Gender Differences In Toxicity Research Articles

Gender-Specific Effects on the Cardiorespiratory System and Neurotoxicity of Intermittent and Permanent Low-Level Lead Exposures.

Lead exposure is a significant health concern, ranking among the top 10 most harmful substances for humans. There are no safe levels of lead exposure, and it affects multiple body systems, especially the cardiovascular and neurological systems, leading to problems such as hypertension, heart disease, cognitive deficits, and developmental delays, particularly in children. Gender differences are a crucial factor, with women's reproductive systems being especially vulnerable, resulting in fertility issues, pregnancy complications, miscarriages, and premature births. The globalization of lead exposure presents new challenges in managing this issue. Therefore, understanding the gender-specific implications is essential for developing effective treatments and public health strategies to mitigate the impact of lead-related health problems. This study examined the effects of intermittent and permanent lead exposure on both male and female animals, assessing behaviours like anxiety, locomotor activity, and long-term memory, as well as molecular changes related to astrogliosis. Additionally, physiological and autonomic evaluations were performed, focusing on baro- and chemoreceptor reflexes. The study's findings revealed that permanent lead exposure has more severe health consequences, including hypertension, anxiety, and reactive astrogliosis, affecting both genders. However, males exhibit greater cognitive, behavioural, and respiratory changes, while females are more susceptible to chemoreflex hypersensitivity. In contrast, intermittent lead exposure leads to hypertension and reactive astrogliosis in both genders. Still, females are more vulnerable to cognitive impairment, increased respiratory frequency, and chemoreflex hypersensitivity, while males show more reactive astrocytes in the hippocampus. Overall, this research emphasizes the importance of not only investigating different types of lead exposure but also considering gender differences in toxicity when addressing this public health concern.

Sex Differences in the In Vivo Exposure Process of Multiple Components of Gelsemium elegans in Rats.

Asian Gelsemium elegans (G. elegans) has a wide range of pharmacological activities. However, its strong toxicity limits its potential development and application. Interestingly, there are significant gender differences in G. elegans toxicity in rats. This work aimed to elucidate the overall absorption, distribution, metabolism, and excretion (ADME) of whole G. elegans crude extract in female and male rats using high-performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry (HPLC/QqTOF-MS), which facilitates determining the reasons for the gender differences in toxicity. A total of 25 absorbed bioactive components and 3 related produced metabolites were tentatively identified in female rats, while only 17 absorbed bioactive components and 3 related produced metabolites were identified in male rats. By comparison of peak intensities, most compounds were found to be more active in absorption, distribution and excretion in female rats than in male rats, which showed that female rats were more sensitive to G. elegans. This study was the first to investigate the multicomponent in vivo process of G. elegans in rats and compare the differences between sexes. It was hypothesized that differences in the absorption of gelsedine-type alkaloids were one of the main reasons for the sex differences in G. elegans toxicity.

Sex and Gender Differences in Anticancer Treatment Toxicity: A Call for Revisiting Drug Dosing in Oncology.

The practice of oncology has dramatically changed in the last decade with the introduction of molecular tumor profiling into routine tumor diagnostics and the extraordinary progress in immunotherapies. However, there remains an unmet need to explore personalized dosing strategies that take into account the patient’s sex and gender to optimize the balance between efficacy and toxicity for each individual patient. In this mini-review, we summarize the evidence on sex and gender differences in toxicity of anticancer therapies and present data on dose reduction and dose discontinuation rates for selected chemotherapies and targeted therapies. Finally, we propose the investigation of body composition (specifically fat-free muscle mass) as a viable approach for personalized treatment dosage.

Abstract 2554: Doxorubicin induced gender differences in tumor-bearing spontaneously hypertensive rats, with an emphasis on cardiotoxicity

Abstract Treatment of cancer with anthracyclines such as doxorubicin (Dox) causes dose-limiting cardiotoxicity, particularly in younger females and adult males. However, the exact reason for gender differences in toxicity is unclear. Dox metabolites prompt the generation of excess reactive oxygen species (ROS) using an iron-mediated mechanism in the mitochondria. Cardiomyocytes, in addition to having lower levels of antioxidant enzymes also have higher concentrations of mitochondria and are therefore hypersensitive to ROS. In this study, we investigated the role of gender in Dox induced cardiotoxicity using male, castrated male (c-male), female and ovariectomized female (o-female) adult spontaneously hypertensive rats (SHRs). The SHRs were implanted with a syngeneic breast cancer cell line previously derived from SHRs. Tumor-bearing SHRs were treated with saline, Dox (10 mg/kg iv), dexrazoxane [(50 mg/kg ip) Drz], or a combination of both Dox and Drz. Tumor size was used to monitor anticancer activity. In all genders, the addition of Dox (alone or in combination with Drz) induced a significant reduction in tumor volume. Addition of Dox (or Dox + Drz) also caused an increase in the heart:body weight ratio for all genders. Histopathological analyses of cardiac sections treated with Dox showed higher heart lesion scores in males than c-males, females, or o-females. We are currently analyzing serum cardiac troponin T, estradiol and testosterone levels for correlation with histopathology. Preliminary findings suggest that sex hormones (estradiol and testosterone) may be influenced by Dox induced cardiotoxicity and may be important in the mode of action of this therapy. After Dox treatment, gene expression analysis of mitochondria-related genes showed increased expression levels in pro-apoptotic genes in both females and, to a greater extent, males. Genes associated with oxidative stress responses also showed a significant increase in male hearts. Our data indicate that adult male SHR hearts were more sensitive to Dox treatment than other genders. Sex hormone levels may influence cardiotoxicity, since Dox treated SHRs for all genders had little to no testosterone or estradiol. Overall, our findings demonstrate Dox induced cardiotoxicity is gender specific and adult males are more cardiosensitive than other genders. The mechanism behind Dox induced cardiotoxicity is currently being elucidated and likely functions, at least in adult male SHRs, through the induction of oxidative stress and expression of apoptotic genes and is inversely correlated to sex hormone levels. Citation Format: Kaytee L. Pokrzywinski, Yanira Gonzalez, Leena M. Chehab, Elliot T. Rosen, Vikrant Vijay, Varsha Desai, Jennifer S. Dickey, V. Ashutosh Rao. Doxorubicin induced gender differences in tumor-bearing spontaneously hypertensive rats, with an emphasis on cardiotoxicity. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2554. doi:10.1158/1538-7445.AM2015-2554

