Sex-dependent Changes Research Articles

Improving community readiness among Iranian local communities to prevent childhood obesity

BackgroundCommunity Readiness Intervention for Tackling Childhood Obesity (CRITCO) is a theory-based intervention being developed to improve the readiness of an Iranian urban population to engage in childhood obesity prevention programs. This study aimed to explore changes in readiness of intervention and control local communities from diverse socio-economic areas of Tehran.MethodsThis study was a seven-month quasi-experimental intervention implemented in four intervention communities and compared with four controls. Aligned strategies and action plans were developed around the six dimensions of community readiness. The Food and Nutrition Committee was established in each intervention community to make collaborative efforts among different sectors and assess the fidelity of the intervention. The pre-and post- readiness change was explored through interviews with 46 community key informants.ResultsThe total readiness of intervention sites increased by 0.48 units (p < 0.001) and shifted to the next higher level, from preplanning to the preparation stage. At the same time, the readiness of control communities decreased by 0.39 units (p < 0.001), although their readiness stage remained unchanged, reflecting the fourth stage. Also, a sex-dependent CR change was observed, such that the girls’ schools showed a more remarkable improvement in interventions and less decline in controls. The readiness stages of interventions significantly improved for four dimensions related to community efforts, knowledge of the efforts, knowledge of childhood obesity issue, and leadership. Furthermore, the readiness of control communities significantly decreased on three of six dimensions related to community effort, knowledge of efforts, and resources.ConclusionsThe CRITCO successfully improved the readiness of intervention sites for addressing childhood obesity. It is hoped that the present study can be a spark for developing readiness-based childhood obesity prevention programs in Middle Eastern and other developing countries.Trial registrationThe CRITCO intervention was registered at Iran Registry for Clinical Trials (http://irct.ir; IRCT20191006044997N1) on 11/11/2019.

Modeling sex differences in human atrial myocyte structural and Ca2+ handling properties: Impact on Ca2+-driven arrhythmia.

Substantial sex differences have been reported in the prevalence, pathophysiology, treatment, and prognosis of atrial fibrillation (AF), the most common cardiac arrhythmia. Knowledge of sex differences in the underlying arrhythmogenic substrate may improve therapy. Recent experimental studies revealed differences in cell geometry, transverse-axial tubule system (TATS) density, and expression, function, and phosphorylation status of Ca2+ handling proteins in female vs. male atrial myocytes, and in their remodeling in AF. However, it remains unknown how these sex-dependent differences contribute (individually or collectively) to arrhythmia propensity in females vs. males. Here, we used our new human atrial myocyte model coupling electrophysiology and spatially-detailed Ca2+ cycling governed by the TATS to integrate these sex-specific features and build sex-specific models of both normal sinus rhythm (nSR) and AF conditions. We tested the responses of the models to a pace-pause protocol and found that in nSR the female myocyte model displays 1) higher Ca2+ spark frequency, and 2) greater and more frequent spontaneous Ca2+ release (SCR) compared to male. These sex differences in Ca2+-driven arrhythmias are exacerbated in AF conditions. A systematic parametric study revealed the precise contribution of each sex-dependent change (i.e., TATS density, cell dimension, and Ca2+-handling protein expression or function) to SCR and Ca2+ spark properties. Both sparse TATS and changes in Ca2+-handling proteins (i.e., larger L-type Ca2+ current, reduced calsequestrin expression, higher RyR phosphorylation, and increased sarcoplasmic reticulum Ca2+-ATPase) promote greater Ca2+-driven arrhythmia in female myocytes, which was slightly attenuated by the smaller cell dimension vs male myocytes. Our study demonstrates the interactive contributions of subcellular structural and ionic sex differences to intracellular Ca2+ instability and provides novel model-based mechanistic insight that may guide future therapeutic sex-specific anti-AF strategies.

