancer in population studies and animal models. We also discuss the impact of pesticides and other endocrine disruptors on the germline epigenome as well as the emerging evidence for how epigenetic information is transmitted between generations. Finally, we discuss the importance of this mode of inheritance in the context of cancer prevention and the challenges ahead.

Systemic alterations play a dominant role in epigenetic predisposition to breast cancer in offspring of obese fathers and is transmitted to a second generation.

We previously showed that environmentally-induced epigenetic inheritance of cancer occurs in rodent models. For instance, we reported that paternal consumption of an obesity-inducing diet (OID) increased breast cancer susceptibility in the offspring (F1). Nevertheless, it is still unclear whether programming of breast cancer in daughters is due to systemic alterations or mammary epithelium-specific factors and whether the breast cancer predisposition in F1 progeny can be transmitted to subsequent generations. In this study, we show that mammary glands from F1 control (CO) female offspring exhibit enhanced growth when transplanted into OID females compared to CO mammary glands transplanted into CO females. Similarly, carcinogen-induced mammary tumors from F1 CO female offspring transplanted into OID females has a higher proliferation/apoptosis rate. Further, we show that granddaughters (F2) from the OID grand-paternal germline have accelerated tumor growth compared to CO granddaughters. This between-generation transmission of cancer predisposition is associated with changes in sperm tRNA fragments in OID males. Our findings indicate that systemic and mammary stromal alterations are significant contributors to programming of mammary development and likely cancer predisposition in OID daughters. Our data also show that breast cancer predisposition is transmitted to subsequent generations and may explain some familial cancers, if confirmed in humans.

Diet and Transgenerational Epigenetic Inheritance of Breast Cancer: The Role of the Paternal Germline.

The past decade has made evident that in addition to passing their genetic material at conception, parents also transmit a molecular memory of past environmental experiences, including nutritional status, to their progeny through epigenetic mechanisms. In the 1990s, it was proposed that breast cancer originates in utero. Since then, an overwhelming number of studies in human cohorts and animal models have provided support for that hypothesis. It is becoming clear, however, that exposure in the parent generation can lead to multigenerational and transgenerational inheritance of breast cancer. Importantly, recent data from our lab and others show that pre-conception paternal diets reprogram the male germline and modulate breast cancer development in offspring. This review explores the emerging evidence for transgenerational epigenetic inheritance of breast cancer focusing on studies associated with ancestral nutritional factors or related markers such as birth weight. We also explore paternal factors and the epigenetic mechanisms of inheritance through the male germline while also reviewing the existing literature on maternal exposures in pregnancy and its effects on subsequent generations. Finally, we discuss the importance of this mode of inheritance in the context of breast cancer prevention, the challenges, and outstanding research questions in the field.

Parental obesity programs pancreatic cancer development in offspring.

Epidemiological studies suggest that timing of obesity onset - and underlying metabolic dysfunction - is important in determining pancreatic cancer rates: early and young adult abdominal overweight/obesity is more strongly associated with this cancer than obesity that develops later in life. Parental obesity and overweight are associated with metabolic dysfunction and obesity in their children. Here, we evaluated the impact of parental overweight on offspring's susceptibility of pancreatic cancer using the P48Cre/+/KrasG12D/+ mouse model. Male mice were fed an obesity-inducing diet (OID) before conception and mated with females raised on a control diet (CO) to generate the offspring. In a separate experiment, pregnant dams were fed CO or OID throughout gestation. The resulting OID offspring from the maternal (OID-m) or paternal lineage (OID-p) were used to study body weight, metabolic parameters and pancreatic cancer development and for molecular analysis. Parental obesity increased offspring's body weight at birth, weaning and in adulthood compared to CO, with gender- and genotype-specific differences. OID-p and OID-m offspring showed metabolic disorder and accelerated development of high-grade PanIN/PDAC. OID offspring also had higher rates of acinar-to-ductal reprogramming assessed by CPA1+/SOX9+-positive pancreatic cells. Levels of Tenascin C (TNC), an ECM glycoprotein shown to suppress apoptosis, were elevated in OID offspring, particularly females. In line with that, OID offspring displayed increased collagen content and decreased apoptosis in pancreatic lesions compared to CO. An ancestral history of obesity through either the paternal or maternal lineages increases offspring's susceptibility to pancreatic cancer development.

