Bisphenol A replacement chemicals,BPF and BPS,induce protumorigenic changes in human mammary gland organoid morphology and proteome

Environmental chemicals such as bisphenol A (BPA) are thought to contribute to carcinogenesis through their endocrine-disrupting properties. Due to accumulating evidence about negative human health effects, BPA is being phased out, but in parallel, exposures to replacement chemicals such as bisphenol S (BPS) and bisphenol F (BPF) are increasing. Little is known about their biologic effects, but because of their high degree of chemical relatedness, they may have overlapping as well as distinct actions as compared with BPA. We investigated this theory using a nonmalignant, human breast tissue-derived organoid system and two end points: morphologic and proteomic alterations. At low-nanomolar doses, replacement chemicals—particularly BPS—disrupted normal mammary organoid architecture and led to an increased branching phenotype. Treatment with the various bisphenols (vs. 17-β-estradiol or a vehicle control) produced distinct proteomic changes. For example, BPS up-regulated Cdc42-interacting protein 4, which supports the formation of invadopodia and a mesenchymal phenotype. In summary, this study used a highly physiologically relevant organoid system to provide evidence that replacement bisphenols have protumorigenic effects on the mammary gland at morphologic and proteomic levels, highlighting the importance of studies to evaluate the potential harmful effects of structurally related environmental chemicals.

Bisphenols, of which the most prevalent is bisphenol A (BPA), are environmental chemicals that are used as plasticizers in a variety of goods, including plastic bottles, children''s toys, eyeglass lenses, food containers, and some types of thermal paper (e.g., cash register receipts). They leach from these products, contaminating humans (and animals) either directly or indirectly via other environmental media, such as household dust. Thus, in most adults, BPA is detected in serum, tissues, and urine (1, 2). Children (ages 6 to 11) have the highest concentrations of urinary BPA (3, 4). This chemical has structural similarities to estrogen (17-β-estradiol [E2]) and as a result, weakly mimics its activity (5). Hormones and growth factors play an important role in controlling prenatal mammary gland development and later on, the morphologic and functional alterations that occur during puberty, pregnancy, and eventually, menopause. Due to this plasticity, the mammary gland is particularly susceptible to the actions of endocrine-disrupting chemicals (EDCs), such as BPA (6–8). In vivo and in vitro studies have consistently shown that exposures to BPA at crucial developmental stages impair mammary gland development and increase neoplastic transformation (9–12). Treating rats with BPA results in mammary epithelial hyperplasia and enhances proliferation (13), common features of precancerous lesions. Additionally, BPA induces cell cycle progression and increases proliferation of human breast cancer cells in vitro via the up-regulated expression of estrogen-dependent genes (14).Based on these and other data, BPA has been removed from many commercial products. Most commonly, this chemical of concern is replaced by bisphenol S (BPS) and bisphenol F (BPF) compounds that share close structural similarities with BPA. However, little is known about their endocrine effects and more broadly, their biological activities. Marketing a product as “BPA free” suggests to the consumer that a product is safer, but research shows that replacement bisphenols have adverse effects similar to, or even greater than, BPA. For example, studies in zebrafish, rodents, and human cell culture models show that BPS and BPF have endocrine-disrupting activities. In zebrafish, despite species-specific differences in estrogen receptor (ER) affinity and specificity, BPF and BPS have estrogenic activities similar to BPA (15–17). In rats, exposure to BPF induces uterine growth, which suggests estrogenic effects (18). BPA, BPF, and BPS promote estrogen-dependent cell cycle progression, proliferation, and migration of human MCF-7 breast cancer cells along with epigenetic changes (19, 20). BPS exposure of pregnant and lactating mice limits milk production, suggesting alterations in mammary gland composition (21). In addition to estrogen signaling, BPF affects other endocrine pathways; in rats, oral administration of this compound alters thyroid hormone levels (22).Current research on bisphenol actions is mainly focused on endocrine effects. It is less well understood whether these chemicals have additional protumorigenic effects independent of their endocrine-disrupting activity. Moreover, tumor development is a multistep process involving heterogeneous cell types and numerous factors, including the potential roles of a variety of environmental chemicals (23, 24). Recapitulating this complexity in an experimental setup is challenging. In this context, tissue organoids are valuable models for understanding the early steps of carcinogenesis. They can be derived from nonmalignant primary tissues ex vivo. When grown for short periods of time in vitro, they maintain many of the genetic and epigenetic features of their normal cognates. Also, organoids have the added advantage of consisting of multiple cell types that are representative of the complexity of the tissue from which they are derived (25, 26).In this study, we exploited the strengths of the human mammary gland organoid culture system to understand the impact of the BPA replacements, BPF and BPS. Organoids established from nonmalignant human mammary gland tissues were exposed to one of the bisphenols, E2, or the vehicle control. The results showed that BPA replacements, in particular BPS, disrupted organoid architecture, enhanced branching, and caused compound-specific proteomic alterations—effects that were mostly E2 independent. Together, these observations suggested that the mammary gland effects of BPA substitutes should be equally or more concerning than those of the compound they are replacing.     