Systems level analysis of sex-dependent gene expression changes in Parkinson’s disease

Parkinson’s disease (PD) is a heterogeneous disorder, and among the factors which influence the symptom profile, biological sex has been reported to play a significant role. While males have a higher age-adjusted disease incidence and are more frequently affected by muscle rigidity, females present more often with disabling tremors. The molecular mechanisms involved in these differences are still largely unknown, and an improved understanding of the relevant factors may open new avenues for pharmacological disease modification. To help address this challenge, we conducted a meta-analysis of disease-associated molecular sex differences in brain transcriptomics data from case/control studies. Both sex-specific (alteration in only one sex) and sex-dimorphic changes (changes in both sexes, but with opposite direction) were identified. Using further systems level pathway and network analyses, coordinated sex-related alterations were studied. These analyses revealed significant disease-associated sex differences in mitochondrial pathways and highlight specific regulatory factors whose activity changes can explain downstream network alterations, propagated through gene regulatory cascades. Single-cell expression data analyses confirmed the main pathway-level changes observed in bulk transcriptomics data. Overall, our analyses revealed significant sex disparities in PD-associated transcriptomic changes, resulting in coordinated modulations of molecular processes. Among the regulatory factors involved, NR4A2 has already been reported to harbor rare mutations in familial PD and its pharmacological activation confers neuroprotective effects in toxin-induced models of Parkinsonism. Our observations suggest that NR4A2 may warrant further research as a potential adjuvant therapeutic target to address a subset of pathological molecular features of PD that display sex-associated profiles.

Effects of Ozone on Sickness and Depressive-like Behavioral and Biochemical Phenotypes and Their Regulation by Serum Amyloid A in Mice.

Ozone (O3) is an air pollutant that primarily damages the lungs, but growing evidence supports the idea that O3 also harms the brain; acute exposure to O3 has been linked to central nervous system (CNS) symptoms such as depressed mood and sickness behaviors. However, the mechanisms by which O3 inhalation causes neurobehavioral changes are limited. One hypothesis is that factors in the circulation bridge communication between the lungs and brain following O3 exposure. In this study, our goals were to characterize neurobehavioral endpoints of O3 exposure as they relate to markers of systemic and pulmonary inflammation, with a particular focus on serum amyloid A (SAA) and kynurenine as candidate mediators of O3 behavioral effects. We evaluated O3-induced dose-, time- and sex-dependent changes in pulmonary inflammation, circulating SAA and kynurenine and its metabolic enzymes, and sickness and depressive-like behaviors in Balb/c and CD-1 mice. We found that 3 parts per million (ppm) O3, but not 2 or 1 ppm O3, increased circulating SAA and lung inflammation, which were resolved by 48 h and was worse in females. We also found that indoleamine 2,3-dioxygenase (Ido1) mRNA expression was increased in the brain and spleen 24 h after 3 ppm O3 and that kynurenine was increased in blood. Sickness and depressive-like behaviors were observed at all O3 doses (1-3 ppm), suggesting that behavioral responses to O3 can occur independently of increased SAA or neutrophils in the lungs. Using SAA knockout mice, we found that SAA did not contribute to O3-induced pulmonary damage or inflammation, systemic increases in kynurenine post-O3, or depressive-like behavior but did contribute to weight loss. Together, these findings indicate that acute O3 exposure induces transient symptoms of sickness and depressive-like behaviors that may occur in the presence or absence of overt pulmonary neutrophilia and systemic increases of SAA. SAA does not appear to contribute to pulmonary inflammation induced by O3, although it may contribute to other aspects of sickness behavior, as reflected by a modest effect on weight loss.

