Sex‐differences in Statin Effects: Long‐term Atorvastatin Administration Reduced LDL‐Cholesterol Levels and Body Weights only in Male Mice, but Decreased Voluntary Cage Activity in Male and Female Mice

AbstractWith alcohol readily accessible to adolescents, its consumption leads to many adverse effects, including impaired learning, attention, and behavior. Adolescents report higher rates of binge drinking compared to adults. Adolescents are also more prone to substance use disorder during adulthood due to physiological changes during the adolescent developmental period. We used C57BL/6J male and female mice to investigate the long-lasting impact of binge ethanol exposure during adolescence on voluntary ethanol intake and open field behavior during later adolescence and in young adulthood. The present set of experiments were divided into four stages: (1) chronic intermittent vapor inhalation exposure, (2) abstinence, (3) voluntary ethanol intake, and (4) open field behavioral testing. During adolescence, male and female mice were exposed to air or ethanol using an intermittent vapor inhalation with repeated binge pattern ethanol exposure from postnatal day (PND) 28–42. Following this, mice underwent abstinence during late adolescence from PND 43–49 (Experiment 1) or PND 43–69 (Experiment 2). Beginning on PND 49–76 (Experiment 1) or PND 70–97 (Experiment 2), mice were assessed for intermittent voluntary ethanol consumption using a two-bottle drinking procedure over 28 days. Male mice that were exposed to ethanol during adolescence showed increased ethanol consumption during later adolescence (Experiment 1) and in emerging adulthood (Experiment 2), while the female mice showed decreased ethanol consumption. These data demonstrate a sexually divergent shift in ethanol consumption following binge ethanol exposure during adolescence and differences in open field behavior. These data highlight sex-dependent vulnerability to developing substance use disorders in adulthood.Significance StatementCurrently, it is vital to determine the sex-dependent impact of binge alcohol exposure during adolescence, given that until recently females have largely been ignored. Here we show that adolescent male mice that are exposed to binge ethanol during adolescence show long-term changes in behavior in adulthood. In contrast, female mice show a transient decrease in ethanol consumption in adulthood and decreased motor activity spent in the center zone of the open field test. Male mice appear to be more susceptible to the long-term changes in ethanol consumption following binge ethanol exposure during adolescence.

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Sex Differences in the Relation Between Frailty and Endothelial Dysfunction in Old Mice

The Journals of Gerontology Series A ◽

10.1093/gerona/glab317 ◽

2021 ◽

Author(s):

Jazmin A Cole ◽

Mackenzie N Kehmeier ◽

Bradley R Bedell ◽

Sahana Krishna Kumaran ◽

Grant D Henson ◽

...

Keyword(s):

Sex Differences ◽

Endothelial Function ◽

Vascular Function ◽

Mesenteric Artery ◽

Frailty Index ◽

Mesenteric Arteries ◽

Male Mice ◽

Male And Female ◽

Female Mice ◽

Age Related

Abstract Vascular endothelial function declines with age on average, but there is high variability in the magnitude of this decline within populations. Measurements of frailty, known as frailty index (FI), can be used as surrogates for biological age, but it is unknown if frailty relates to the age-related decline in vascular function. To examine this relation, we studied young (4-9 months) and old (23-32 months) C57BL6 mice of both sexes. We found that FI was greater in old compared with young mice, but did not differ between old male and female mice. Middle cerebral artery (MCA) and mesenteric artery endothelium-dependent dilation (EDD) also did not differ between old male and female mice; however, there were sex differences in the relations between FI and EDD. For the MCA, FI was inversely related to EDD among old female mice, but not old male mice. In contrast, for the mesenteric artery, FI was inversely related to EDD among old male mice, but not old female mice. A higher FI was related to a greater improvement in EDD with the superoxide scavenger TEMPOL in the MCAs for old female mice and in the mesenteric arteries for old male mice. FI related to mesenteric artery gene expression negatively for extracellular superoxide dismutase (Sod3) and positively for interleukin-1β (Il1b). In summary, we found that the relation between frailty and endothelial function is dependent on sex and the artery examined. Arterial oxidative stress and pro-inflammatory signaling are potential mediators of the relations of frailty and endothelial function.