Paternal malnutrition programs breast cancer risk and tumor metabolism in offspring.

BACKGROUND: While many studies have shown that maternal factors in pregnancy affect the cancer risk for offspring, few studies have investigated the impact of paternal exposures on their progeny's risk of this disease. Population studies generally show a U-shaped association between birthweight and breast cancer risk, with both high and low birthweight increasing the risk compared with average birthweight. Here, we investigated whether paternal malnutrition would modulate the birthweight and later breast cancer risk of daughters. METHODS: Male mice were fed AIN93G-based diets containing either 17.7% (control) or 8.9% (low-protein (LP)) energy from protein from 3 to 10 weeks of age. Males on either group were mated to females raised on a control diet. Female offspring from control and LP fathers were treated with 7,12-dimethylbenz[a]anthracene (DMBA) to initiate mammary carcinogenesis. Mature sperm from fathers and mammary tissue and tumors from female offspring were used for epigenetic and other molecular analyses. RESULTS: We found that paternal malnutrition reduces the birthweight of daughters and leads to epigenetic and metabolic reprogramming of their mammary tissue and tumors. Daughters of LP fathers have higher rates of mammary cancer, with tumors arising earlier and growing faster than in controls. The energy sensor, the AMP-activated protein kinase (AMPK) pathway, is suppressed in both mammary glands and tumors of LP daughters, with consequent activation of mammalian target of rapamycin (mTOR) signaling. Furthermore, LP mammary tumors show altered amino-acid metabolism with increased glutamine utilization. These changes are linked to alterations in noncoding RNAs regulating those pathways in mammary glands and tumors. Importantly, we detect alterations in some of the same microRNAs/target genes found in our animal model in breast tumors of women from populations where low birthweight is prevalent. CONCLUSIONS: Our study suggests that ancestral paternal malnutrition plays a role in programming offspring cancer risk and phenotype by likely providing a metabolic advantage to cancer cells.

Uso de una aplicación para registrar información sobre pacientes estomatológicos desde la perspectiva de los cirujanos dentales / The use of an application to record information on Dentistry patients from the perspective of dental surgeons

Dental records are complex documents and not all dental surgeons have been careful to fill them correctly. On the other hand, a number of apps for professional support has been observed on the market aimed at healthcare. The purpose of this study was to show how dental surgeons have noticed the technology of mobile devices and how it would help in their work routine by analysing an application for recording patient information. This study was exploratory, qualitative, descriptive, and transversal, with data obtained through a semi-structured interview with open-ended questions applied to ten dental surgeons who have downloaded the App OdontoExame as study population. The answers were analysed by the content analysis technique. The results showed that this technology could be useful in storing information. Besides, 90 percent of respondents stated that the application would help in clinical practices, while 10 percent considered such a technology still limited to this function(AU)

Los registros estomatológicos son documentos complejos y no todos los cirujanos dentales han sido cuidadosos al llenarlos correctamente. Por otra parte, un conjunto de aplicaciones de apoyo profesional han aparecido en el mercado, las que están dirigidas a la atención médica. El propósito del presente estudio es mostrar cómo los cirujanos dentales han notado la presencia de la tecnología de dispositivos móviles y cómo esta los podría ayudar en su trabajo diario, a partir del análisis de una aplicación para el registro de información de los pacientes. Se trata de un estudio exploratorio, cualitativo, descriptivo y transversal, basado en datos obtenidos mediante una entrevista semiestructurada con preguntas abiertas dirigidas a una población de diez cirujanos dentales que han descargado la aplicación OdontoExame. Las respuestas se analizaron aplicando la técnica de análisis de contenidos. Los resultados mostraron que esa tecnología puede ser útil para almacenar información. El 90 por ciento de los encuestados plantearon que la aplicación podría ser útil en la práctica clínica, mientras que el 10 por ciento consideró que esta aún estaba limitada a esa función(AU)