Prenatal social support in low-risk pregnancy shapes placental epigenome

BackgroundPoor social support during pregnancy has been linked to inflammation and adverse pregnancy and childhood health outcomes. Placental epigenetic alterations may underlie these links but are still unknown in humans.MethodsIn a cohort of low-risk pregnant women (n = 301) from diverse ethnic backgrounds, social support was measured using the ENRICHD Social Support Inventory (ESSI) during the first trimester. Placental samples collected at delivery were analyzed for DNA methylation and gene expression using Illumina 450K Beadchip Array and RNA-seq, respectively. We examined association between maternal prenatal social support and DNA methylation in placenta. Associated cytosine-(phosphate)-guanine sites (CpGs) were further assessed for correlation with nearby gene expression in placenta.ResultsThe mean age (SD) of the women was 27.7 (5.3) years. The median (interquartile range) of ESSI scores was 24 (22–25). Prenatal social support was significantly associated with methylation level at seven CpGs (PFDR < 0.05). The methylation levels at two of the seven CpGs correlated with placental expression of VGF and ILVBL (PFDR < 0.05), genes known to be involved in neurodevelopment and energy metabolism. The genes annotated with the top 100 CpGs were enriched for pathways related to fetal growth, coagulation system, energy metabolism, and neurodevelopment. Sex-stratified analysis identified additional significant associations at nine CpGs in male-bearing pregnancies and 35 CpGs in female-bearing pregnancies.ConclusionsThe findings suggest that prenatal social support is linked to placental DNA methylation changes in a low-stress setting, including fetal sex-dependent epigenetic changes. Given the relevance of some of these changes in fetal neurodevelopmental outcomes, the findings signal important methylation targets for future research on molecular mechanisms of effect of the broader social environment on pregnancy and fetal outcomes.Trial registrationNCT00912132 (ClinicalTrials.gov).

Neonatal hyperoxia induces activated pulmonary cellular states and sex-dependent transcriptomic changes in a model of experimental bronchopulmonary dysplasia.

Hyperoxia disrupts lung development in mice and causes bronchopulmonary dysplasia (BPD) in neonates. To investigate sex-dependent molecular and cellular programming involved in hyperoxia, we surveyed the mouse lung using single cell RNA sequencing (scRNA-seq), and validated our findings in human neonatal lung cells in vitro. Hyperoxia-induced inflammation in alveolar type (AT) 2 cells gave rise to damage-associated transient progenitors (DATPs). It also induced a new subpopulation of AT1 cells with reduced expression of growth factors normally secreted by AT1 cells, but increased mitochondrial gene expression. Female alveolar epithelial cells had less EMT and pulmonary fibrosis signaling in hyperoxia. In the endothelium, expansion of Car4+ EC (Cap2) was seen in hyperoxia along with an emergent subpopulation of Cap2 with repressed VEGF signaling. This regenerative response was increased in females exposed to hyperoxia. Mesenchymal cells had inflammatory signatures in hyperoxia, with a new distal interstitial fibroblast subcluster characterized by repressed lipid biosynthesis and a transcriptomic signature resembling myofibroblasts. Hyperoxia-induced gene expression signatures in human neonatal fibroblasts and alveolar epithelial cells in vitro resembled mouse scRNA-seq data. These findings suggest that neonatal exposure to hyperoxia programs distinct sex-specific stem cell progenitor and cellular reparative responses that underpin lung remodeling in BPD.

Sex-dependent changes in emotional memory associated with cerebral blood flow alterations during Alzheimer's disease progression.

Sex differences in Alzheimer's disease (AD) progression provide clues to pathogenesis and better patient management. We examined sex differences in emotional memory among AD patients, amnesticmild cognitive impairment (aMCI) patients, and healthy controls (HCs) as well as potential associations with altered regional cerebral blood flow (rCBF). The recognition memory task with emotional pictures was applied to evaluate enhancement of emotional memory (EEM) and 3D pseudo-continuous arterial spin labeling MRI was performed to measure the rCBF in 74 AD patients (41 females), 74 aMCI patients (45 females), and 74 HCs (43 females). Group differences in EEM were tested by two-way analysis of covariance (ANCOVA) with repeated measures. The main effects of clinical group and sex as well as group × sex interactions on rCBF were assessed by two-way ANCOVA. Correlation analyses were conducted to investigate associations between EEM and rCBF. With disease progression, EEM gradually disappeared. Among aMCI patients, females exhibited a greater index of recollection (Pr) for positive/high-arousal and negative/low-arousal pictures versus neutral pictures (P = 0.005, P = 0.003), while males exhibited a greater Pr for negative/high-arousal versus neutral pictures (P = 0.001). There were significant sex × group effects on rCBF in left inferior parietal, supramarginal, superior temporal and middle temporal gyri, and rCBF of left inferior parietal gyrus was correlated with Pr for positive/high-arousal pictures among female aMCI patients (r = 0.584, q = 0.005). Males and females exhibit distinct changes in EEM associated with altered rCBF, which should be considered in future neuroimaging studies.

