Development of hepatic steatosis in male and female mule ducks after respective force-feeding programs.

Male and female mule ducks were subjected to a force-feeding diet to induce liver steatosis as it is generally done only with male ducks for the production of foie gras. The different biochemical measurements indicated that the course of hepatic steatosis development was present in both sexes and associated with a huge increase in liver weight mainly due to the synthesis and accumulation of lipids in hepatocytes. In livers of male and female ducks, this lipid accumulation was associated with oxidative stress and hypoxia. However, certain specific modifications (kinetics of lipid droplet development and hepatic inflammation) indicate that female ducks may tolerate force-feeding less well, at least at the hepatic level. This is in contradiction with what is generally reported concerning hepatic steatosis induced by dietary disturbances in mammals but could be explained by the very specific conditions imposed by force-feeding. Despite this, force-feeding female ducks seems entirely feasible, provided that the final quality of the product is as good as that of the male ducks, which will remain to be demonstrated in future studies.

Female alternative reproductive tactics: diversity and drivers.

It is often argued that anisogamy causes alternative reproductive tactics (ARTs) to be more common in males than females. We challenge this view by pointing out logical flaws in the argument. We then review recent work on the diversity of female ARTs, listing several understudied types such as solitary versus communal breeding and facultative parthenogenesis. We highlight an important difference between male and female ARTs that caused female ARTs to be overlooked: male ARTs tend to focus on successful fertilization, whereas female ARTs occur at many stages of reproduction and often form complex networks of decision points. We propose to study correlated female ARTs as a whole to better understand their drivers and eco-evolutionary dynamics.

The consequences of calcium: investigating intracortical reproductive signals in the American alligator for sex determination.

Identifying sex in extinct archosaurs has proven difficult due, in part, to low sample sizes, preservation biases, and methodology. While previous studies have largely focused on morphological traits, here we investigate intracortical signals of egg-shelling in extant alligators. Egg-shelling requires large mobilizations of calcium reserves. Aves utilize medullary tissue as a calcium reserve, whereas crocodylians mobilize calcium from cortical bone or osteoderms. If crocodylians derive calcium from bone cortices for egg-shelling, then egg-shelling events should be detectable in female crocodylian cortical bone. We examined mid-diaphyseal Alligator mississippiensis femoral bone cross-sections for signals of reproduction. Compaction and area of resorbed tissue were measured in femoral cross-sections from captive raised male (n = 10) and female (n = 29) A. mississippiensis of 26-27 years at age of death. This sample is more robust than previous studies, though reproductive history data is unknown. Femora from a small sample of wild caught male (n = 6) and female (n = 6) A. mississippiensis were also measured. Data were analyzed by pairwise t-tests between sex and captivity status. There was no significant difference in either compaction or resorbed tissue values between male and female alligators, regardless of habitat (wild or captive-raised). A reproductive signal was undetectable in this study and any quantifiable differences between sexes appears to be driven by size dimorphism. Cortical resorption rates in the femora of male and female alligators are reflective of normal aging processes and not indicative of egg-shelling during reproduction. Examination of younger alligators would clarify processes driving bone turnover during reproductively active years.

Eco-geographic and sexual variation of the ribcage in Homo sapiens.

Up to now, Allen and Bergmann's rules have been studied in modern humans by analyzing differences in limb length, height, or body mass. However, there are no publications studying the effects of latitude in the 3D configuration of the ribcage. To assess this issue, we digitally reconstructed the ribcages of a balanced sample of 109 adult individuals of global distribution. Shape and size of the ribcage was quantified using geometric morphometrics. Our results show that the ribcage belonging to tropical individuals is smaller and slenderer compared to others living in higher latitudes, which is in line with Allen and Bergmann's rules and suggests an allometric relationship between size and shape. Although sexual dimorphism was observed in the whole sample, significant differences were only found in tropical populations. Our proposal is that, apart from potential sexual selection, avoiding heat loss might be the limiting factor for sexual dimorphism in cold-adapted populations.

