Aging is associated with sex-specific alteration in the expression of genes encoding for neuroestradiol synthesis and signaling proteins in the mouse trigeminal somatosensory input.

Pain perception is influenced by sex and aging, with previous studies indicating the involvement of aromatase, the estradiol synthase enzyme, in regulating pain perception. Previous research has established the presence of aromatase in dorsal root ganglia sensory neurons and its role in modulating pain perception. The present study aims to explore the implications of aging and sex on the expression of aromatase and estrogen receptors in the trigeminal ganglion. The study examined mRNA levels of aromatase, ERs, and the androgen receptor (AR) in the trigeminal ganglion of 3-month-old and 27-month-old male and female mice, as well as 3-month-old mice from the four-core genotype (FCG) transgenic model. The latter facilitates the assessment of gonadal hormone and sex chromosome implications for sex-specific traits. Aromatase localization in the ganglion was further assessed through immunohistochemistry. Aromatase immunoreactivity was observed for the first time in sensory neurons within the trigeminal ganglion. Trigeminal ganglion gene expressions were detected for aromatase, ERs, and AR in both sexes. Aromatase, ERß, and GPER gene expressions were higher in young males versus young females. Analyses of the FCG model indicated that sex differences depended solely on gonadal sex. The aging process induced an enhancement in the expression of aromatase, ERs, and AR genes across both sexes, culminating in a reversal of the previously observed gender-based differences. the potential impact of estrogen synthesis and signaling in the trigeminal ganglion on age and sex differences warrants consideration, particularly in relation to trigeminal sensory functions and pain perception.

Gonadal hormone deprivation regulates response to tibolone in neurodegenerative pathways.

Gonadal hormone deprivation (GHD) and decline such as menopause and bilateral oophorectomy are associated with an increased risk of neurodegeneration. Yet, hormone therapies (HTs) show varying efficacy, influenced by factors such as sex, drug type, and timing of treatment relative to hormone decline. We hypothesize that the molecular environment of the brain undergoes a transition following GHD, impacting the effectiveness of HTs. Using a GHD model in mice treated with Tibolone, we conducted proteomic analysis and identified a reprogrammed response to Tibolone, a compound that stimulates estrogenic, progestogenic, and androgenic pathways. Through a comprehensive network pharmacological workflow, we identified a reprogrammed response to Tibolone, particularly within "Pathways of Neurodegeneration", as well as interconnected pathways including "cellular respiration", "carbon metabolism", and "cellular homeostasis". Analysis revealed 23 proteins whose Tibolone response depended on GHD and/or sex, implicating critical processes like oxidative phosphorylation and calcium signalling. Our findings suggest the therapeutic efficacy of HTs may depend on these variables, suggesting a need for greater precision medicine considerations whilst highlighting the need to uncover underlying mechanisms.

Sex chromosome complement interacts with gonadal hormones in determining regional-specific neuroactive steroid levels in plasma, hippocampus, and hypothalamus. A study using the four core genotype mouse model.

An important aspect of the neuromodulatory and neuroprotective actions exerted by neuroactive steroids is that they are sex-specific, as determined by the sexually dimorphic levels of these molecules in plasma and the nervous tissue. Thus, the identification of the factors that generate the sex-dimorphic levels of neuroactive steroids may be crucial from a neuroprotectant perspective. The main driver for sex determination in mammals is the SRY gene and the subsequent presence of a specific gonad: testes for males and ovaries for females, thus producing hormonal compounds, primarily androgens and estrogens, respectively. Nowadays, it is well established that despite the relevance of gonads, other factors control sexual features, and, among them, sex chromosome complement is highly relevant. In this study, neuroactive steroids were evaluated by liquid chromatography-tandem mass spectrometry in the hypothalamus, the hippocampus, and plasma of the four core genotype mouse model, to determine the relative contribution of sex chromosome complement and gonads in determining their sex dimorphic levels. The data obtained reveal that although gonads are the main contributing factor for sex differences in neuroactive steroid levels, the levels of some neuroactive steroids, including testosterone, are also influenced in brain and plasma by tissue-specific actions of sex chromosomes. The data presented here adds a new piece to the puzzle of steroid level regulation, which may be useful in designing sex-specific neuroprotective approaches to pathological conditions affecting the nervous system.

Effects of maternal calcium propionate supplementation on offspring productivity and meat metabolomic profile in sheep.

