BRCA1 protein dose-dependent risk for embryonic oxidative DNA damage, embryopathies and neurodevelopmental disorders with and without ethanol exposure.

Although widely known as a tumor suppressor, the breast cancer 1 susceptibility protein (BRCA1) is also important in development, where it regulates fetal DNA repair pathways that protect against DNA damage caused by physiological and drug-enhanced levels of reactive oxygen species (ROS). We previously showed that conditional heterozygous (+/-) knockout (cKO) mouse embryos with a minor 28% BRCA1 deficiency developed normally in culture, but when exposed to the ROS-initiating drug, alcohol (ethanol, EtOH), exhibited embryopathies not evident in wild-type (+/+) littermates. Herein, we characterized a directBrca1 +/- knockout (KO) model with a 2-fold greater (58%) reduction in BRCA1 protein vs. the cKO model. We also characterized and compared learning & memory deficits in both the cKO and KO models. Even saline-exposed Brca1 +/- vs. +/+ KO progeny exhibited enhanced oxidative DNA damage and embryopathies in embryo culture and learning & memory deficits in females in vivo, which were not observed in the cKO model, revealing the potential pathogenicity of physiological ROS levels. The embryopathic EtOH concentration for cultured direct KO embryos was half that for cKO embryos, and EtOH affected Brca1 +/+ embryos only in the direct KO model. The spectrum and severity of EtOH embryopathies in culture were greater in both Brca1 +/- vs. +/+ embryos, and direct KO vs. cKO +/- embryos. Motor coordination deficits were evident in both male and female Brca1 +/- KO progeny exposed in utero to EtOH. The results in our direct KO model with a greater BRCA1 deficiency vs. cKO mice provide the first evidence for BRCA1 protein dose-dependent susceptibility to developmental disorders caused by physiological and drug-enhanced oxidative stress.

Cortical circuits modulate mouse social vocalizations.

Vocalizations provide a means of communication with high fidelity and information rate for many species. Diencephalon and brainstem neural circuits have been shown to control mouse vocal production; however, the role of cortical circuits in this process is debatable. Using electrical and optogenetic stimulation, we identified a cortical region in the anterior cingulate cortex in which stimulation elicits ultrasonic vocalizations. Moreover, fiber photometry showed an increase in Ca2+ dynamics preceding vocal initiation, whereas optogenetic suppression in this cortical area caused mice to emit fewer vocalizations. Last, electrophysiological recordings indicated a differential increase in neural activity in response to female social exposure dependent on vocal output. Together, these results indicate that the cortex is a key node in the neuronal circuits controlling vocal behavior in mice.

Breast cancer 1 (BRCA1) protection in altered gene expression and neurodevelopmental disorders due to physiological and ethanol-enhanced reactive oxygen species formation.

The breast cancer 1 (Brca1) susceptibility gene regulates the repair of reactive oxygen species (ROS)-mediated DNA damage, which is implicated in neurodevelopmental disorders. Alcohol (ethanol, EtOH) exposure during pregnancy causes fetal alcohol spectrum disorders (FASD), including abnormal brain function, associated with enhanced ROS-initiated DNA damage. Herein, oxidative DNA damage in fetal brains and neurodevelopmental disorders were enhanced in saline-exposed +/- vs. +/+ Brca1 littermates. A single EtOH exposure during gestation further enhanced oxidative DNA damage, altered the expression of developmental/DNA damage response genes in fetal brains, and resulted in neurodevelopmental disorders, all of which were BRCA1-dependent. Pretreatment with the ROS inhibitor phenylbutylnitrone (PBN) blocked DNA damage and some neurodevelopmental disorders in both saline- and EtOH-exposed progeny, corroborating a ROS-dependent mechanism. Fetal BRCA1 protects against altered gene expression and neurodevelopmental disorders caused by both physiological and EtOH-enhanced levels of ROS formation. BRCA1 deficiencies may enhance the risk for FASD.

Prevalence of metabolic syndrome in the United States National Health and Nutrition Examination Survey 2011-18.

PURPOSE: To estimate the prevalence of metabolic syndrome (MetS) in the US National Health and Nutrition Examination Survey (NHANES) 2011-18. METHODS: This study included 8183 eligible nonpregnant participants aged ≥20 years from the NHANES 2011-18. MetS was defined as the presence of at least three of the following components: central obesity, reduced high-density lipoprotein cholesterol, elevated triglycerides, elevated blood pressure, and elevated fasting blood glucose. The prevalence of MetS was estimated taking into account the complex sampling. The time trend was evaluated using logistic regression. RESULTS: The total prevalence of MetS increased from 37.6% [95% confidence interval (CI): 34.0%-41.4%] in 2011-12 to 41.8% (95% CI: 38.1%-45.7%) in 2017-18 (P for trend = .028). Among the MetS components, the prevalence of elevated glucose increased from 48.9% (95% CI: 45.7%-52.5%) in 2011-12 to 64.7% (95% CI: 61.4%-67.9%) in 2017-18 (P for trend <.001). The prevalence of MetS in participants with low educational attainment increased from 44.4% (95% CI: 38.8%-50.1%) in 2011-12 to 55.0% (95% CI: 50.8%-59.1%) in 2017-18 (P for trend = .01). CONCLUSION: The prevalence of MetS increased during 2011-18, notably in participants with low educational attainment. Lifestyle modification is needed to prevent MetS and the associated risks of diabetes and cardiovascular disease. Key messages What is already known on this topic: Prevalence of metabolic syndrome is an index of the cardiometabolic health of a population. What this study adds: The prevalence of metabolic syndrome in US adults increased during 2011-18, notably in participants with low educational attainment. How this study might affect research, practice, or policy: Lifestyle modification is needed to prevent metabolic syndrome and the associated risks of diabetes and cardiovascular disease.

A 2020 Vision of Hypertension.

Hypertension is a common chronic disease affecting a large section of the general population. Hypertension is highly prevalent in the elderly because blood pressure (BP) rises with age. The risk of developing hypertension increases with predisposing genes, intrauterine growth retardation, prematurity and childhood obesity. BP is easier to control in the young. Non-pharmacological treatment through lifestyle changes, such as weight control and leisure-time physical activity, is more likely to be successful in young people. Hypertension in older adults is more difficult to control, requiring the use of more than one antihypertensive drug. Adverse effects and compliance become problematic. Much research is now directed at novel ways of controlling BP such as denervation. The change in definition of hypertension in the American guideline highlights the need to identify and manage hypertension early, at a stage when it is potentially reversible.