Abstract:Exposure to low doses of environmental estrogens such as bisphenol A and genistein (G) alters mammary gland development. The effects of environmental anti-androgens, such as the fungicide vinclozolin (V), on mammary gland morphogenesis are unknown. We previously reported that perinatal exposure to G, V, and the GV combination causes histological changes in the mammary gland during the peripubertal period, suggesting alterations to the peripubertal hormone response. We now investigate whether perinatal exposure… Show more
“…3b), presumably restricting paracellular permeability although no permeability data appear to be available. Claudin-1 has been clearly observed in mammary epithelia from 35 day old rats as well [54]. Fig.…”
Section: Part 2: Claudin Expression and Localization During Mammary Gmentioning
confidence: 97%
“…Claudin-1 was located at the tight junctions of the mammary ducts [29, 52–54] (Fig. 3b), presumably restricting paracellular permeability although no permeability data appear to be available.…”
Section: Part 2: Claudin Expression and Localization During Mammary Gmentioning
Claudins are a large family of membrane proteins whose classic function is to regulate the permeability of tight junctions in epithelia. They are tetraspanins, with four alpha-helices crossing the membrane, two extracellular loops, a short cytoplasmic N-terminus and a longer and more variable C-terminus. The extracellular ends of the helices are known to undergo side-to-side (cis) interactions that allow the formation of claudin polymers in the plane of the membrane. The extracellular loops also engage in head-to-head (trans) interactions thought to mediate the formation of tight junctions. However, claudins are also present in intracellular structures, thought to be vesicles, with less well-characterized functions. Here, we briefly review our current understanding of claudin structure and function followed by an examination of changes in claudin mRNA and protein expression and localization through mammary gland development. Claudins-1, 3, 4, 7, and 8 are the five most prominent members of the claudin family in the mouse mammary gland, with varied abundance and intracellular localization during the different stages of post-pubertal development. Claudin-1 is clearly localized to tight junctions in mammary ducts in non-pregnant non-lactating animals. Cytoplasmic puncta that stain for claudin-7 are present throughout development. During pregnancy claudin-3 is localized both to the tight junction and basolaterally while claudin-4 is found only in sparse puncta. In the lactating mouse both claudin-3 and claudin-8 are localized at the tight junction where they may be important in forming the paracellular barrier. At involution and under challenge by lipopolysaccharide claudins −1, −3, and −4 are significantly upregulated. Claudin-3 is still colocalized with tight junction molecules but is also distributed through the cytoplasm as is claudin-4. These largely descriptive data provide the essential framework for future mechanistic studies of the function and regulation of mammary epithelial cell claudins.Electronic supplementary materialThe online version of this article (doi:10.1007/s10911-017-9379-6) contains supplementary material, which is available to authorized users.
“…3b), presumably restricting paracellular permeability although no permeability data appear to be available. Claudin-1 has been clearly observed in mammary epithelia from 35 day old rats as well [54]. Fig.…”
Section: Part 2: Claudin Expression and Localization During Mammary Gmentioning
confidence: 97%
“…Claudin-1 was located at the tight junctions of the mammary ducts [29, 52–54] (Fig. 3b), presumably restricting paracellular permeability although no permeability data appear to be available.…”
Section: Part 2: Claudin Expression and Localization During Mammary Gmentioning
Claudins are a large family of membrane proteins whose classic function is to regulate the permeability of tight junctions in epithelia. They are tetraspanins, with four alpha-helices crossing the membrane, two extracellular loops, a short cytoplasmic N-terminus and a longer and more variable C-terminus. The extracellular ends of the helices are known to undergo side-to-side (cis) interactions that allow the formation of claudin polymers in the plane of the membrane. The extracellular loops also engage in head-to-head (trans) interactions thought to mediate the formation of tight junctions. However, claudins are also present in intracellular structures, thought to be vesicles, with less well-characterized functions. Here, we briefly review our current understanding of claudin structure and function followed by an examination of changes in claudin mRNA and protein expression and localization through mammary gland development. Claudins-1, 3, 4, 7, and 8 are the five most prominent members of the claudin family in the mouse mammary gland, with varied abundance and intracellular localization during the different stages of post-pubertal development. Claudin-1 is clearly localized to tight junctions in mammary ducts in non-pregnant non-lactating animals. Cytoplasmic puncta that stain for claudin-7 are present throughout development. During pregnancy claudin-3 is localized both to the tight junction and basolaterally while claudin-4 is found only in sparse puncta. In the lactating mouse both claudin-3 and claudin-8 are localized at the tight junction where they may be important in forming the paracellular barrier. At involution and under challenge by lipopolysaccharide claudins −1, −3, and −4 are significantly upregulated. Claudin-3 is still colocalized with tight junction molecules but is also distributed through the cytoplasm as is claudin-4. These largely descriptive data provide the essential framework for future mechanistic studies of the function and regulation of mammary epithelial cell claudins.Electronic supplementary materialThe online version of this article (doi:10.1007/s10911-017-9379-6) contains supplementary material, which is available to authorized users.