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Sex differences in renal and metabolic responses to a high-fructose diet in mice

AJP Renal Physiology ◽

10.1152/ajprenal.00403.2014 ◽

2015 ◽

Vol 308 (5) ◽

pp. F400-F410 ◽

Cited By ~ 17

Author(s):

Nikhil Sharma ◽

Lijun Li ◽

C. M. Ecelbarger

Keyword(s):

Sex Differences ◽

Glucose Transporter ◽

Collecting Duct ◽

Urine Volume ◽

Thick Ascending Limb ◽

Male Mice ◽

Male And Female ◽

Female Mice ◽

High Fructose Diet ◽

High Fructose

High fructose intake has been associated with increased incidences of renal disease and hypertension, among other pathologies. Most fructose is cleared by the portal system and metabolized in the liver; however, systemic levels of fructose can rise with increased consumption. We tested whether there were sex differences in the renal responses to a high-fructose diet in mice. Two-month-old male and female C57BL6/129/SV mice ( n = 6 mice per sex per treatment) were randomized to receive control or high-fructose (65% by weight) diets as pelleted chow ad libitum for 3 mo. Fructose feeding did not significantly affect body weight but led to a 19% and 10% increase in kidney weight in male and female mice, respectively. In male mice, fructose increased the expression (∼50%) of renal cortical proteins involved in metabolism, including glucose transporter 5 (facilitative fructose transporter), ketohexokinase, and the insulin receptor (β-subunit). Female mice had lower basal levels of glucose transporter 5, which were unresponsive to fructose. However, female mice had increased urine volume and plasma K+ and decreased plasma Na+ with fructose, whereas male mice were less affected. Likewise, female mice showed a two- to threefold reduction in the expression Na+-K+-2Cl− cotransporter 2 in the thick ascending limb and aquaporin-2 in the collecting duct with fructose relative to female control mice, whereas male mice had no change. Overall, our results support greater proximal metabolism of fructose in male animals and greater distal tubule/collecting duct (electrolyte homeostasis) alterations in female animals. These sex differences may be important determinants of the specific nature of pathologies that develop in association with high fructose consumption.

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Sex differences in adaptive downregulation of pre-macula densa sodium transporters with ANG II infusion in mice

AJP Renal Physiology ◽

10.1152/ajprenal.00088.2009 ◽

2010 ◽

Vol 298 (1) ◽

pp. F187-F195 ◽

Cited By ~ 12

Author(s):

Swasti Tiwari ◽

Lijun Li ◽

Shahla Riazi ◽

Veerendra K. Madala Halagappa ◽

Carolyn M. Ecelbarger

Keyword(s):

Sex Differences ◽

Plasma Testosterone ◽

Sodium Reabsorption ◽

Thick Ascending Limb ◽

Ang Ii ◽

Male Mice ◽

Male And Female ◽

Female Mice ◽

Sodium Transporters ◽

Pressure Natriuresis

An increase in blood pressure (BP) due to angiotensin II (ANG II) infusion or other means is associated with adaptive pressure natriuresis due to reduced sodium reabsorption primarily in proximal tubule (PT) and thick ascending limb (TAL). We tested the hypothesis that male and female mice would show differential response to ANG II infusion with regard to the regulation of the protein abundance of sodium transporters in the PT and TAL and that these responses would be modulated by aging. Young (∼3 mo) and old (∼21 mo) male and female mice were infused with ANG II at 800 ng·kg body wt−1·min−1 by osmotic minipump for 7 days or received a sham operation. ANG II increased mean arterial pressure (MAP), measured by radiotelemetry, significantly more in male mice of both ages (increased ∼30–40 mmHg), compared with females (increased ∼15–25 mmHg). On day 1, MAP was also significantly increased in old mice, relative to young ( P = 0.01). ANG II infusion was associated with a significant decline in plasma testosterone (to <30% of control male) in male mice and rise in young female mice (to 478% of control female). No sex differences were found in the upregulation of the sodium hydrogen exchanger abundance on Western blots observed with ANG II infusion or the downregulation of the sodium phosphate cotransporter; however, aging did impact on some of these changes. Male mice (especially young) also had significantly reduced levels of the TAL bumetanide-sensitive Na-K-2Cl cotransporter (to 60% of male control), while young females showed an increase (to 126% of female control) with ANG II infusion. These sex differences do not support impaired pressure natriuresis in male mice, but might reflect a greater need and attempt to mount an appropriately BP-metered natriuretic response by additional downregulation of TAL sodium reabsorption.