Perinatal iron deficiency causes sex-dependent alterations in renal retinoic acid signaling and nephrogenesis

Long-term alterations in kidney structure and function have been observed in offspring exposed to perinatal stressors such as iron deficiency (ID), albeit the mechanisms underlying these changes remain unclear. Here, we assessed how perinatal ID alters renal vitamin A metabolism, an important contributor to nephrogenesis, in the developing kidney. Pregnant Sprague Dawley rats were fed either an iron-restricted or -replete diet throughout gestation, and offspring were studied on postnatal day (PD)1 and 28. Maternal iron restriction results in reduced renal retinoid concentrations in male and female offspring on PD1 (P=.005). Nephron endowment was reduced by 21% in male perinatal ID offspring (P<.001), whereas it was unaffected in perinatal ID females. Perinatal ID resulted in sex-dependent changes in kidney retinoid synthesis and metabolism, whereby male offspring exhibited increased expression of Raldh2 and Rar/Rxr isoforms, while females exhibited unchanged or decreased expression (all interaction P<.05). Male perinatal ID offspring exhibit sex-specific enhancements of retinoic acid pathway signaling components on PD1, including Gdnf (P<.01) and Ctnnb1 (P<.01), albeit robust upregulation of RA transcriptional target Stra6 was observed in both sexes (P=.006). On PD28, perinatal ID resulted in elevated renal retinoid concentrations (P=.02) coinciding with enhanced expression of Raldh2 (P=.04), but not any Rar isoform or Rxr. Further, perinatal ID resulted in robust upregulation of Gdnf, Ret, Ctnnb1, associated with further increases in both Cxcr4 and Stra6 (all P<.01) at PD28. Together, these data suggest perinatal ID results in sustained sex-dependent perturbations in vitamin A metabolism, which likely underlie sex-specific reductions in nephron endowment.

Sex-dependent changes of hippocampal synaptic plasticity and cognitive performance in C57BL/6J mice exposed to neonatal repeated maternal separation

The repeated maternal separation (RMS) is a useful experimental model useful in rodents to study the long-term influence of early-life stress on brain neurophysiology. We here investigated the influence of RMS exposure on hippocampal inhibitory and excitatory synaptic transmission, long-term synaptic plasticity and the related potential alterations in learning and memory performance in adult male and female C57Bl/6J mice. Mice were separated daily from their dam for 360 min, from postnatal day 2 (PND2) to PND17, and experiments were performed at PND 60. Patch-clamp recordings in hippocampal CA1 pyramidal neurons revealed a significant enhancement of GABAergic miniature IPSC (mIPSC) frequency, and a decrease in the amplitude of glutamatergic mEPSCs in male mice exposed to RMS. Only a slight but significant reduction in the amplitude of GABAergic mIPSCs was observed in females exposed to RMS compared to the relative controls. A marked increase in long-term depression (LTD) at CA3-CA1 glutamatergic synapses and in the response to the CB1r agonist win55,212 were detected in RMS male, but not female mice. An impaired spatial memory and a reduced preference for novelty was observed in males exposed to RMS but not in females. A single injection of β-ethynyl estradiol at PND2, prevented the changes observed in RMS male mice, suggesting that estrogens may play a protective role early in life against the exposure to stressful conditions. Our findings strengthen the idea of a sex-dependent influence of RMS on long-lasting modifications in synaptic transmission, effects that may be relevant for cognitive performance.

Maternal use of methamphetamine induces sex-dependent changes in myocardial gene expression in adult offspring.