This study determined the effect of dietary calcium propionate (CaPr) as a source of energy supplementation during the First Half of Gestation (FMG), the Second Half of Gestation (SMG), and during All Gestation (AG), on offspring post-weaning growth performance, meat quality, and meat metabolomic profile. Thirty-one pregnant ewes were assigned to one of four treatments: a) supplementation of 30 gd-1 of CaPr during the first half of gestation (day 1 to day 75, n = 8) (FMG); b) supplementation of 30 gd-1 of CaPr during the second half of gestation (day 76 to day 150, n = 8) (SMG); c) supplementation of 30 gd-1 of CaPr during all gestation (AG, n = 8); d) no CaPr supplementation (control; CS, n = 7). The ewes were ad libitum fed a basal diet based on oat hay and corn silage. Ewes were distributed in a completely randomized unbalanced design to four treatments. The FMG group had lower (P ≤ 0.05) birth weight and weaning weight than the CS group. However, the average daily gain was similar across all treatments. Empty body weight and FMG had lower values (P ≤ 0.05) than the other groups. Both FMG and AG had lower hot carcass weight (P ≤ 0.05) compared to CS, while CaPr treatments resulted in reduced hot carcass yield (P ≤ 0.05). Meat color and texture were similar among treatments. A principal component analysis between gestation stages showed a trend for separating CS and FMG from SMG and AG, and that was explained by 93.7% of the data variability (PC1 = 87.9% and PC2 = 5.8%). Regarding meat metabolomic profile, 23 compounds were positively correlated between all treatments. Only 2 were negatively correlated (eicosane and naphthalene 1,2,3); but tetradecanoic acid, hexadecane, undecane 5-methyl, (-)-alpha, hexadecenoic acid, octadecanoic acid, and octadecane had a highly significant correlation (P ≤ 0.05). Overall, dam supplementation with CaPr during different periods of gestation provoked changes in meat metabolites related to the biosynthesis of fatty acids in lambs without negative changes in lamb's growth performance and carcass quality.

Drug overdose deaths in Brazil between 2000 and 2020: an analysis of sociodemographics and intentionality

Objectives: To examine drug overdose records in Brazil from 2000 to 2020, analyzing trends over time in overdoses and overall sociodemographic characteristics of the deceased. Methods: Using data from the Brazilian Mortality Information System (Sistema de Informações sobre Mortalidade), we identified records from 2000-2020 in which the underlying cause-of-death was one of the following codes: X40-X45 (accidental poisoning), X60-X65 (intentional poisoning), or Y10-Y15 (undetermined intentionality poisoning). The Brazilian dataset included 21,410 deaths. We used joinpoint regression analysis to assess changes in trends over time. Results: People who died of drug overdoses in Brazil between 2000 and 2020 had a mean age of 38.91 years; 38.45% were women, and 44.01% were identified as White. Of the overdose deaths, 44.70% were classified as intentional and 32.12% were classified as unintentional. Among the identified drugs, stimulants were the most common class. However, most records did not report which drug was responsible for death. Conclusion: Sociodemographic trends in overdose deaths in Brazil must guide country-specific policies. Nevertheless, data collection protocols must be improved, particularly regarding the drug used in overdoses.

Neuroestradiol and neuronal development: Not an exclusive male tale anymore.

The brain synthesizes a variety of neurosteroids, including neuroestradiol. Inhibition of neuroestradiol synthesis results in alterations in basic neurodevelopmental processes, such as neurogenesis, neuroblast migration, neuritogenesis and synaptogenesis. Although the neurodevelopmental actions of neuroestradiol are exerted in both sexes, some of them are sex-specific, such as the well characterized effects of neuroestradiol derived from the metabolism of testicular testosterone during critical periods of male brain development. In addition, recent findings have shown sex-specific actions of neuroestradiol on neuroblast migration, neuritic growth and synaptogenesis in females. Among other factors, the epigenetic regulation exerted by X linked genes, such as Kdm6a/Utx, may determine sex-specific actions of neuroestradiol in the female brain. This review evidences the impact of neuroestradiol on brain formation in both sexes and highlights the interaction of neural steriodogenesis, hormones and sex chromosomes in sex-specific brain development.

Drug overdose deaths in Brazil between 2000 and 2020: an analysis of sociodemographics and intentionality.

