The mammary gland

Whole-genome assemblies of humans and non-human primates are yielding data on the evolutionary origins of the human genome, as well as insights into genetic similarities and differences between species used as models for disease-related research. This Review discusses current knowledge and opportunities for comparative primate genomics created by recent advances in genome sequencing technologies. Advances in genome sequencing technologies have created new opportunities for comparative primate genomics. Genome assemblies have been published for various primate species, and analyses of several others are underway. Whole-genome assemblies for the great apes provide remarkable new information about the evolutionary origins of the human genome and the processes involved. Genomic data for macaques and other non-human primates offer valuable insights into genetic similarities and differences among species that are used as models for disease-related research. This Review summarizes current knowledge regarding primate genome content and dynamics, and proposes a series of goals for the near future.

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Comparative primate genomics: emerging patterns of genome content and dynamics

Breast cancer risk has both heritable and environment/lifestyle components. The heritable component is a small contribution (5–27 %), leaving the majority of risk to environment (e.g., applied chemicals, food residues, occupational hazards, pharmaceuticals, stress) and lifestyle (e.g., physical activity, cosmetics, water source, alcohol, smoking). However, these factors are not well-defined, primarily due to the enormous number of factors to be considered. In both humans and rodent models, environmental factors that act as endocrine disrupting compounds (EDCs) have been shown to disrupt normal mammary development and lead to adverse lifelong consequences, especially when exposures occur during early life. EDCs can act directly or indirectly on mammary tissue to increase sensitivity to chemical carcinogens or enhance development of hyperplasia, beaded ducts, or tumors. Protective effects have also been reported. The mechanisms for these changes are not well understood. Environmental agents may also act as carcinogens in adult rodent models, directly causing or promoting tumor development, typically in more than one organ. Many of the environmental agents that act as EDCs and are known to affect the breast are discussed. Understanding the mechanism(s) of action for these compounds will be critical to prevent their effects on the breast in the future.

/pdf/endocrine-disruptors-and-the-breast-early-life-effects-and-23s9y3u6yu.pdf

Endocrine Disruptors and the Breast: Early Life Effects and Later Life Disease

The idea that susceptibility to breast cancer is determined not only through inherited germline mutations but also by epigenetic changes induced by alterations in hormonal environment during fetal development is gaining increasing support. Using findings obtained in human and animal studies, this review addresses the mechanisms that may explain why daughters of mothers who took synthetic estrogen diethylstilbestrol (DES) during pregnancy have two times higher breast cancer risk than women who were not exposed to it. The mechanisms likely involve epigenetic alterations, such as increased DNA methylation and modifications in histones and microRNA expression. Further, these alterations may target genes that regulate stem cells and prevent differentiation of their daughter cells. Recent findings in a preclinical model suggest that not only are women exposed to DES in utero at an increased risk of developing breast cancer, but this risk may extend to their daughters and granddaughters as well. It is critical, therefore, to determine if the increased risk is driven by epigenetic alterations in genes that increase susceptibility to breast cancer and if these alterations are reversible.

/pdf/maternal-exposure-to-diethylstilbestrol-during-pregnancy-and-21uamwsdnq.pdf

Maternal exposure to diethylstilbestrol during pregnancy and increased breast cancer risk in daughters

The purpose of our publication is to widely communicate pictures of spontaneous findings occurring in cynomolgus monkeys. Focal lymphoplasmacytic infiltration is commonly seen in the general organs. The frequency and severity of these lesions may be influenced by the administration of drugs with an effect on the immune system. Lymphoplasmacytic infiltration in the lamina propria of the stomach is also frequently seen in cynomolgus monkeys, and it is caused mainly by a Helicobacter pylori infection. Various degrees of brown pigments are observed in various organs, and it is possible to distinguish the material of the pigments by its morphological features and site. A focal/segmental glomerular lesion is occasionally seen in a section of the kidney, and the minimal lesion has no influence on the urinalysis. We showed the common glomerular lesions in HE-stained sections, as well as in PAM- or PAS-stained sections, for understanding the details. Young and pubertal monkeys are usually used in toxicity studies; therefore, understanding various maturation stages of the genital system is important. In particular, the female genital system needs to be understood in the morphology, because their cyclic changes are different from other laboratory animals. Thus, we present the normal features of the cyclic changes of the female genital organs. Furthermore, we provide more information on spontaneous findings in cynomolgus monkeys for exact diagnoses in toxicity studies.

Histopathology of Incidental Findings in Cynomolgus Monkeys (Macaca Fascicularis) Used in Toxicity Studies

In this study, we demonstrated growth curves and reference values for hematological and serum biochemical parameters of Microminipigs, the world smallest experimental minipigs. In both male and female animals, the body weights (BWs) at 3 and 6 months of age were <5 kg and <10 kg, respectively, and growth curve revealed almost plateau (approximately 20 kg BW) after 18 months of age. Major hematological and serum biochemical parameters showed no gender differences and the values were very similar to those in Gottingen and Yukatan minipigs. The values obtained in this study can serve as fundamental reference, and thereby facilitate the use of Microminipig in life science research.