Uso de una aplicación para registrar información sobre pacientes estomatológicos desde la perspectiva de los cirujanos dentales / The use of an application to record information on Dentistry patients from the perspective of dental surgeons

Dental records are complex documents and not all dental surgeons have been careful to fill them correctly. On the other hand, a number of apps for professional support has been observed on the market aimed at healthcare. The purpose of this study was to show how dental surgeons have noticed the technology of mobile devices and how it would help in their work routine by analysing an application for recording patient information. This study was exploratory, qualitative, descriptive, and transversal, with data obtained through a semi-structured interview with open-ended questions applied to ten dental surgeons who have downloaded the App OdontoExame as study population. The answers were analysed by the content analysis technique. The results showed that this technology could be useful in storing information. Besides, 90 percent of respondents stated that the application would help in clinical practices, while 10 percent considered such a technology still limited to this function(AU)

Los registros estomatológicos son documentos complejos y no todos los cirujanos dentales han sido cuidadosos al llenarlos correctamente. Por otra parte, un conjunto de aplicaciones de apoyo profesional han aparecido en el mercado, las que están dirigidas a la atención médica. El propósito del presente estudio es mostrar cómo los cirujanos dentales han notado la presencia de la tecnología de dispositivos móviles y cómo esta los podría ayudar en su trabajo diario, a partir del análisis de una aplicación para el registro de información de los pacientes. Se trata de un estudio exploratorio, cualitativo, descriptivo y transversal, basado en datos obtenidos mediante una entrevista semiestructurada con preguntas abiertas dirigidas a una población de diez cirujanos dentales que han descargado la aplicación OdontoExame. Las respuestas se analizaron aplicando la técnica de análisis de contenidos. Los resultados mostraron que esa tecnología puede ser útil para almacenar información. El 90 por ciento de los encuestados plantearon que la aplicación podría ser útil en la práctica clínica, mientras que el 10 por ciento consideró que esta aún estaba limitada a esa función(AU)

Developmental Origins of Breast Cancer: A Paternal Perspective.

The developmental origins of breast cancer have been considered predominantly from a maternal perspective. Although accumulating evidence suggests a paternal programming effect on metabolic diseases, the potential impact of fathers' experiences on their daughters' breast cancer risk has received less attention. In this chapter, we focus on the developmental origins of breast cancer and examine the emerging evidence for a role of fathers' experiences.

Investigation of Paternal Programming of Breast Cancer Risk in Female Offspring in Rodent Models.

Emerging experimental evidence show that fathers' experiences during preconception can influence their daughters' risk of developing breast cancer. Here we describe detailed protocols for investigation in rats and mice of paternally mediated breast cancer risk programming effects.

Maternal intake of high n-6 polyunsaturated fatty acid diet during pregnancy causes transgenerational increase in mammary cancer risk in mice.

BACKGROUND: Maternal and paternal high-fat (HF) diet intake before and/or during pregnancy increases mammary cancer risk in several preclinical models. We studied if maternal consumption of a HF diet that began at a time when the fetal primordial germ cells travel to the genital ridge and start differentiating into germ cells would result in a transgenerational inheritance of increased mammary cancer risk. METHODS: Pregnant C57BL/6NTac mouse dams were fed either a control AIN93G or isocaloric HF diet composed of corn oil high in n-6 polyunsaturated fatty acids between gestational days 10 and 20. Offspring in subsequent F1-F3 generations were fed only the control diet. RESULTS: Mammary tumor incidence induced by 7,12-dimethylbenz[a]anthracene was significantly higher in F1 (p < 0.016) and F3 generation offspring of HF diet-fed dams (p < 0.040) than in the control offspring. Further, tumor latency was significantly shorter (p < 0.028) and burden higher (p < 0.027) in F1 generation HF offspring, and similar trends were seen in F3 generation HF offspring. RNA sequencing was done on normal mammary glands to identify signaling differences that may predispose to increased breast cancer risk by maternal HF intake. Analysis revealed 1587 and 4423 differentially expressed genes between HF and control offspring in F1 and F3 generations, respectively, of which 48 genes were similarly altered in both generations. Quantitative real-time polymerase chain reaction analysis validated 13 chosen up- and downregulated genes in F3 HF offspring, but only downregulated genes in F1 HF offspring. Ingenuity Pathway Analysis identified upregulation of Notch signaling as a key alteration in HF offspring. Further, knowledge-fused differential dependency network analysis identified ten node genes that in the HF offspring were uniquely connected to genes linked to increased cancer risk (ANKEF1, IGFBP6, SEMA5B), increased resistance to cancer treatments (SLC26A3), poor prognosis (ID4, JAM3, TBX2), and impaired anticancer immunity (EGR3, ZBP1). CONCLUSIONS: We conclude that maternal HF diet intake during pregnancy induces a transgenerational increase in offspring mammary cancer risk in mice. The mechanisms of inheritance in the F3 generation may be different from the F1 generation because significantly more changes were seen in the transcriptome.