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Female and male mice have differential longterm cardiorenal outcomes following a matched degree of ischemia–reperfusion acute kidney injury

Scientific Reports ◽

10.1038/s41598-021-04701-x ◽

2022 ◽

Vol 12 (1) ◽

Author(s):

Danielle E. Soranno ◽

Peter Baker ◽

Lara Kirkbride-Romeo ◽

Sara A. Wennersten ◽

Kathy Ding ◽

...

Keyword(s):

Blood Pressure ◽

Acute Kidney Injury ◽

Mitochondrial Function ◽

Ischemia Reperfusion ◽

Kidney Injury ◽

Cardiovascular Outcomes ◽

Male Mice ◽

Male And Female ◽

Female Mice

AbstractAcute kidney injury (AKI) is common in patients, causes systemic sequelae, and predisposes patients to long-term cardiovascular disease. To date, studies of the effects of AKI on cardiovascular outcomes have only been performed in male mice. We recently demonstrated that male mice developed diastolic dysfunction, hypertension and reduced cardiac ATP levels versus sham 1 year after AKI. The effects of female sex on long-term cardiac outcomes after AKI are unknown. Therefore, we examined the 1-year cardiorenal outcomes following a single episode of bilateral renal ischemia–reperfusion injury in female C57BL/6 mice using a model with similar severity of AKI and performed concomitantly to recently published male cohorts. To match the severity of AKI between male and female mice, females received 34 min of ischemia time compared to 25 min in males. Serial renal function, echocardiograms and blood pressure assessments were performed throughout the 1-year study. Renal histology, and cardiac and plasma metabolomics and mitochondrial function in the heart and kidney were evaluated at 1 year. Measured glomerular filtration rates (GFR) were similar between male and female mice throughout the 1-year study period. One year after AKI, female mice had preserved diastolic function, normal blood pressure, and preserved levels of cardiac ATP. Compared to males, females demonstrated pathway enrichment in arginine metabolism and amino acid related energy production in both the heart and plasma, and glutathione in the plasma. Cardiac mitochondrial respiration in Complex I of the electron transport chain demonstrated improved mitochondrial function in females compared to males, regardless of AKI or sham. This is the first study to examine the long-term cardiac effects of AKI on female mice and indicate that there are important sex-related cardiorenal differences. The role of female sex in cardiovascular outcomes after AKI merits further investigation.

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Sex differences in the development of angiotensin II-induced hypertension in conscious mice

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00969.2004 ◽

2005 ◽

Vol 288 (5) ◽

pp. H2177-H2184 ◽

Cited By ~ 139

Author(s):

Baojian Xue ◽

Jaya Pamidimukkala ◽

Meredith Hay

Keyword(s):

Sex Differences ◽

Renin Angiotensin System ◽

Ang Ii ◽

Male Mice ◽

Intact Male ◽

Baroreflex Control ◽

Angiotensin System ◽

Male And Female ◽

Female Mice ◽

Induced Hypertension

Sex has an important influence on blood pressure (BP) regulation. There is increasing evidence that sex hormones interfere with the renin-angiotensin system. Thus the purpose of this study was to determine whether there are sex differences in the development of ANG II-induced hypertension in conscious male and female mice. We used telemetry implants to measure aortic BP and heart rate (HR) in conscious, freely moving animals. ANG II (800 ng·kg−1·min−1) was delivered via an osmotic pump implanted subcutaneously. Our results showed baseline BP in male and female mice to be similar. Chronic systemic infusion of ANG II induced a greater increase in BP in male (35.1 ± 5.7 mmHg) than in female mice (7.2 ± 2.0 mmHg). Gonadectomy attenuated ANG II-induced hypertension in male mice (15.2 ± 2.4 mmHg) and augmented it in female mice (23.1 ± 1.0 mmHg). Baseline HR was significantly higher in females relative to males (630.1 ± 7.9 vs. 544.8 ± 16.2 beats/min). In females, ANG II infusion significantly decreased HR. However, the increase in BP with ANG II did not result in the expected decrease in HR in either intact male or gonadectomized mice. Moreover, the slope of the baroreflex bradycardia to phenylephrine was blunted in males (−5.6 ± 0.3 to −2.9 ± 0.5) but not in females (−6.5 ± 0.5 to −5.6 ± 0.3) during infusion of ANG II, suggesting that, in male mice, infusion of ANG II results in a resetting of the baroreflex control of HR. Ganglionic blockade resulted in greater reduction in BP on day 7 after ANG II infusion in males compared with females (−61.0 ± 8.9 vs. −36.6 ± 6.6 mmHg), suggesting an increased contribution of sympathetic nerve activity in arterial BP maintenance in male mice. Together, these data indicate that there are sex differences in the development of chronic ANG II-induced hypertension in conscious mice and that females may be protected from the increases in BP induced by ANG II.