“…To ask whether in utero exposure to the metal also affected the postpubertal mammary gland, the expression of Aldh1A1, telomerase [ 61 , 62 ], and Six1 [ 63 , 64 , 65 ], genes that are associated with stem and progenitor cells, was determined on postnatal day 60. To avoid the effects of estradiol on gene expression, the animals were ovariectomized on postnatal day 45 ( Figure 3 E) [ 66 ]. In the adult animals exposed in utero to cadmium, there was a significant increase in Aldh1A1 mRNA (2.74-fold increase; p < 0.05) as well as an increase in telomerase mRNA (1.9-fold; p = 0.057) and Six1 mRNA (2.9-; p = 0.075).…”
Environmental exposure to estrogens and estrogen like contaminants during early development is thought to contribute to the risk of developing breast cancer primarily due to an early onset of puberty; however, exposure during key developing windows may also influence the risk of developing the disease. The goal of this study was to ask whether in utero exposure to the metalloestrogen cadmium alters mammary gland development due to acceleration of puberty onset or to an effect on early development of the mammary gland. The results show that, in addition to advancing the onset of puberty, in utero exposure to the metalloestrogen cadmium altered mammary gland development prior to its effect on puberty onset. In utero exposure resulted in an expansion of the number of mammosphere-forming cells in the neonatal mammary gland and an increase in branching, epithelial cells, and density in the prepubertal mammary gland. In the postpubertal mammary gland, there was a further expansion of the mammary stem/progenitor cell population and overexpression of estrogen receptor-alpha (ERα) that was due to the overexpression and altered regulation of the ERα transcripts derived from exons O and OT in response to estradiol. These results suggest that in utero exposure to cadmium increases stem/progenitor cells, cell density, and expression of estrogen receptor-alpha that may contribute to the risk of developing breast cancer.
“…Subsequent works have demonstrated several actions of vinclozolin as an antiandrogen, including reducing prostate weight (Monosson et al 1999), modulating sex steroid levels (Quignot et al 2012) and elevating the prevalence of tumors in the prostate and testis (Anway et al 2006). In the female, vinclozolin exposure in rats results in the formation of mammary tumors (Anway et al 2006) and disrupts mammary gland development, where epithelial branching and TEBs are increased compared with controls (El Sheikh Saad et al 2011, 2013). However, very few epidemiological studies have been performed on the association of vinclozolin exposure with breast cancer.…”
The heritable component of breast cancer accounts for only a small proportion of total incidences. Environmental and lifestyle factors are therefore considered to among the major influencing components increasing breast cancer risk. Endocrine-disrupting chemicals (EDCs) are ubiquitous in the environment. The estrogenic property of EDCs has thus shown many associations between ongoing exposures and the development of endocrine-related diseases, including breast cancer. The environment consists of a heterogenous population of EDCs and despite many identified modes of action, including that of altering the epigenome, drawing definitive correlations regarding breast cancer has been a point of much discussion. In this review, we describe in detail well-characterized EDCs and their actions in the environment, their ability to disrupt mammary gland formation in animal and human experimental models and their associations with exposure and breast cancer risk. We also highlight the susceptibility of early-life exposure to each EDC to mediate epigenetic alterations, and where possible describe how these epigenome changes influence breast cancer risk.
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