Effects of In Utero Exposure to Ethinyl Estradiol on Tamoxifen Resistance and Breast Cancer Recurrence in a Preclinical Model.

Background: Responses to endocrine therapies vary among patients with estrogen receptor (ER+) breast cancer. We studied whether in utero exposure to endocrine-disrupting compounds might explain these variations. Methods: We describe a novel ER+ breast cancer model to study de novo and acquired tamoxifen (TAM) resistance. Pregnant Sprague Dawley rats were exposed to 0 or 0.1 ppm ethinyl estradiol (EE2), and the response of 9,12-dimethylbenz[a]anthracene (DMBA)-induced mammary tumors to 15 mg/kg TAM, with (n = 17 tumors in the controls and n = 20 tumors in EE2 offspring) or without 1.2 g/kg valproic acid and 5 mg/kg hydralazine (n = 24 tumors in the controls and n = 32 tumors in EE2 offspring) in the female offspring, was assessed. One-sided Chi2 tests were used to calculate P values. Comparisons of differentially expressed genes between mammary tumors in in utero EE2-exposed and control rats, and between anti-estrogen-resistant LCC9 and -sensitive LCC1 human breast cancer cells, were also performed. Results: In our preclinical model, 54.2% of mammary tumors in the control rats exhibited a complete response to TAM, of which 23.1% acquired resistance with continued anti-estrogen treatment and recurred. Mammary tumors in the EE2 offspring were statistically significantly less likely to respond to TAM (P = .047) and recur (P = .007). In the EE2 offspring, but not in controls, adding valproic acid and hydralazine to TAM prevented recurrence (P < .001). Three downregulated and hypermethylated genes (KLF4, LGALS3, MICB) and one upregulated gene (ETV4) were identified in EE2 tumors and LCC9 breast cancer cells, and valproic acid and hydralazine normalized the altered expression of all four genes. Conclusions: Resistance to TAM may be preprogrammed by in utero exposure to high estrogen levels and mediated through reversible epigenetic alterations in genes associated with epithelial-mesenchymal transition and tumor immune responses.

Paternal programming of breast cancer risk in daughters in a rat model: opposing effects of animal- and plant-based high-fat diets.