Nutraceuticals for Androgenetic Alopecia

BackgroundSeveral oral nutraceuticals have recently emerged as products marketed to increase hair growth and thickness. However, these supplements typically lack the rigorous testing and statistically significant data that apply to pharmaceuticals. Therefore, the potential benefits of oral nutraceuticals for conditions of hair loss, such as androgenetic alopecia, have yet to be fully understood by dermatologists. ObjectiveThe purpose of this article is to evaluate current studies in the literature to assess the efficacy of popular oral nutraceuticals marketed for hair growth in subjects with androgenetic alopecia.MethodsThis article reviews the currently available literature on the nutraceuticals Nutrafol^® and Viviscal^® for hair growth and describes and evaluates the results observed.ResultsOral nutraceuticals are effective to a modest degree in promoting hair growth in men and women with androgenetic alopecia.ConclusionOral nutraceuticals have demonstrated efficacy in promoting modest hair growth in men and women with androgenetic alopecia and may serve as useful adjuncts to current treatments. As the popularity of nutraceuticals grows, it is important for dermatologists to be knowledgeable of the potential benefits and pitfalls of these supplements to appropriately counsel patients seeking treatment for hair loss.     

Professionals’ Perspectives about the Challenges of Using Interpreters in Child Sexual Abuse Interviews

Interpreters play a crucial role in many investigative interviews with child complainants of sexual abuse; however, little has been written about the interpreting process from the perspective of the interviewers. This study elicited interviewers’ perspectives about the challenges of using interpreters, with the aim of understanding how investigative interviews could be improved. The participants consisted of 21 investigative interviewers and prosecutors of child abuse cases (from a range of jurisdictions) who use interpreters on a regular basis. Thematic analysis of semi-structured interviews with the professionals about the interpreting process revealed two main challenges particular to child abuse interviews, namely the interpreters’ lack of preparedness to deal with the traumatic and sensitive nature of children's abuse histories, and an insufficient understanding of ‘best-practice’ child interview process. The recommendations focus on the need for more specialised training for, and screening of, interpreters, and more extensive use of pre-conferencing to familiarise children with the interpreter-mediated interview process.     

Estimation of fetal weight with the use of head, body, and femur measurements--a prospective study

In utero estimates of fetal weight were evaluated prospectively in 109 fetuses with the use of sonographic models developed in a previous study. This report confirms that the best in utero weight estimates result from the use of models based on measurements of head size, abdominal size, and femur length. Since the accuracy of these models (1 SD = 7.5%) is significantly better than those based on measurements of head and body (e.g., biparietal diameter, abdominal circumference), we recommend routine use of such models in obstetric sonography.     

Fcgamma receptor transmembrane domains: role in cell surface expression,gamma chain interaction,and phagocytosis

We constructed chimeric receptors to dissect the role of the transmembrane (TM) domain in cell surface expression of and phagocytosis by the gamma chain-dependent Fcgamma receptors FcgammaRIIIA and FcgammaRI. FcgammaR chimeras containing the TM and cytoplasmic (CY) domains of the gamma chain were expressed on the cell surface and mediated an efficient phagocytic signal. In contrast, chimeras containing the FcgammaRIIIA TM were poorly expressed. Receptors containing the FcgammaRI TM and the gamma chain CY but lacking the gamma chain TM also were expressed efficiently and mediated phagocytosis, suggesting that a gamma chain dimer induced by the gamma chain TM is not required for efficient phagocytosis. Cotransfection of FcgammaRI or FcgammaRIIIA with the chimera CD8-gamma-gamma (EC-TM-CY) resulted in FcgammaR cell surface expression and phagocytosis, whereas CD8-CD8-gamma, whose TM does not associate with FcgammaR, allowed cell surface expression of (but not phagocytosis by) FcgammaRI. CD8-CD8-gamma also did not allow surface expression of FcgammaRIIIA. Exchanging FcgammaRI and CD8 TMs indicated that the C-terminal 11 amino acids of the FcgammaRI TM are essential for association of FcgammaRI with the gamma chain and phagocytosis. The data indicate that specific sequences in the FcgammaRIIIA and FcgammaRI TMs govern their different interactions with the gamma chain in cell surface expression and phagocytosis and that gamma chain TM sequences are not required for gamma chain-mediated phagocytosis. The data identify a specific region of the FcgammaRI TM and its asparagine as important for FcgammaRI cell surface expression in the absence of the gamma chain and for distinguishing the FcgammaRI and FcgammaRIIIA phenotypes.     

An effect of haloperidol on the increased food and water intake induced in rabbits by 2-deoxy-D-glucose.

Rabbits treated with 2-deoxy-D-glucose (2DG) (300 mg/kg) show an increased intake of food and water. Pretreatment with haloperidol (1 mg/kg) abolishes the increase in water intake but does not prevent the increase in food intake.