Hair products used by Black women and children contained multiple chemicals associated with endocrine disruption and asthma. The prevalence of parabens and DEP is consistent with higher levels of these compounds in biomonitoring samples from Black women compared with White women. These results indicate the need for more information about the contribution of consumer products to exposure disparities. A precautionary approach would reduce the use of endocrine disrupting chemicals in personal care products and improve labeling so women can select products consistent with their values.

Knowledge about established breast carcinogens can support improved and modernized toxicological testing methods by identifying key mechanistic events. Ionizing radiation (IR) increases the risk of breast cancer, especially for women and for exposure at younger ages, and evidence overall supports a linear dose-response relationship. We used the Adverse Outcome Pathway (AOP) framework to outline and evaluate the evidence linking ionizing radiation with breast cancer from molecular initiating events to the adverse outcome through intermediate key events, creating a qualitative AOP. We identified key events based on review articles, searched PubMed for recent literature on key events and IR, and identified additional papers using references. We manually curated publications and evaluated data quality. Ionizing radiation directly and indirectly causes DNA damage and increases production of reactive oxygen and nitrogen species (RONS). RONS lead to DNA damage and epigenetic changes leading to mutations and genomic instability (GI). Proliferation amplifies the effects of DNA damage and mutations leading to the AO of breast cancer. Separately, RONS and DNA damage also increase inflammation. Inflammation contributes to direct and indirect effects (effects in cells not directly reached by IR) via positive feedback to RONS and DNA damage, and separately increases proliferation and breast cancer through pro-carcinogenic effects on cells and tissue. For example, gene expression changes alter inflammatory mediators, resulting in improved survival and growth of cancer cells and a more hospitable tissue environment. All of these events overlap at multiple points with events characteristic of "background" induction of breast carcinogenesis, including hormone-responsive proliferation, oxidative activity, and DNA damage. These overlaps make the breast particularly susceptible to ionizing radiation and reinforce that these biological activities are important characteristics of carcinogens. Agents that increase these biological processes should be considered potential breast carcinogens, and predictive methods are needed to identify chemicals that increase these processes. Techniques are available to measure RONS, DNA damage and mutation, cell proliferation, and some inflammatory proteins or processes. Improved assays are needed to measure GI and chronic inflammation, as well as the interaction with hormonally driven development and proliferation. Several methods measure diverse epigenetic changes, but it is not clear which changes are relevant to breast cancer. In addition, most toxicological assays are not conducted in mammary tissue, and so it is a priority to evaluate if results from other tissues are generalizable to breast, or to conduct assays in breast tissue. Developing and applying these assays to identify exposures of concern will facilitate efforts to reduce subsequent breast cancer risk.Biological systems studied This review article summarizes and synthesizes data from cell-culture, experimental animals, and human epidem...

Activation of protein kinase C (PKC) potentiates secretion in Aplysia peptidergic neurons, in part by inducing new sites for peptide release at growth cone terminals. The mechanisms by which ion channels are trafficked to such sites are, however, not well understood. We now show that PKC activation rapidly recruits new Ca V 2 subunits to the plasma membrane, and that recruitment is blocked by latrunculin B, an inhibitor of actin polymerization. In contrast, inhibition of microtubule polymerization selectively prevents the appearance of Ca V 2 subunits only at the distal edge of the growth cone. In resting neurons, Ca V 2-containing organelles reside in the central region of growth cones, but are absent from distal lamellipodia. After activation of PKC, these organelles are transported on microtubules to the lamellipodium. The ability to traffic to the most distal sites of channel insertion inside the lamellipodium does, therefore, not require intact actin but requires intact microtubules. Only after activation of PKC do Ca V 2 channels associate with actin and undergo insertion into the plasma membrane.

The input, processing, and output characteristics of inhibitory interneurons help shape information flow through layers 2/3 of the visual cortex. Parvalbumin (PV)-positive interneurons modulate and synchronize the gain and dynamic responsiveness of pyramidal neurons. To define the diversity of PV interneurons in layers 2/3 of the developing visual cortex, we characterized their passive and active membrane properties. Using Ward's and k-means multidimensional clustering, we identified four PV interneuron subgroups. The most notable difference between the subgroups was their firing patterns in response to moderate stimuli just above rheobase. Two subgroups showed regular and continuous firing at all stimulus intensities above rheobase. The difference between these two continuously firing subgroups was that one fired at much higher frequencies and transitioned into this high-frequency firing rate at or near rheobase. The two other subgroups showed irregular, stuttering firing patterns just above rheobase. Both of these subgroups typically transitioned to regular and continuous firing at intense stimulations, but one of these subgroups, the strongly stuttering subgroup, showed irregular firing across a wider range of stimulus intensities and firing frequencies. The four subgroups also differed in excitatory synaptic input, providing independent support for the classification of subgroups. The subgroups of PV interneurons identified here would respond differently to inputs of varying intensity and frequency, generating diverse patterns of PV inhibition in the developing neural circuit.

Reactive oxygen species (ROS) and reactive nitrogen species (RNS) are formed as a result of natural cellular processes, intracellular signaling, or as adverse responses associated with diseases or exposure to oxidizing chemical and non-chemical stressors. The action of ROS and RNS, collectively referred to as reactive oxygen and nitrogen species (RONS), has recently become highly relevant in a number of adverse outcome pathways (AOPs) that capture, organize, evaluate and portray causal relationships pertinent to adversity or disease progression. RONS can potentially act as a key event (KE) in the cascade of responses leading to an adverse outcome (AO) within such AOPs, but are also known to modulate responses of events along the AOP continuum without being an AOP event itself. A substantial discussion has therefore been undertaken in a series of workshops named “Mystery or ROS” to elucidate the role of RONS in disease and adverse effects associated with exposure to stressors such as nanoparticles, chemical, and ionizing and non-ionizing radiation. This review introduces the background for RONS production, reflects on the direct and indirect effects of RONS, addresses the diversity of terminology used in different fields of research, and provides guidance for developing a harmonized approach for defining a common event terminology within the AOP developer community.