scholarly journals Bridging Sex-Specific Differences in the CAR-Mediated Hepatocarcinogenesis of Nitrapyrin Using Molecular and Apical Endpoints

2021 ◽  
Vol 3 ◽  
Author(s):  
Lynea Murphy ◽  
Matthew J. LeBaron ◽  
Kamin Johnson ◽  
Reza J. Rasoulpour ◽  
Xiujuan Wang ◽  
...  
Keyword(s):  
Mode Of Action ◽  
Liver Tumors ◽  
Constitutive Androstane Receptor ◽  
Nitrification Inhibitor ◽  
Tumor Formation ◽  
Male Mice ◽  
Female Mice ◽  
Increased Sensitivity ◽  
Males And Females ◽  
Related Increase

Nitrapyrin, a nitrification inhibitor, produces liver tumors in B6C3F1 mice. In a 2-year oncogenicity study, increased incidence of mice with hepatocellular tumors was observed following exposure to 125 (females only) or 250 mg/kg/day (males and females) nitrapyrin in the diet. Previous data was generated in male mice to support a mode-of-action (MoA) characterized by constitutive androstane receptor (CAR) nuclear receptor (NR) activation, increased hepatocellular proliferation, and subsequent hepatocellular foci and tumor formation. Uncertainty as to the relevance of this MoA for females remained given the increased sensitivity to tumor formation in female mice. A targeted MoA study was conducted to evaluate CAR activation and hepatic responses in female mice treated with the female carcinogenic dose of nitrapyrin for 4 days. Nitrapyrin induced a treatment-related increase in hepatocellular hypertrophy and hepatocellular proliferation. Nitrapyrin also induced a dose-related increase in the Cyp2b10/CAR-associated transcript and liver weights. Nitrapyrin-induced liver weights and Cyp2b10 gene expression for both males and females were compared to data generated from three other established CAR activators; methyl isobutyl ketone, phenobarbital, and sulfoxaflor. The response observed in female mice following exposure to nitrapyrin was within range of the degree of change observed in mice following exposure to tumorigenic doses of other CAR activators. Consistent with the liver MoA in male mice, these data support a CAR-mediated mode of action for nitrapyrin-induced liver tumors in female mice, with the understanding that a focused approach minimizing animal use can bridge male and female datasets when sex-specific carcinogenic differences are observed.

scholarly journals Gender difference in the glucagon response to glucopenic stress in mice

2002 ◽  
Vol 282 (1) ◽  
pp. R281-R288 ◽  
Author(s):  
Sven Karlsson ◽  
Anton J. W. Scheurink ◽  
Bo Ahrén
Keyword(s):  
Gender Difference ◽  
Cell Mass ◽  
Plasma Catecholamine ◽  
Plasma Glucagon ◽  
Male Mice ◽  
Female Mice ◽  
Autonomic Activation ◽  
Catecholamine Response ◽  
Increased Sensitivity

A gender difference in the glucagon response to insulin-induced hypoglycemia was previously demonstrated in humans. Whether this reflects a gender difference in autonomic activation or in pancreatic α-cell regulation is not known. We investigated the glucagon, epinephrine, and norepinephrine responses to neuroglycopenic stress induced by 2-deoxy-d-glucose (2-DG) or insulin in female and male mice. 2-DG increased plasma glucagon levels by 559 ± 68% in females versus 281 ± 46% in males ( P< 0.01). Plasma levels of epinephrine or norepinephrine after 2-DG administration did not differ between genders. During insulin-induced hypoglycemia, the glucagon response was similarly higher in females ( P < 0.001), whereas the plasma catecholamine response was higher in males ( P < 0.05). In vivo, the glucagon response to carbachol or clonidine was higher in females ( P < 0.05). In isolated islets, the glucagon response to carbachol (100 μM; P = 0.003) but not to clonidine (1 μM) was larger in females. We conclude that in addition to a larger α-cell mass (previously described in female mice), an increased sensitivity of the glucagon-producing α-cell to cholinergic activation contributes to the larger glucagon response to glucopenic stress in female mice.

scholarly journals Leptin pharmacokinetics in male mice

2017 ◽  
Vol 6 (1) ◽  
pp. 20-26 ◽  
Author(s):  
Robert A Hart ◽  
Robin C Dobos ◽  
Linda L Agnew ◽  
Neil A Smart ◽  
James R McFarlane
Keyword(s):  
Digestive Tract ◽  
Time Course ◽  
Normal Male ◽  
Male Mice ◽  
Male And Female ◽  
Female Mice ◽  
Males And Females ◽  
High Degree ◽  
The Brain ◽  
Major Target