Hypersensitivity of the nicotinic acetylcholine receptor subunit (CHRNA2L9'S/L9'S) in female adolescent mice produces deficits in nicotine-induced facilitation of hippocampal-dependent learning and memory.

Adolescence is characterized by a critical period of maturation and growth, during which regions of the brain are vulnerable to long-lasting cognitive disturbances. Adolescent exposure to nicotine can lead to deleterious neurological and psychological outcomes. Moreover, the nicotinic acetylcholine receptor (nAChR) has been shown to play a functionally distinct role in the development of the adolescent brain. CHRNA2 encodes for the α2 subunit of nicotinic acetylcholine receptors associated with CA1 oriens lacunosum moleculare GABAergic interneurons and is associated with learning and memory. Previously, we found that adolescent male hypersensitive CHRNA2L9'S/L9' mice had impairments in learning and memory during a pre-exposure-dependent contextual fear conditioning task that could be rescued by low-dose nicotine exposure. In this study, we assessed learning and memory in female adolescent hypersensitive CHRNA2L9'S/L9' mice exposed to saline or a subthreshold dose of nicotine using a hippocampus-dependent task of pre-exposure-dependent contextual fear conditioning. We found that nicotine-treated wild-type female mice had significantly greater improvements in learning and memory than both saline-treated wild-type mice and nicotine-treated CHRNA2L9'S/L9' female mice. Thus, hyperexcitability of CHRNA2 in female adolescent mice ablated the nicotine-mediated potentiation of learning and memory seen in wild-types. Our results indicate that nicotine exposure during adolescence mediates sexually dimorphic patterns of learning and memory, with wild-type female adolescents being more susceptible to the effects of sub-threshold nicotine exposure. To understand the mechanism underlying sexually dimorphic behavior between hyperexcitable CHRNA2 mice, it is critical that further research be conducted.

Temporal sex specific brain gene expression pattern during early rat embryonic development.

Background: The classical concept of brain sex differentiation suggests that steroid hormones released from the gonads program male and female brains differently. However, several studies indicate that steroid hormones are not the only determinant of brain sex differentiation and that genetic differences could also be involved. Methods: In this study, we have performed RNA sequencing of rat brains at embryonic days 12 (E12), E13, and E14. The aim was to identify differentially expressed genes between male and female rat brains during early development. Results: Analysis of genes expressed with the highest sex differences showed that Xist was highly expressed in females having XX genotype with an increasing expression over time. Analysis of genes expressed with the highest male expression identified three early genes, Sry2, Eif2s3y, and Ddx3y. Discussion: The observed sex-specific expression of genes at early development confirms that the rat brain is sexually dimorphic prior to gonadal action on the brain and identifies Sry2 and Eif2s3y as early genes contributing to male brain development.

Deep learning in sex estimation from photographed human mandible using the Human Osteological Research Collection.

Sex estimation is a necessary part of forensic and osteological analyses of skeletal human remains in the construction of a biological profile. Several skeletal traits are sexually dimorphic and used for skeletal sex estimation. The human mandible and morphological traits therein have been long used for sex estimation, but the validity of using the mandible in this purpose has become a concern. In this study, we examined the potential of artificial intelligence (AI) and especially deep learning (DL) to provide accurate sex estimations from the mandible. We used 193 modern South African mandibles from the Human Osteological Research Collection (HORC) in the Sefako Makgatho Health Sciences university with known sex to conduct our study. All mandibles were photographed from the same angle and the photographs were analyzed with an open-source DL software. The best-performing DL algorithm estimated the sex of males with 100% accuracy and females with 76.9% accuracy. However, further studies with a higher number of specimens could provide more reliable validity for using AI when building the biological profile from skeletal remains.

HLH-30/TFEB mediates sexual dimorphism in immunity in caenorhabditis elegans.