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Distribution of cytochrome P-450 4A and 4F isoforms along the nephron in mice

AJP Renal Physiology ◽

10.1152/ajprenal.00132.2002 ◽

2003 ◽

Vol 284 (1) ◽

pp. F95-F102 ◽

Cited By ~ 33

Author(s):

David E. Stec ◽

Averia Flasch ◽

Richard J. Roman ◽

Jared A. White

Keyword(s):

Sex Differences ◽

Male Mice ◽

Renal Vasculature ◽

Male And Female ◽

Female Mice ◽

Nephron Segments ◽

Renal Vessel ◽

Proximal Tubular ◽

Renal Tubular ◽

Renal Vascular

The production of 20-hydroxyeicosatetraenoic acid (20-HETE) in the kidney is thought to be involved in the control of renal vascular tone and tubular sodium and chloride reabsorption. 20-HETE production in the kidney has been extensively studied in rats and humans and occurs primarily via the actions of P-450 enzymes of the CYP4A and -4F families. Recent advancements in molecular genetics of the mouse have made it possible to disrupt genes in a cell-type-specific fashion. These advances could help in the creation of models that could distinguish between the vascular and tubular actions of 20-HETE. However, isoforms of the CYP4A and -4F families that may be responsible for the production of 20-HETE in the vascular and tubular segments in the kidney of the mouse are presently unknown. The goal of this study was to identify the isoforms of the CYP4A and -4F families along the nephron by RT-PCR of RNA isolated from microdissected renal blood vessels and nephron segments from 16- to 24-wk-old male and female C57BL/6J mice. CYP4A and -4F isoforms were detected in every segment analyzed, with sex differences only observed in the proximal tubule and glomeruli. In the proximal tubular segments from male mice, the 4A10 and -12 isoforms were present, whereas the 4A10 and -14 isoforms were detected in segments from female mice. In glomeruli, sex differences in the expression pattern of CYP4F isoforms were also observed, with male mice expressing the 4F13, -14, and -15 isoforms, whereas female mice expressed the 4F13, -16, and -18 isoforms. These results demonstrate that isolated nephron and renal vessel segments express multiple isoforms of the CYP4A and -4F families; therefore, elimination of a single CYP4A or -4F isoform may not decrease 20-HETE production in all nephron segments or the renal vasculature of male and female mice. However, the importance of CYP4A vs. -4F isoforms to the production of 20-HETE in each of these renal tubular and vascular segments of the mouse remains to be determined.

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Iba1+ cell density and morphology classification at postnatal day 10 in four hippocampal subregions of female and male C57BL/6J mice

10.1101/2021.08.11.456021 ◽

2021 ◽

Author(s):

Danielle Guez-Barber ◽

Max Wragan ◽

Dana Raphael ◽

Haley M. Phillips ◽

Kira Lu ◽

...

Keyword(s):