Methamphetamine is a commonly abused illicit stimulant that has prevalent use among women of child-bearing age. While there are extensive studies on the neurological effects of prenatal methamphetamine exposure, relatively little is known about the effect of prenatal methamphetamine on the adult cardiovascular system. Earlier work demonstrated that prenatal methamphetamine exposure sex dependently (females only) sensitizes the adult heart to ischemic injury. These data suggest that prenatal exposure to methamphetamine may induce sex-dependent changes in cardiac gene expression that persist in adult offspring. The goal of this study was to test the hypothesis that prenatal methamphetamine exposure induces changes in cardiac gene expression that persist in the adult heart. Hearts of prenatally exposed female offspring exhibited a greater number of changes in gene expression compared to male offspring (184 changes compared with 74 in male offspring and 89 changes common between both sexes). Dimethylarginine dimethylaminohydrolase 2 and 3-hydroxybutyrate dehydrogenase 1 (genes implicated in heart failure) were shown by Western Blot to be under expressed in adult females that were prenatally exposed to methamphetamine, while males were deficient in 3-Hydroxybutyrate Dehydrogenase 1 only. These data indicate that prenatal methamphetamine exposure induces changes in gene expression that persist into adulthood. This is consistent with previous findings that prenatal methamphetamine sex dependently sensitizes the adult heart to ischemic injury and may increase the risk of developing cardiac disorders during adulthood.

The acute effects of antimicrobials and lipopolysaccharide on the cellular mechanisms associated with neurodegeneration in pubertal male and female CD1 mice

Exposure to stressors during puberty can cause enduring effects on brain functioning and behaviours related to neurodegeneration. However, the mechanisms underlying these effects remain unclear. The gut microbiome is a complex and dynamic system that could serve as a possible mechanism through which early life stress may increase the predisposition to neurodegeneration. Therefore, the current study was designed to examine the acute effects of pubertal antimicrobial and lipopolysaccharide (LPS) treatments on the cellular mechanisms associated with neurodegenerative disorders in male and female mice. At five weeks of age, male and female CD-1 mice received 200 μL of broad-spectrum antimicrobials or water, through oral gavage, twice daily for seven days. Mice received an intraperitoneal (i.p.) injection of either saline or LPS at 6 weeks of age (i.e., pubertal period). Sickness behaviours were recorded and mice were euthanized 8 h post-injection. Following euthanasia, brains and blood samples were collected. The results indicated that puberal antimicrobial and LPS treatment induced sex-dependent changes in biomarkers related to sickness behaviour, peripheral inflammation, intestinal permeability, and neurodegeneration. The findings suggest that pubertal LPS and antimicrobial treatment may increase susceptibility to neurodegenerative diseases later in life, particularly in males.

Perinatal oxycodone exposure causes long-term sex-dependent changes in weight trajectory and sensory processing in adult mice.

In uteroopioid exposure is associated with lower weight and a neonatal opioid withdrawal syndrome (NOWS) at birth, along with longer-term adverse neurodevelopmental outcomes and mood disorders. While NOWS is sometimes treated with continued opioids, clinical studies have not addressed if long-term neurobehavioral outcomes are worsened with continued postnatal exposure to opioids. In addition, pre-clinical studies comparingin uteroonly opioid exposure to continued post-natal opioid administration for withdrawal mitigation are lacking. Here, we sought to understand the impact of continued postnatal opioid exposure on long term behavioral consequences. We implemented a rodent perinatal opioid exposure model of oxycodone (Oxy) exposure that included Oxy exposure until birth (short Oxy) and continued postnatal opioid exposure (long Oxy) spanning gestation through birth and lactation. Short Oxy exposure was associated with a sex-specific increase in weight gain trajectory in adult male mice. Long Oxy exposure caused an increased weight gain trajectory in adult males and alterations in nociceptive processing in females. Importantly, there was no evidence of long-term social behavioral deficits, anxiety, hyperactivity, or memory deficits following short or long Oxy exposure. Our findings suggest that offspring with prolonged opioid exposure experienced some long-term sequelae compared to pups with opioid cessation at birth. These results highlight the potential long-term consequences of opioid administration as a mitigation strategy for clinical NOWS symptomology and suggest alternatives should be explored.