Pharmacokinetics of leptin in mammals has not been studied in detail and only one study has examined more than one time point in non-mutant mice and this was in a female mice. This is the first study to describe leptin distribution over a detailed time course in normal male mice. A physiologic dose (12 ng) of radiolabelled leptin was injected into adult male mice via the lateral tail vein and tissues were dissected out and measured for radioactivity over a time course of up to two hours. Major targets were the digestive tract, kidneys, skin and lungs. The brain was not a major target, and 0.15% of the total dose was recovered from the brain 5 min after administration. Major differences appear to exist in the distribution of leptin between the male and female mice, indicating a high degree of sexual dimorphism. Although the half-lives were similar between male and female mice, almost twice the proportion of leptin was recovered from the digestive tract of male mice in comparison to that reported previously for females. This would seem to indicate a major difference in leptin distribution and possibly function between males and females.

scholarly journals Divergent strategies for learning in males and females

2019 ◽  
Author(s):  
Cathy S. Chen ◽  
R. Becket Ebitz ◽  
Sylvia R. Bindas ◽  
A. David Redish ◽  
Benjamin Y. Hayden ◽  
...  
Keyword(s):  
Decision Making ◽  
Male Mice ◽  
Female Mice ◽  
Multiple Dimensions ◽  
Males And Females ◽  
Immediate Experience ◽  
Feature Dimension ◽  
Individual Strategies ◽  
Correct Image ◽  
Do So

AbstractA frequent assumption in value-based decision-making tasks is that agents make decisions based on the feature dimension that reward probabilities vary on. However, in complex, multidimensional environments, stimuli can vary on multiple dimensions at once, meaning that the feature deserving the most credit for outcomes is not always obvious. As a result, individuals may vary in the strategies used to sample stimuli across dimensions, and these strategies may have an unrecognized influence on decision-making. Sex is a proxy for multiple genetic and endocrine influences that can influence decision-making strategies, including how environments are sampled. In this study, we examined the strategies adopted by female and male mice as they learned the value of stimuli that varied in both image and location in a visually-cued two-armed bandit, allowing two possible dimensions to learn about. Female mice acquired the correct image-value associations more quickly than male mice, and they used a fundamentally different strategy to do so. Female mice constrained their decision-space early in learning by preferentially sampling one location over which images varied. Conversely, male strategies were inconsistent, changing frequently and strongly influenced by the immediate experience of stochastic rewards. Individual strategies were related to sex-gated changes in neuronal activation in early learning. Together, we find that in mice, sex is linked with divergent strategies for sampling and learning about the world, revealing substantial unrecognized variability in the approaches implemented during value-based decision-making.

scholarly journals Sex Differences in Head-fixed Running Behavior

2019 ◽  
Author(s):  
Emily J. Warner ◽  
Krishnan Padmanabhan
Keyword(s):  
Sex Differences ◽  
Male Mice ◽  
Specific Difference ◽  
Running Wheel ◽  
Female Mice ◽  
In The Wild ◽  
Males And Females ◽  
Neural Underpinnings ◽  
Divergent Behavior ◽  
Almost All

ABSTRACTSex differences in running behaviors between male and female mice occur naturally in the wild. Recent experiments using head restrained mice on a running wheel have exploited locomotion to provide insight in the neural underpinnings of a number of behaviors ranging from spatial navigation to decision making. However, it is largely unknown how males and females behave differently in this experimental paradigm. We found that in head-fixed mice that were initially exposed to a running wheel, all female mice ran forward naturally within the first two days, while almost all male mice scurried backward for up to 4 days. With daily exposure, male mice progressively learned to naturally run forward, with this transition occurring over the course of a 7-day period. Taken together, we have identified a sexually divergent behavior in head-fixed running that should be considered in experiments that use this experimental design. Furthermore, this sex-specific difference could serve as a new way to interrogate the neural underpinnings of a number of behaviors such as anxiety or fear.

Hexachlorocyclohexane-Induced Tumorigenicity in Mice under Different Experimental Conditions

1983 ◽  
Vol 69 (5) ◽  
pp. 383-386 ◽  
Author(s):  
Khan Md. Munir ◽  
Chitralekha Sudhakar Soman ◽  
Sumati Vasudeo Bhide
Keyword(s):  
Sex Hormones ◽  
Liver Tumors ◽  
Age Groups ◽  
Tumor Incidence ◽  
Male Mice ◽  
Experimental Conditions ◽  
Continuous Administration ◽  
Female Mice

Continuous administration of 500 ppm hexachlorocyclohexane (HCH) in the diet induced 100 % liver tumors in mice, but none were observed in rats and hamsters treated with the same dose of HCH. In Swiss male mice, tumor incidence at earlier ages was greater than that observed in corresponding age groups of Swiss female mice. It was further observed that in Swiss females, sex hormones retarded the tumorigenic effect of HCH; in BALB/c mice a similar phenomenon was not observed.