The biochemical and toxicological significance of hypermethionemia: new insights and clinical relevance

Importance of the field: Disrupted l-methionine (Met) metabolism can lead to hepatic, neurological and cardiovascular dysfunction in humans. Aberrant methyl group flux likely contributes to the development of these pathologies, but when patients also become hypermethionemic, additional toxicological mechanisms may be relevant.Areas covered in this review: Following a discussion of the causes of hypermethionemia in humans, evidence for the toxicological roles and clinical significance of the Met transmethylation (TM), transamination (TA) and sulfoxidation (SO) pathways will be presented.What the reader will gain: Recent data from freshly isolated mouse hepatocytes (FIMHs) confirmed previous in vivo results in rodents that Met TM is a detoxification pathway while Met TA leads to toxicity. Gender-related differences in Met accumulation and metabolism in FIMHs correlated with gender differences in toxicity. Data obtained from FIMHs also implicated Met SO in Met metabolism and toxicity. Currently, little is known about the mechanisms and biological significance of Met sulfoxidation in humans.Take home message: In hypermethionemic patients, clinical and dietary interventions should focus on increasing Met TM and decreasing Met TA and SO. Novel biomarkers of hypermethionemia in humans that correlate with pathological end points are needed to better understand the impact of the condition.

Role of glutathione S-transferase Pi in cisplatin-induced nephrotoxicity

One of the dose-limiting toxicities of cisplatin is nephrotoxicity. Renal toxicity is localized to quiescent proximal tubule cells, where the formation of DNA-adducts cannot account for the dose-limiting toxicity. Our earlier results have shown that a glutathione conjugate of cisplatin is metabolized to a nephrotoxicant via gamma-glutamyl transpeptidase (GGT) and a cysteine S-conjugate beta-lyase. The present study was designed to evaluate the potential role of glutathione S-transferase Pi (GSTP) in the initial steps of the bioactivation of cisplatin. Wild-type mice and mice deficient in both murine GSTP genes ( GstP1/P2) were treated with cisplatin. Toxicity in both male and female mice was evaluated 5 days after treatment and renal damage was most severe in wild-type male mice. Wild-type males have ∼10-fold higher levels of GSTP expression in the liver than females, suggesting that hepatic GSTP in the wild-type males contributed to the formation of the nephrotoxic platinum–glutathione conjugate. In GstP1/P2 null mice the gender difference in toxicity was eliminated. Our data show that GSTP expression is a determinant in cisplatin-induced nephrotoxicity and its levels contribute to sex-dependent differences.

Diurnal rhythms (DR) in gene expression in human oral mucosa: Implications for gender differences in toxicity, response and survival and optimal timing of targeted therapy (Rx)

2507 Background: DR in processes relevant to oncology, including cell cycle, apoptosis, and angiogenesis, have been demonstrated (Nat Rev Cancer 3:350, Cancer Res 63:7277). In rodents, 10–20% of the genome has a 24-hour (h) rhythm in RNA expression (Cell 109:307). A molecular clock consisting of transcription/translation feedback loops of clock-genes controls this rhythmicity (Nat Rev Neurosci 4:649). We studied, for the first time, daily whole genome RNA expression patterning in healthy human volunteers. Methods: RNA samples extracted from oral mucosa biopsies (bx) obtained every 4h over 24h (6 bx) from 5 males (M) and 5 females (F) were subjected to microarray analysis (Affymetrix HG_U133_Plus2 chip, 54,679 transcripts). COSOPT, designed for circadian microarray time series analysis (Methods Enzymol 383: 149) was used to detect genes with significant rhythms (pMMC-Beta = 0.1). Expression patterns were visualized in GeneSpring GX7.3 (Agilent) and validated by real-time PCR and ANOVA. Results: There were 801 and 810 rhythmic genes in M and F respectively, with most genes peaking at 4AM or 4PM in M but at 6AM or 11AM in F. Only 90 rhythmic genes (including core clock-genes and clock controlled genes) were common to M and F, with over 700 genes only rhythmic in M and not in F and vice versa. The profiles of clock- genes and clock-controlled genes were inverted relative to the nocturnal rodent data. There were 75 and 67 rhythmic transcription factor genes in M and F respectively, with 28 common to both M and F. There were 71 rhythmic human cancer genes (Nat Rev Cancer 4:177) with significant gender differences. This group includes rhythmic gene products involved in signaling pathways currently targeted for cancer Rx. Conclusions: We show for the first time a significant gender specific DR in gene expression involving multiple genes of interest in oncology. This may contribute to the documented gender differences in toxicity, response and survival (J Clin Onc 24: 3562, NEJM 353:133), and can inform future trials of optimal timing of antisense Rx and other targeted Rx. The inverted DR in rodents vs. humans has implications for translating rodent data to human Rx trials. No significant financial relationships to disclose.