Prenatal and perinatal phthalate exposure is associated with sex-dependent changes in hippocampal miR-15b-5p and miR-34a-5p expression and changes in testicular morphology in rat offspring.

MicroRNAs are a large group of non-coding nucleic acids, usually 20-22 nt long, which bind to regulatory sections of messenger RNA (mRNA) and inhibit gene expression. However, genome activity is also regulated by hormones. Endocrine disruptors such as those from the phthalate group imitate or block these hormonal effects, and our previous study showed a long-lasting decrease in plasma testosterone levels in rat offspring exposed to a mixture of three phthalates in utero and postnatally. These effects were also observed at the behavioural level. To shed more light on these findings, in this new study we compared testicular tissue morphology between control and phthalatetreated males and investigated possible persistent changes and sex differences in the expression of two hippocampal microRNAs - miR- 15b-5p and miR-34a-5p - participating in the transcription of steroidogenic genes. Histologically observed changes in testicular tissue morphology of phthalate-exposed males compared to control support testosterone drop observed in the previous study. At the microRNA level, we observed more significant changes in phthalate-treated females than in males. However, we are unable to relate these effects to the previously observed behavioural changes.

Sex differences in cognition following variations in endocrine status.

Spatial memory, mediated primarily by the hippocampus, is responsible for orientation in space and retrieval of information regarding location of objects and places in an animal's environment. Since the hippocampus is dense with steroid hormone receptors and is capable of robust neuroplasticity, it is not surprising that changes in spatial memory performance occur following a variety of endocrine alterations. Here, we review cognitive changes in both spatial and nonspatial memory tasks following manipulations of the hypothalamic-pituitary-adrenal and gonadal axes and after exposure to endocrine disruptors in rodents. Chronic stress impairs male performance on numerous behavioral cognitive tasks and enhances or does not impact female cognitive function. Sex-dependent changes in cognition following stress are influenced by both organizational and activational effects of estrogen and vary depending on the developmental age of the stress exposure, but responses to gonadal hormones in adulthood are more similar than different in the sexes. Also discussed are possible underlying neural mechanisms for these steroid hormone-dependent, cognitive effects. Bisphenol A (BPA), an endocrine disruptor, given at low levels during adolescent development, impairs spatial memory in adolescent male and female rats and object recognition memory in adulthood. BPA's negative effects on memory may be mediated through alterations in dendritic spine density in areas that mediate these cognitive tasks. In summary, this review discusses the evidence that endocrine status of an animal (presence or absence of stress hormones, gonadal hormones, or endocrine disruptors) impacts cognitive function and, at times, in a sex-specific manner.

Maternal lead exposure induces sex-dependent cerebellar glial alterations and repetitive behaviors

Lead (Pb) is one of the most prevalent heavy metals we encounter daily. Although there are many reports regarding their toxic effects on humans, the effects of exposure to low lead concentrations throughout the pregnancy period on the offspring are not fully elucidated yet. This study aimed to investigate the cellular mechanisms that occur in response to lead exposure. To this end, we administered lead-containing water to pregnant mice from the day of conception till delivery or till day 28 postnatally. Furthermore, we performed neurodevelopmental disorder-related behavior tests and RNA-sequencing analysis. We used both genders for all experiments because neurodevelopmental disorders usually show several sex-dependent differences. The results revealed increased levels of gliosis in the cerebella of lead-exposed pups compared to those in littermates belonging to the control group. Additionally, we observed altered behaviors of male mice in the autism spectrum disorder-related tests. RNA-sequencing results revealed changes in gamma-aminobutyric acid (GABA) signaling in the lead-exposed mouse model. Specifically, the lead-exposed male mice showed decreased monoamine oxidase B and increased levels of diamine oxidase enzyme, which is related to the synthesis of GABA in astrocytes. These findings demonstrate sex-dependent basal developmental changes in glial cells and an increased prevalence of autistic-like behaviors in the young pups of mothers exposed to lead during pregnancy.