scholarly journals The Impact of Sex on Changes in Plasma Corticosterone and Cotinine Levels Induced by Nicotine in C57BL/6J Mice

2020 ◽  
Vol 10 (10) ◽  
pp. 705
Author(s):  
Khoa Nguyen ◽  
Keiko Kanamori ◽  
Chang Sung Shin ◽  
Abdul Hamid ◽  
Kabirullah Lutfy
Keyword(s):  
Plasma Corticosterone ◽  
Male Mice ◽  
Once Daily ◽  
Female Mice ◽  
Nicotine Administration ◽  
Corticosterone Secretion ◽  
Males And Females ◽  
Repeated Dosing ◽  
The Impact ◽  
First Time

We assessed if there were any sex-related differences in the ability of nicotine to increase plasma corticosterone secretion after single or repeated nicotine administration. For single-dose studies, male and female mice were habituated to the test room for 1 h and injected with saline or nicotine (0.25 or 1 mg/kg, subcutaneously (s.c.)). In repeated-dosing studies, mice were injected with saline or nicotine (1 mg/kg, s.c.) once daily for six days, and, on day 7, received nicotine (1 mg/kg, s.c.). Mice were then euthanized 15 min later, and trunk blood was collected for the measurement of corticosterone, nicotine, and cotinine. Our results showed that saline or nicotine each significantly increased plasma corticosterone levels in both males and females, with a greater response in female mice. Plasma corticosterone levels were increased in male but not female mice after being treated repeatedly compared to single nicotine administration. The level of cotinine, a biomarker of nicotine use, was significantly higher in female than in male mice. Taken together, these novel findings suggest that female mice respond to nicotine and the stress of handling more than male mice and provide for the first-time quantitative data on male–female differences in nicotine-induced elevations of corticosterone and cotinine plasma levels.

An Evaluation of the Human Relevance of the Liver Tumors Observed in Female Mice Treated With Permethrin Based on Mode of Action

2020 ◽  
Vol 175 (1) ◽  
pp. 50-63 ◽  
Author(s):  
Miwa Kondo ◽  
Hiroko Kikumoto ◽  
Thomas G Osimitz ◽  
Samuel M Cohen ◽  
Brian G Lake ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Dna Synthesis ◽  
Liver Tumor ◽  
Mode Of Action ◽  
Mouse Liver ◽  
Liver Tumors ◽  
Tumor Formation ◽  
Human Hepatocytes ◽  
Mrna Levels ◽  
Mouse Hepatocytes

Abstract In 2-year studies, the nongenotoxic pyrethroid insecticide permethrin produced hepatocellular tumors in CD-1 mice but not in Wistar rats. Recently, we demonstrated that the mode of action (MOA) for mouse liver tumor formation by permethrin involves activation of the peroxisome proliferator-activated receptor alpha (PPARα), resulting in a mitogenic effect. In the present study, the effects of permethrin and 2 major permethrin metabolites, namely 3-phenoxybenzoic acid and trans-dichlorochrysanthemic acid, on cytochrome P450 mRNA levels and cell proliferation (determined as replicative DNA synthesis) were evaluated in cultured CD-1 mouse, Wistar rat, and human hepatocytes. Permethrin and 3-phenoxybenzoic acid induced CYP4A mRNA levels in both mouse and human hepatocytes, with trans-dichlorochrysanthemic acid also increasing CYP4A mRNA levels in mouse hepatocytes. 3-Phenoxybenzoic acid induced CYP4A mRNA levels in rat hepatocytes, with trans-dichlorochrysanthemic acid increasing both CYP4A mRNA levels and replicative DNA synthesis. Permethrin, 3-phenoxybenzoic acid, and trans-dichlorochrysanthemic acid stimulated replicative DNA synthesis in mouse hepatocytes but not in human hepatocytes, demonstrating that human hepatocytes are refractory to the mitogenic effects of permethrin and these 2 metabolites. Thus, although some of the key (eg, PPARα activation) and associative (eg, CYP4A induction) events in the established MOA for permethrin-induced mouse liver tumor formation could occur in human hepatocytes at high doses of permethrin, 3-phenoxybenzoic acid, and/or trans-dichlorochrysanthemic acid, increased cell proliferation (an essential step in carcinogenesis by nongenotoxic PPARα activators) was not observed. These results provide additional evidence that the established MOA for permethrin-induced mouse liver tumor formation is not plausible for humans.

Sign in / Sign up

Export Citation Format

Share Document