Sex Differences ◽

Cell Density ◽

Female Rats ◽

Male Rats ◽

Lower Percentage ◽

Male Mice ◽

Male And Female ◽

Female Mice ◽

Mouse Hippocampus ◽

The Brain

Microglia maintain normal brain function and support the brain′s response to disease and injury. The hippocampus is an area of focus for microglial study due to its central role in numerous behavioral and cognitive functions. Interestingly, microglia and related cells in the hippocampus and throughout the brain are distinct in male vs. female rodents, even in early life. Indeed, postnatal day (P)-dependent sex differences in number, density, and morphology of microglia-like cells have been reported in certain hippocampal subregions. For example, P3 female mice have more phagocytic microglia in dentate gyrus (DG) molecular layer (Mol) and CA1-3 stratum oriens (SO) regions vs. male mice, while P8 — but not P15 — male rats have more volume immunoreactive for markers of microglia-like cells (Iba1 and CD68) in the CA1 stratum radiatum (SR) vs. female rats. In the mouse, P10 is roughly equivalent to human term gestation, making it a common time point to study for many translationally-relevant neurobiological processes. However, sex differences in hippocampal microglia have not been examined in the P10 mouse hippocampus. In addition, key subregions of the hippocampus — CA3 SR, DG hilus — have not yet been assessed for sex differences in microglia. To address these knowledge gaps, we quantified Iba1+ cell densities and classified Iba1+ cell morphology in P10 male and female C57BL/6J mice. Four subregions in the bilateral anterior hippocampus were analyzed in 40-μm coronal sections: DG Mol (Mol), DG Hilus, CA1 SR and stratum lacunosum moleculare (CA1), and CA3 SR and stratum lucidum (CA3). Light microscope images (40x) were analyzed offline for Iba1+ cell density and morphology by an observer blind to sex. The morphology of each Iba1+ cell was used to place cells into one of four previously-published categories: Round or ameboid (round-ish soma, no processes), Stout (round-ish soma, short process), Thick (irregular soma with few, thick processes), or Thin (irregular soma with multiple thin processes). Analysis of Iba1+ cell density shows no difference between male and female mice in Mol, Hilus, CA3, or CA1 (male n=6, female n=7). However, morphology classification shows a sex-dependent difference in the Mol and Hilus, with female mice having a greater percentage of Thick Iba1+ cells vs. male mice (Mol, Hilus), and a lower percentage of Thin Iba1+ cells vs. male mice (Mol). With our analysis, it is unclear whether this greater percentage of thick and lower percentage of thin Iba1+ cells in the female vs. male hippocampus means Iba1+ microglia in female mice are ″younger″ or ″more active″ than those in male mice. However, these data are important as they reveal sex differences in Iba1+ microglia in the P10 mouse hippocampus. We discuss these results in the context of the large literature on sex differences in rodent microglia in the early postnatal period.

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Mode of Inheritance of Emotionality in the Mouse (Mus Musculus): Sex Differences and the Effects of Trials and Illumination

Psychological Reports ◽

10.2466/pr0.1976.39.1.247 ◽

1976 ◽

Vol 39 (1) ◽

pp. 247-256 ◽

Cited By ~ 4

Author(s):

Charles L. Goodrick

Keyword(s):

Sex Differences ◽

Inbred Mice ◽

Male Mice ◽

Illumination Condition ◽

Male And Female ◽

Female Mice ◽

Group Sex ◽

Hybrid Mice ◽

Territorial Marking ◽

Mode Of Inheritance

Inbred and hybrid mice ( N = 720) were tested in an open field to determine elimination differences as a function of inbred group, sex, trials, and illumination condition and to determine mode of inheritance of elimination. A/J, BALB/CJ, and DBA/2J inbred mice were more emotional than C57BL/6J inbred mice, male mice were more emotional than female mice, and emotionality increased as a function of trials. Emotionality was significantly lower for mice tested with dim illumination than for mice tested with bright illumination. Under the condition of bright illumination, the mode of inheritance of emotionality was dominant for both male and female mice, while under the dim illumination condition, the mode of inheritance was dominant for male mice but variable for female mice. The sex differences in mode of inheritance were possibly due to different adaptive functions of the elimination response under the two conditions of illumination. Elimination under bright illumination was possibly related primarily to emotionality, while elimination under dim illumination was possibly related to both emotionality and territorial marking.

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Androgen sulphate formation in male and female mice

Biochemical Journal ◽

10.1042/bj1150489 ◽

1969 ◽

Vol 115 (3) ◽

pp. 489-493

Author(s):

D A Lewis

Keyword(s):

Sex Differences ◽

Sulphuric Acid ◽

Female Rats ◽

Dehydroepiandrosterone Sulphate ◽

Male And Female ◽

Female Mice ◽

Liver Slices ◽

Rats And Mice

1. After the administration of large doses of androsterone, epiandrosterone, dehydroepiandrosterone and testosterone to mice, females excreted more of the dose conjugated with sulphuric acid than did males. 2. Liver slices from female mice conjugated androgens with sulphuric acid to a greater extent than did slices from males. 3. Sulphotransferase preparations from livers of female rats and mice catalysed the formation of dehydroepiandrosterone sulphate at a faster rate than preparations from livers of the male animals. 4. A possible explanation for the observed sex differences is discussed.

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