OBJECTIVES: To examine drug overdose records in Brazil from 2000 to 2020, analyzing trends over time in overdoses and overall sociodemographic characteristics of the deceased. METHODS: Using data from the Brazilian Mortality Information System (Sistema de Informações sobre Mortalidade), we identified records from 2000-2020 in which the underlying cause-of-death was one of the following codes: X40-X45 (accidental poisoning), X60-X65 (intentional poisoning), or Y10-Y15 (undetermined intentionality poisoning). The Brazilian dataset included 21,410 deaths. We used joinpoint regression analysis to assess changes in trends over time. RESULTS: People who died of drug overdoses in Brazil between 2000 and 2020 had a mean age of 38.91 years; 38.45% were women, and 44.01% were identified as White. Of the overdose deaths, 44.70% were classified as intentional and 32.12% were classified as unintentional. Among the identified drugs, stimulants were the most common class. However, most records did not report which drug was responsible for death. CONCLUSION: Sociodemographic trends in overdose deaths in Brazil must guide country-specific policies. Nevertheless, data collection protocols must be improved, particularly regarding the drug used in overdoses.

Interaction of gonadal hormones, dopaminergic system, and epigenetic regulation in the generation of sex differences in substance use disorders: A systematic review.

Substance use disorder (SUD) is a chronic condition characterized by pathological drug-taking and seeking behaviors. Remarkably different between males and females, suggesting that drug addiction is a sexually differentiated disorder. The neurobiological bases of sex differences in SUD include sex-specific reward system activation, influenced by interactions between gonadal hormone level changes, dopaminergic reward circuits, and epigenetic modifications of key reward system genes. This systematic review, adhering to PICOS and PRISMA-P 2015 guidelines, highlights the sex-dependent roles of estrogens, progesterone, and testosterone in SUD. In particular, estradiol elevates and progesterone reduces dopaminergic activity in SUD females, whilst testosterone and progesterone augment SUD behavior in males. Finally, SUD is associated with a sex-specific increase in the rate of opioid and monoaminergic gene methylation. The study reveals the need for detailed research on gonadal hormone levels, dopaminergic or reward system activity, and epigenetic landscapes in both sexes for efficient SUD therapy development.

Recreational cannabis legislation and binge drinking in U.S. adolescents and adults.

BACKGROUND: Recreational cannabis laws (RCLs) may have spillover effects on binge drinking. Our aims were to investigate binge drinking time trends and the association between RCLs and changes in binge drinking in the United States (U.S.). METHODS: We used restricted National Survey on Drug Use and Health data (2008-2019). We examined trends in the prevalence of past-month binge drinking by age groups (12-20, 21-30, 31-40, 41-50, 51+). Then, we compared model-based prevalences of past-month binge drinking before and after RCL by age group, using multi-level logistic regression with state random intercepts, an RCL by age group interaction term, and controlling for state alcohol policies. RESULTS: Binge drinking declined overall from 2008 to 2019 among people aged 12-20 (17.54% to 11.08%), and those aged 21-30 (43.66% to 40.22%). However, binge drinking increased among people aged 31+ (ages 31-40: 28.11% to 33.34%, ages 41-50: 25.48% to 28.32%, ages 51+: 13.28% to 16.75%). When investigating model-based prevalences after versus before RCL, binge drinking decreased among people aged 12-20 (prevalence difference=-4.8%; adjusted odds ratio (aOR)=0.77, [95% confidence interval (CI) 0.70-0.85]), and increased among participants aged 31-40 (+1.7%; 1.09[1.01-1.26]), 41-50 (+2.5; 1.15[1.05-1.26]) and 51+ (+1.8%; 1.17[1.06-1.30]). No RCL-related changes were noted in respondents ages 21-30. CONCLUSIONS: Implementation of RCLs was associated with increased past-month binge drinking in adults aged 31+ and decreased past-month binge drinking in those aged < 21. As the cannabis legislative landscape continues to change in the U.S., efforts to minimize harms related to binge drinking are critical.

Efficient implementation of time-dependent auxiliary density functional theory.

The random phase approximation of time-dependent auxiliary density functional theory (TDADFT) is rederived from auxiliary density perturbation theory. Our exhaustive validation of TDADFT reveals an upshift of the excitation energies by ∼0.1 eV with respect to standard time-dependent density functional theory. For the computationally efficient implementation of TDADFT, floating point operation optimized three-center electron repulsion integral recurrence relations and their double asymptotic expansions are implemented into the Davidson solver. The computational efficiency of TDADFT is benchmarked with four sets of molecules comprising alkanes, fullerenes, DNA fragments, and zeolites. The results show that TDADFT has a computational scaling between 1.3 and 1.9 with respect to the number of basis functions, which is lower than the scaling of standard time-dependent density functional theory. Due to its computational simplifications, TDADFT is particularly well suited for Born-Oppenheimer molecular dynamics simulations. As illustrative examples, we present the temperature effects on the gas-phase absorption spectra of benzene, naphthalene, and anthracene.