Reference values of hematological and biochemical parameters for the world smallest microminipigs.

The authors evaluated dermal phototoxicity using the world smallest minipig (MMPig: Microminipig). MMPigs were administered 100 mg/kg ciprofloxacin hydrochloride with an infusion pump. The dorsal area of each animal was irradiated with ultraviolet-A irradiation. The left dorsal skin was irradiated at intensities of 5, 10, 15, and 20 J/cm2, and the right dorsal back skin was set as a nonirradiated site. Gross and histopathological examinations were conducted before irradiation and from 1 to 72 hr after irradiation. Initial changes in the skin were necrosis of the basal and/or prickle cell layer and cellular infiltration from 24 hr after irradiation. Vesicle formation observed from 48 hr after irradiation was considered similar to bullous eruptions, a known side effect of fluoroquinolones in humans. Therefore, the authors suggest that the MMPig may be a useful experimental animal model for dermal phototoxicity studies.

https://journals.sagepub.com/doi/pdf/10.1177/0192623312452489

A Dermal Phototoxicity Study Following Intravenous Infusion Administration of Ciprofloxacin Hydrochloride in the Novel Microminipigs

The aim of this study was to investigate the effects of neonatal administration of a relatively high dose of diethylstilbestrol (DES) on the induction of mammary carcinomas (MCs) and benign proliferative lesions (PLs) induced by 7,12-dimethylbenz[a]anthracene (DMBA) in female rats. Three different terms of daily administration of DES (10 microg) were used: 0-14, 0-5, and 6-14 days after birth. Control animals were administered solvent (oil) alone once daily from 0 to 14 days after birth. Rats were given DMBA (10 mg) at 50 days after birth. All rats administered DES showed persistent estrus and anovulatory ovaries. In rats administered DES from 0 to 14 and 0 to 5 days after birth there was protection from development of MCs and PLs, and serum levels of both estrogen and progesterone were significantly lower than in the control animals at 100 days after birth. In rats administered DES from 6 to 14 days after birth, the incidence of MCs was equal to that of the control animals (100%), and the number of PLs was significantly higher than in the control animals. The critical period for exposure to endocrine disruptors, such as DES, affecting the induction of MCs and PLs may be from 0 to 5 days after birth.

https://journals.sagepub.com/doi/pdf/10.1354/vp.46-1-142

Effects of neonatally administered high-dose diethylstilbestrol on the induction of mammary tumors induced by 7,12-dimethylbenz[a]anthracene in female rats.

Alzheimer’s disease (AD) in humans is a progressive neurogenic disease that can be linked with such characteristic pathological findings in the cerebrum as senile plaques (SPs), neurofibrillary tangles (NFTs), cerebral amyloid angiopathy (CAA), and neuronal loss. In the present study, the authors investigated the age-related morphological changes in 12 middle-aged and 12 young cynomolgus monkeys. Low numbers of neurons and astrocytes in the hippocampal region in cynomolgus monkeys accompanied ageing, and there was a high number of microglial cells; however, no clearly neurotoxic abnormalities due to b-amyloid were noted before the age of 20 years. The onset of SPs and CAA in the cerebrum in cynomolgus monkeys can occur beforethe age of20years. SPs were almostall categorized as diffuse plaques (DPs);theydid not have amyloid cores and wereunaccompanied by neuritic degeneration. In cynomolgus monkeys, SPs (DPs) occur before the appearance of CAA. From the above, it was concluded that cynomolgus monkeys showed pathological changes due to ageing similar to those related to Alzheimer’s disease in humans, even before they were 20 years old.

https://journals.sagepub.com/doi/pdf/10.1177/0192623309358904

Age-related lesions in the cerebrum in middle-aged female cynomolgus monkeys.

Severe bilateral cataract was found in a 7 year-old naive female cynomolgus monkey (Macaca fascicularis) 3 months before necropsy. During macroscopic examination, severe opacity and thinning of the lens were observed in both eyes. Histopathology revealed that the lens nuclei and majority of cortex lens fibers had disappeared and become excavated, while the lens fibers in the subcapsular area were swollen and distorted. Other observations included atrophy and vacuolation in the lens epithelial cells and proliferation of spindle cells and collagen fiber beneath the anterior capsule of the right eye. Immunohistochemical staining of these spindle cells revealed the presence of vimentin, cytokeratin and α-smooth muscle actin (α-SMA), which were considered to be derived from lens epithelial cells. This is a rare case of spontaneous, bilateral, hypermature cataract in a cynomolgus monkey.

Tsuyoshi Yoshikawa

Papers

Reference values of hematological and biochemical parameters for the world smallest microminipigs.

A Dermal Phototoxicity Study Following Intravenous Infusion Administration of Ciprofloxacin Hydrochloride in the Novel Microminipigs

Effects of neonatally administered high-dose diethylstilbestrol on the induction of mammary tumors induced by 7,12-dimethylbenz[a]anthracene in female rats.

Age-related lesions in the cerebrum in middle-aged female cynomolgus monkeys.

Bilateral cataract in a cynomolgus monkey.