BACKGROUND: Although males contribute half of the embryo's genome, only recently has interest begun to be directed toward the potential impact of paternal experiences on the health of offspring. While there is evidence that paternal malnutrition may increase offspring susceptibility to metabolic diseases, the influence of paternal factors on a daughter's breast cancer risk has been examined in few studies. METHODS: Male Sprague-Dawley rats were fed, before and during puberty, either a lard-based (high in saturated fats) or a corn oil-based (high in n-6 polyunsaturated fats) high-fat diet (60 % of fat-derived energy). Control animals were fed an AIN-93G control diet (16 % of fat-derived energy). Their 50-day-old female offspring fed only a commercial diet were subjected to the classical model of mammary carcinogenesis based on 7,12-dimethylbenz[a]anthracene initiation, and mammary tumor development was evaluated. Sperm cells and mammary gland tissue were subjected to cellular and molecular analysis. RESULTS: Compared with female offspring of control diet-fed male rats, offspring of lard-fed male rats did not differ in tumor latency, growth, or multiplicity. However, female offspring of lard-fed male rats had increased elongation of the mammary epithelial tree, number of terminal end buds, and tumor incidence compared with both female offspring of control diet-fed and corn oil-fed male rats. Compared with female offspring of control diet-fed male rats, female offspring of corn oil-fed male rats showed decreased tumor growth but no difference regarding tumor incidence, latency, or multiplicity. Additionally, female offspring of corn oil-fed male rats had longer tumor latency as well as decreased tumor growth and multiplicity compared with female offspring of lard-fed male rats. Paternal consumption of animal- or plant-based high-fat diets elicited opposing effects, with lard rich in saturated fatty acids increasing breast cancer risk in offspring and corn oil rich in n-6 polyunsaturated fatty acids decreasing it. These effects could be linked to alterations in microRNA expression in fathers' sperm and their daughters' mammary glands, and to modifications in breast cancer-related protein expression in this tissue. CONCLUSIONS: Our findings highlight the importance of paternal nutrition in affecting future generations' risk of developing breast cancer.

Paternal overweight is associated with increased breast cancer risk in daughters in a mouse model.

While many studies have shown that maternal weight and nutrition in pregnancy affects offspring's breast cancer risk, no studies have investigated the impact of paternal body weight on daughters' risk of this disease. Here, we show that diet-induced paternal overweight around the time of conception can epigenetically reprogram father's germ-line and modulate their daughters' birth weight and likelihood of developing breast cancer, using a mouse model. Increased body weight was associated with changes in the miRNA expression profile in paternal sperm. Daughters of overweight fathers had higher rates of carcinogen-induced mammary tumors which were associated with delayed mammary gland development and alterations in mammary miRNA expression. The hypoxia signaling pathway, targeted by miRNAs down-regulated in daughters of overweight fathers, was activated in their mammary tissues and tumors. This study provides evidence that paternal peri-conceptional body weight may affect daughters' mammary development and breast cancer risk and warrants further studies in other animal models and humans.

Lipidomic fatty acid profile and global gene expression pattern in mammary gland of rats that were exposed to lard-based high fat diet during fetal and lactation periods associated to breast cancer risk in adulthood.

The persistent effects of animal fat consumption during pregnancy and nursing on the programming of breast cancer risk among female offspring were studied here. We have previously found that female offspring of rat dams that consumed a lard-based high-fat (HF) diet (60% fat-derived energy) during pregnancy, or during pregnancy and lactation, were at a reduced risk of developing mammary cancer. To better understand the unexpected protective effects of early life lard exposure, we have applied lipidomics and nutrigenomics approaches to investigate the fatty acid profile and global gene expression patterns in the mammary tissue of the female offspring. Consumption of this HF diet during gestation had few effects on the mammary tissue fatty acids profile of young adult offspring, while exposure from gestation throughout nursing promoted significant alterations in the fatty acids profile. Major differences were related to decreases in saturated fatty acids (SFA) and increases in omega-6 polyunsaturated fatty acids (PUFAs), monounsaturated fatty acids (MUFAs) and conjugated linolenic acid (CLA) concentrations. In addition several differences in gene expression patterns by microarray analysis between the control and in utero or in utero and during lactation HF exposed offspring were identified. Differential dependency network (DDN) analysis indicated that many of the genes exhibited unique connections to other genes only in the HF offspring. These unique connections included Hrh1-Ythdf1 and Repin1-Elavl2 in the in utero HF offspring, and Rnf213-Htr3b and Klf5-Chrna4 in the in utero and lactation HF offspring, compared with the control offspring. We conclude that an exposure to a lard-based HF diet during early life changes the fatty acid profile and transcriptional network in mammary gland in young adult rats, and these changes appear to be consistent with reduced mammary cancer risk observed in our previous study.

Exposure to lard-based high-fat diet during fetal and lactation periods modifies breast cancer susceptibility in adulthood in rats.