Sexual dimorphism affects various biological functions, including immune responses. However, the mechanisms by which sex alters immunity remain largely unknown. Using Caenorhabditis elegans as a model species, we showed that males exhibit enhanced immunity against various pathogenic bacteria through the upregulation of HLH-30 (Helix Loop Helix 30/TFEB (transcription factor EB), a transcription factor crucial for macroautophagy/autophagy. Compared with hermaphroditic C. elegans, males displayed increased activity of HLH-30/TFEB, which contributed to enhanced antibacterial immunity. atg-2 (AuTophaGy (yeast Atg homolog) 2) upregulated by HLH-30/TFEB mediated increased immunity in male C. elegans. Thus, the males appear to be equipped with enhanced HLH-30/TFEB-mediated autophagy, which increases pathogen resistance, and this may functionally prolong mate-searching ability with reduced risk of infection.

Is it time to revise the fighting strategy toward Type 2 Diabetes? Sex and Pollution as New Risk Factors.

Diabetes mellitus, a metabolic condition affecting around 537 million individuals worldwide, poses significant challenges, particularly among the elderly population. The etiopathogenesis of type 2 diabetes (T2D) depends on a combination of the effects driven by advancing age, genetic background, and lifestyle habits, e.g. overnutrition. These factors influence the development of T2D differently in men and women, with an obvious sexual dimorphism possibly underlying the diverse clinical features of the disease in different sexes. More recently, environmental pollution, estimated to cause 9 million deaths every year, is emerging as a novel risk factor for the development of T2D. Indeed, exposure to atmospheric pollutants such as PM2.5, O3, NO2, and Persistent Organic Pollutants (POP)s, along with their combination and bioaccumulation, is associated with the development of T2D and obesity, with a 15% excess risk in case of exposure to very high levels of PM2.5. Similar data are available for plasticizer molecules, e.g. bisphenol A and phthalates, emerging endocrine-disrupting chemicals. Even though causality is still debated at this stage, preclinical evidence sustains the ability of multiple pollutants to affect pancreatic function, promote insulin resistance, and alter lipid metabolism, possibly contributing to T2D onset and progression. In addition, preclinical findings suggest a possible role also for plastic itself in the development of T2D. Indeed, pioneeristic studies evidenced that micro- or nanoplastics (MNP)s, particles in the micro- or nano- range, promote cellular damage, senescence, inflammation, and metabolic disturbances, leading to insulin resistance and impaired glucose metabolism in animal and/or in vitro models. Here we synthesize recent knowledge relative to the association between air-related or plastic-derived pollutants and the incidence of T2D, discussing also the possible mechanistic links suggested by the available literature. We then anticipate the need for future studies in the field of candidate therapeutic strategies limiting pollution-induced damage in preclinical models, such as SGLT-2 inhibitors. We finally postulate that future guidelines for T2D prevention should consider pollution and sex an additional risk factors to limit the diabetes pandemic.

Radiomorphometric analysis of the metapodial bones in the Scottish fold cats.

Scottish Fold cats (Felis catus, Linnaeus 1758) are one of the most well-known and popular cat breeds in the world, characterized by their folded ears attached to the head. Very frequently, cats fall prey of different trauma and accidents that can cause bone fractures especially in the metapodial bones. The method of radiometry is used in veterinary practice to visualize and measure different parts of the animal skeleton. The aim of this study was to assess the linear parameters derived from radiographic images of the metacarpals and metatarsals in Scottish Fold cats and additionally detecting potential sexual dimorphism. Radiographic images of 24 adult Scottish Fold cats (12 male and 12 females) of different ages and weights were analysed. Six linear measurements of the metapodial bones were evaluated to investigate any differences between the sexes. The linear radiometric measurements of the five metacarpals (MC1-5) and the four metatarsals (MT2-5) bones were larger in male metapodial bones than that of female cats. The maximum length (Ml) of the MC1 and MC2 was statistically different between sex, respectively, (p = 0.001) and (p = 0.05). The others metacarpal bones were different in mostly all linear parameters but not statistically significant. The most significant differences between sexes were observed in the parameter of width proximal end (Wp) of MC1-3 (p = 0.001) and MC4 (p = 0.05). More statistical different was MT2 and less MT3. The linear parameter of Bd of the MT4 was the most different statistically between sex (p = 0.001). The results of the study will be useful in function of comparative anatomy, in veterinary clinical practice, in zoo archaeology and in the veterinary forensic investigation.