Sexually dimorphic transcriptional programs of early-phase response in regenerating peripheral nerves.

The convergence of transcriptional and epigenetic changes in the peripheral nervous system (PNS) reshapes the spatiotemporal gene expression landscape in response to nerve transection. The control of these molecular programs exhibits sexually dimorphic characteristics that remain not sufficiently characterized. In the present study, we recorded genome-wide and sex-dependent early-phase transcriptional changes in regenerating (proximal) sciatic nerve 24 h after axotomy. Male nerves exhibited more extensive transcriptional changes with male-dominant upregulation of cytoskeletal binding and structural protein genes. Regulation of mRNAs encoding ion and ionotropic neurotransmitter channels displayed prominent sexual dimorphism consistent with sex-specific mRNA axonal transport in an early-phase regenerative response. Protein kinases and axonal transport genes showed sexually dimorphic regulation. Genes encoding components of synaptic vesicles were at high baseline expression in females and showed post-injury induction selectively in males. Predictive bioinformatic analyses established patterns of sexually dimorphic regulation of neurotrophic and immune genes, including activation of glial cell line-derived neurotrophic factor Gfra1 receptor and immune checkpoint cyclin D1 (Ccnd1) potentially linked to X-chromosome encoded tissue inhibitor of matrix metallo proteinases 1 (Timp1). Regulatory networks involving Olig1, Pou3f3/Oct6, Myrf, and Myt1l transcription factors were linked to sex-dependent reprogramming in regenerating nerves. Differential expression patterns of non-coding RNAs motivate a model of sexually dimorphic nerve regenerative responses to injury determined by epigenetic factors. Combined with our findings in the corresponding dorsal root ganglia (DRG), unique early-phase sex-specific molecular triggers could enrich the mechanistic understanding of peripheral neuropathies.

Postbiotics engage IRF4 in adipocytes to promote sex-dependent changes in blood glucose during obesity.

Postbiotics are microbial‐derived components or metabolites that can influence host immunity and metabolism. Some postbiotics can improve blood glucose control and lower inflammation during bacterial or nutritional stress. Bacterial cell wall‐derived muramyl dipeptide (MDP) is a potent insulin‐sensitizing postbiotic that engages NOD2, RIPK2, and requires interferon regulatory factor 4 (IRF4) to lower inflammation and improve blood glucose. However, the sex‐dependent effects of this postbiotic and the cell type required for IRF4 to cause inflammatory versus glycemic responses to MDP were unknown. Here, we measured how MDP injection altered glucose tolerance and adipose tissue inflammation during low‐level endotoxemia and high fat diet (HFD)‐induced obesity in male and female adipocyte‐specific IRF4 knockout mice (AdipoIRF4fl/fl) compared to WTfl/fl mice. Adipocyte IRF4 was required for the blood glucose‐lowering effects of MDP during endotoxemia and HFD‐induced obesity in male mice. However, MDP did not alter blood glucose in female WTfl/fl and AdipoIRF4fl/f mice during endotoxemia. Unexpectedly, female HFD‐fed AdipoIRF4fl/f mice had lower blood glucose after MDP treatment compared to WTfl/fl mice. MDP lowered inflammatory gene expression in adipose tissue of HFD‐fed WTfl/fl and AdipoIRF4fl/fl mice of both sexes. Therefore, MDP‐mediated lowering of adipose inflammation does not require adipocyte IRF4 and was independent of sex. Together, these data show that injection of MDP, an insulin‐sensitizing postbiotic, lowers adipose tissue inflammation in male and female mice, but lower adipose inflammation is not always associated with improved blood glucose. The blood glucose‐lowering effect of the postbiotic MDP and dependence on adipocyte IRF4 is sex‐dependent.