The present study investigated whether early life exposure to high levels of animal fat increases breast cancer risk in adulthood in rats. Dams consumed a lard-based high-fat (HF) diet (60% fat-derived energy) or an AIN93G control diet (16% fat-derived energy) during gestation or gestation and lactation. Their 7-week-old female offspring were exposed to 7,12-dimethyl-benzo[a]anthracene to induce mammary tumors. Pregnant dams consuming an HF diet had higher circulating leptin levels than pregnant control dams. However, compared to the control offspring, significantly lower susceptibility to mammary cancer development was observed in the offspring of dams fed an HF diet during pregnancy (lower tumor incidence, multiplicity and weight), or pregnancy and lactation (lower tumor multiplicity only). Mammary epithelial elongation, cell proliferation (Ki67) and expression of NFκB p65 were significantly lower and p21 expression and global H3K9me3 levels were higher in the mammary glands of rats exposed to an HF lard diet in utero. They also tended to have lower Rank/Rankl ratios (P=.09) and serum progesterone levels (P=.07) than control offspring. In the mammary glands of offspring of dams consuming an HF diet during both pregnancy and lactation, the number of terminal end buds, epithelial elongation and the BCL-2/BAX ratio were significantly lower and serum leptin levels were higher than in the controls. Our data confirm that the breast cancer risk of offspring can be programmed by maternal dietary intake. However, contrary to our expectation, exposure to high levels of lard during early life decreased later susceptibility to breast cancer.

Exposure to excess estradiol or leptin during pregnancy increases mammary cancer risk and prevents parity-induced protective genomic changes in rats.

Using a preclinical model, we investigated whether excess estradiol (E2) or leptin during pregnancy affects maternal mammary tumorigenesis in rats initiated by administering carcinogen 7,12-dimethylbenz(a)anthracene (DMBA) on day 50. Two weeks later, rats were mated, and pregnant dams were treated daily with 10 µg of 17ß-estradiol, 15 µg of leptin, or vehicle from gestation day 8 to 19. Tumor development was assessed separately during weeks 1 to 12 and 13 to 22 after DMBA administration, because pregnancy is known to induce a transient increase in breast cancer risk, followed by a persistent reduction. Parous rats developed less (32%) mammary tumors than nulliparous rats (59%, P < 0.001), and the majority (93%) of tumors in the parous rats appeared before week 13 (vs. 41% in nulliparous rats), indicating that pregnancy induced a transient increase in breast cancer risk. Parous rats exposed to leptin (final tumor incidence 65%) or E2 (45%) during pregnancy developed mammary tumors throughout the tumor-monitoring period, similar to nulliparous control rats, and the incidence was significantly higher in both the leptin- and E2-exposed dams after week 12 than in the vehicle-exposed parous dams (P < 0.001). The mammary glands of the exposed parous rats contained significantly more proliferating cells (P < 0.001). In addition, the E2- or leptin-treated parous rats did not exhibit the protective genomic signature induced by pregnancy and seen in the parous control rats. Specifically, these rats exhibited downregulation of genes involved in differentiation and immune functions and upregulation of genes involved in angiogenesis, growth, and epithelial-to-mesenchymal transition.

Exposures to synthetic estrogens at different times during the life, and their effect on breast cancer risk.

Women are using estrogens for many purposes, such as to prevent pregnancy or miscarriage, or to treat menopausal symptoms. Estrogens also have been used to treat breast cancer which seems puzzling, since there is convincing evidence to support a link between high lifetime estrogen exposure and increased breast cancer risk. In this review, we discuss the findings that maternal exposure to the synthetic estrogen diethylstilbestrol during pregnancy increases breast cancer risk in both exposed mothers and their daughters. In addition, we review data regarding the use of estrogens in oral contraceptives and as postmenopausal hormone therapy and discuss the opposing effects on breast cancer risk based upon timing of exposure. We place particular emphasis on studies investigating how maternal estrogenic exposures during pregnancy increase breast cancer risk among daughters. New data suggest that these exposures induce epigenetic modifications in the mammary gland and germ cells, thereby causing an inheritable increase in breast cancer risk for multiple generations.