Cannabis Recreational Legalization and Prevalence of Simultaneous Cannabis and Alcohol Use in the United States.

BACKGROUND: Simultaneous cannabis/alcohol use, using both substances within a short time interval so that their effects overlap, has a greater risk of potential negative consequences than single-substance use and is more common in younger age. Relationships between recreational cannabis laws (RCLs) and changes in simultaneous cannabis/alcohol use prevalence remain untested. OBJECTIVE: To examine trends in simultaneous cannabis/alcohol use from 2008 to 2019, and investigate associations between implementation of RCLs (i.e., presence of active legal dispensaries or legal home cultivation) and simultaneous cannabis/alcohol use in the United States (U.S.). DESIGN: Repeated cross-sectional samples from the 2008-2019 U.S. National Survey on Drug Use and Health (NSDUH). PARTICIPANTS: Respondents (51% female) aged 12 and older. INTERVENTIONS: Changes in simultaneous cannabis/alcohol use before and after RCL implementation (controlling for medical cannabis law implementation) were compared in different age groups (12-20, 21-30, 31-40, 41-50, 51+), using adjusted multi-level logistic regression with state random intercepts and an RCL/age group interaction. MEASUREMENTS: Self-reported simultaneous cannabis/alcohol use. RESULTS: From 2008 to 2019, the overall prevalence of simultaneous cannabis/alcohol use declined among those aged 12-20 but increased in adults aged 21+. Model-based simultaneous cannabis/alcohol use prevalence increased after RCL implementation among respondents aged 21-30 years (+1.2%; aOR= 1.15 [95%CI = 1.04-1.27]), 31-40 years (+1.0; 1.15 [1.04-1.27]), and 41-50 years (+1.75; 1.63 [1.34-1.98]), but not in individuals aged <21 or 51+ years. CONCLUSIONS: Implementation of recreational cannabis policies resulted in increased simultaneous use of cannabis and alcohol, supporting the complementarity hypothesis, but only among adults aged 21+. Efforts to minimize harms related to simultaneous cannabis/alcohol use are critical, especially in states with RCLs. Future studies should investigate cultural norms, perceived harm, and motives related to simultaneous use.

Respirasome Proteins Are Regulated by Sex-Hormone Interactions in the Brain.

The existence of sex differences in disease incidence is attributed, in part, to sex differences in metabolism. Uncovering the precise mechanism driving these differences is an extraordinarily complex process influenced by genetics, endogenous hormones, sex-specific lifetime events, individual differences and external environmental/social factors. In fact, such differences may be subtle, but across a life span, increase susceptibility to a pathology. Whilst research persists in the hope of discovering an elegant biological mechanism to underpin sex differences in disease, here, we show, for the first time, that such a mechanism may be subtle in nature but influenced by multiple sex-specific factors. A proteomic dataset was generated from a gonadectomized mouse model treated with Tibolone, a menopausal hormone therapy. Following functional enrichment analysis, we identified that Alzheimer's disease and the electron transport chain-associated pathways were regulated by sex-hormone interactions. Specifically, we identified that the expression of three respirasome proteins, NDUFA2, NDUFA7 and UQCR10, is significantly altered by compounding factors that contribute to sex differences. These proteins function in bioenergetics and produce reactive oxygen species, which are each dysregulated in many diseases with sex differences in incidence. We show sex-specific reprogrammed responses to Tibolone following gonadectomy, which primarily influence the expression of proteins contributing to metabolic pathways. This further infers that metabolic differences may underpin the observed sex differences in disease, but also that hormone therapy research now has potential in exploring sex-specific interventions to produce an effective method of prevention or treatment.

Genetics and Epigenetics of the X and Y Chromosomes in the Sexual Differentiation of the Brain.