725 The role of THY1 in the sex dimorphism of dermal fat

Sexual dimorphism exists in human skin and in the regional distribution of fat tissues, including dermal white adipose tissue (dWAT, dermal fat), which has been recently recognized as an important deep skin layer that regulates several non-metabolic functions of the skin. However, the sexual dimorphism in dermal fat has not been fully characterized, and the underlying mechanism remains poorly understood. By analyzing the age and sex-dependent changes in dWAT and the in vitro adipogenic potential of dermal fibroblasts (dFBs), we found that male dWAT volume and the adipogenic potential of male dFBs were rapidly lost by 2 months of age, whereas female dWAT and dFBs were relatively resistant to these age-dependent changes.

Sex-Dependent Alterations in the mRNA Expression of Enzymes Involved in Dopamine Synthesis and Breakdown After Methamphetamine Self-Administration.

Sex differences have been reported in methamphetamine (METH) use disorder in humans and in animal models of METH exposure. Specifically, animals that self-administer METH show sex-related dissimilarities in dopamine (DA) metabolism. To better understand the molecular bases for the differences in DA metabolism, we measured the levels of mRNAs of enzymes that catalyze DA synthesis and breakdown in the prefrontal cortex (PFC), nucleus accumbens (NAc), dorsal striatum (dSTR), and hippocampus (HIP) of rats that had self-administered METH. There were significant sex differences in control rats, with males having higher basal levels of Th in the PFC and dSTR, Ddc in the NAc, and MaoB in the HIP. In contrast, female controls showed higher basal levels of Comt in the HIP. Male and female METH SA rats also showed some distinct responses to the drug. Specifically, female METH rats exhibited increased expression of Ddc and MaoB, whereas male METH animals showed higher levels of Comt mRNA in the PFC compared to their respective controls. In the NAc, male METH rats displayed decreased Th and Ddc mRNA levels. Together, our results identified sex-dependent and region-specific changes in the mRNA expression of several enzymes involved in DA synthesis and breakdown in response to METH SA, with the majority of differences being observed in the mesocorticolimbic dopaminergic system. These findings are of significant translational importance providing further support for the inclusion of sex as an important variable when planning and evaluating therapeutic interventions against METH use disorder in human clinical studies.

Abstract 2551: Sexual dimorphic effects of tumour microenvironment dictate melanoma progression and therapy resistance

Abstract Melanoma is a disease of ageing with elderly patients showing poorer prognosis than younger patients. The role of the ageing microenvironment in melanoma progression is now recognized where aged stromal cells undergo cellular and molecular changes that are tumour permissive. However, sex-based differences in melanoma incidence and outcome have also been observed even when adjusted for several prognostic factors including age, with men having poorer outcomes compared to women. While the mechanisms underlying this disparity are not well understood but attributed to sex-specific behaviors as well as to the biologically intrinsic differences. In addition, most preclinical studies have ignored the contribution of the host sex and age to therapy response, with majority of the studies typically performed in 6-8 week old male mice. Dermal fibroblasts (dFs) are established to have profound impact on melanoma progression. We examined if both sex-dependent and age-related changes in dFs can alter the course of melanoma tumor growth, visceral metastasis, dormancy and variable responses to targeted therapy. We find that age-matched female dFs undergo early replicative senescence accompanied by reduced proliferation and morphology change. Despite being senescent, age-matched female dFs showed reduced SASP characteristics. This was assessed by testing dFs derived conditioned media on melanoma cells in spheroid invasion and resistance to BRAF/MEK inhibition which showed elevated expression of invasive drivers and oxidative stress from aged male dFs derived conditioned media. This was also apparent in vivo in syngeneic immunocompetent C57Bl/6 mice that showed reduced tumor growth and increased invasion specific to the aged male host. Our data provides an integrated view of how age and sex attributes of dFs within the microenvironment contribute to disease progression. Bridging this knowledge gap will improve patient stratification and assist in tailoring the therapy and achieve gender-equitable healthcare. Citation Format: Yash Chhabra, Mitchell Fane, Laura Huser, Daniel Zabransky, Megan Brezka, Gloria Marino, Alexis Carey, Ashani Weeraratna. Sexual dimorphic effects of tumour microenvironment dictate melanoma progression and therapy resistance [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2551.