For many decades to date, neuroendocrinologists have delved into the key contribution of gonadal hormones to the generation of sex differences in the developing brain and the expression of sex-specific physiological and behavioral phenotypes in adulthood. However, it was not until recent years that the role of sex chromosomes in the matter started to be seriously explored and unveiled beyond gonadal determination. Now we know that the divergent evolutionary process suffered by X and Y chromosomes has determined that they now encode mostly dissimilar genetic information and are subject to different epigenetic regulations, characteristics that together contribute to generate sex differences between XX and XY cells/individuals from the zygote throughout life. Here we will review and discuss relevant data showing how particular X- and Y-linked genes and epigenetic mechanisms controlling their expression and inheritance are involved, along with or independently of gonadal hormones, in the generation of sex differences in the brain.

Sex Differences in Hypothalamic Changes and the Metabolic Response of TgAPP Mice to a High Fat Diet.

The propensity to develop neurodegenerative diseases is influenced by diverse factors including genetic background, sex, lifestyle, including dietary habits and being overweight, and age. Indeed, with aging, there is an increased incidence of obesity and neurodegenerative processes, both of which are associated with inflammatory responses, in a sex-specific manner. High fat diet (HFD) commonly leads to obesity and markedly affects metabolism, both peripherally and centrally. Here we analyzed the metabolic and inflammatory responses of middle-aged (11-12 months old) transgenic amyloid precursor protein (TgAPP) mice of both sexes to HFD for 18 weeks (starting at 7-8 months of age). We found clear sex differences with females gaining significantly more weight and fat mass than males, with a larger increase in circulating leptin levels and expression of inflammatory markers in visceral adipose tissue. Glycemia and insulin levels increased in HFD fed mice of both sexes, with TgAPP mice being more affected than wild type (WT) mice. In the hypothalamus, murine amyloid ß (Aß) levels were increased by HFD intake exclusively in males, reaching statistical significance in TgAPP males. On a low fat diet (LFD), TgAPP males had significantly lower mRNA levels of the anorexigenic neuropeptide proopiomelanocortin (POMC) than WT males, with HFD intake decreasing the expression of the orexigenic neuropeptides Agouti-related peptide (AgRP) and neuropeptide Y (NPY), especially in TgAPP mice. In females, HFD increased POMC mRNA levels but had no effect on AgRP or NPY mRNA levels, and with no effect on genotype. There was no effect of diet or genotype on the hypothalamic inflammatory markers analyzed or the astrogliosis marker glial acidic protein (GFAP); however, levels of the microglial marker Iba-1 increased selectively in male TgAPP mice. In summary, the response to HFD intake was significantly affected by sex, with fewer effects due to genotype. Hypothalamic inflammatory cytokine expression and astrogliosis were little affected by HFD in middle-aged mice, although in TgAPP males, which showed increased Aß, there was microglial activation. Thus, excess intake of diets high in fat should be avoided because of its possible detrimental consequences.

Simultaneous Alcohol/Cannabis Use and Driving Under the Influence in the U.S.

INTRODUCTION: Alcohol and cannabis are commonly involved in motor vehicle crashes and fatalities. This study examines whether simultaneous use of alcohol/cannabis is associated with higher odds of reporting driving under the influence of alcohol and cannabis in the U.S. METHODS: Drivers aged ≥16 years with any past-year alcohol and cannabis use in the 2016-2019 National Survey on Drug Use and Health (N=34,514) reported any past-year driving under the influence of alcohol-only, cannabis-only, both alcohol/cannabis, or not driving under the influence. Survey-weighted associations between simultaneous alcohol/cannabis use and each of the driving under the influence outcomes were computed adjusting for sociodemographics and daily alcohol/cannabis use. Analyses were conducted from November 2020 to September 2021. RESULTS: In 2016-2019, 42% of drivers with past-year alcohol and cannabis use reported driving under the influence (8% alcohol-only, 20% cannabis-only, 14% alcohol/cannabis). Simultaneous alcohol/cannabis use was associated with 2.88-times higher adjusted odds of driving under the influence of cannabis-only (95% CI=2.59, 3.19) and 3.51-times higher adjusted odds of driving under the influence of both alcohol/cannabis (95% CI=3.05, 4.05), compared to not driving under the influence. Associations with driving under the influence of alcohol-only were unexpectedly in the opposite direction (adjusted conditional odds ratio=0.59, 95% CI=0.45, 0.79). CONCLUSIONS: Overall, 2 in 5 drivers who used alcohol and cannabis reported driving under the influence of alcohol and/or cannabis. People reporting simultaneous alcohol/cannabis use were more likely to report cannabis-related driving under the influence. Prevention strategies should target individuals reporting simultaneous alcohol/cannabis use to reduce the occurrence of driving under the influence.