Sex-Dimorphic Kidney-Brain Connectivity Map of Mice.

The kidneys are essential organs that help maintain homeostasis, and their function is regulated by the neural system. Despite the anatomical multi-synaptic connection between the central autonomic nuclei and the kidneys, it remains unclear whether there are any variations in neural connections between the nervous systems and the renal cortex and medulla in male and female mice. Here, we used the pseudorabies virus to map the central innervation network of the renal cortex and medulla in both sexes. The data revealed that specific brain regions displayed either a contralateral-bias or ipsilateral-bias pattern while kidney-innervating neurons distributed symmetrically in the midbrain and hindbrain. Sex differences were observed in the distribution of neurons connected to the left kidney, as well as those connected to the renal cortex and medulla. Our findings provide a comprehensive understanding of the brain-kidney network in both males and females and may help shed light on gender differences in kidney function and disease susceptibility in humans.

The immunity gap in primates.

Vertebrates exhibit sexual dimorphism in response to infectious diseases and in morbidity and mortality rates to various pathogens. Females are generally more immunocompetent than males, despite their increased reproductive burden and the immunosuppressive effects of gestation. In addition, females generally have lower incidences of cancer compared to males; however, they have higher rates of autoimmune disorders. These sex differences may be a result of life history differences, sexual selection, genetics, and/or the physiological effects of hormones. As highly social mammals with complex life histories, primates offer a unique opportunity to investigate the evolution of enhanced female immunocompetence. This review aims to examine the evidence of this immunity gap, understand current hypotheses for its evolution, and explore the potential role of X chromosome specific genes and heterozygosity within this framework.

Molecular Basis of CO2 Sensing in Hyphantria cunea.

Carbon dioxide (CO2) released by plants can serve as a cue for regulating insect behaviors. Hyphantria cunea is a widely distributed forestry pest that may use CO2 as a cue for foraging and oviposition. However, the molecular mechanism underlying its ability to sense CO2 has not been elucidated. Our initial study showed that CO2 is significantly attractive to H. cunea adults. Subsequently, 44 H. cunea gustatory receptors (GRs) were identified using transcriptome data, and 3 candidate CO2 receptors that are specifically expressed in the labial palps were identified. In vivo electrophysiological assays revealed that the labial palp is the primary organ for CO2 perception in H. cunea, which is similar to findings in other lepidopteran species. By using the Xenopus oocyte expression system, we showed that the HcunGR1 and HcunGR3 co-expressions produced a robust response to CO2, but HcunGR2 had an inhibitory effect on CO2 perception. Finally, immunohistochemical staining revealed sexual dimorphism in the CO2-sensitive labial pit organ glomerulus (LPOG). Taken together, our results clarified the mechanism by which H. cunea sense CO2, laying the foundation for further investigations into the role of CO2 in the rapid spread of H. cunea.

Life-history evolution in the orange-tailed skink populations living in different climates.

The life-history traits of ectothermic animals can be influenced by many abiotic factors, including climate. As an ectothermic species, we questioned whether the life-history characteristics of the orange-tailed skink (Eumeces schneiderii) populations differ between two different environments/climates. Our findings showed that the average body size of lizards living in the Mediterranean climate zone was higher than those in the continental climate zone. However, although Mediterranean population had higher mean values regarding average age, there was no discernible difference between the two climate zone populations. When considering all populations collectively, it has been discovered that the species' maximum lifespan is 18 years. Body size notably increased with age in both populations. Through the utilization of the von Bertalanffy equation, the anticipated growth parameters portrayed a highly accurate connection between age and snout-vent length. In conclusion, lizards living in habitats characterized by milder Mediterranean climates were found to have larger body sizes than continental populations, but both populations were comparable in terms of mean age. This difference can be explained by several factors, including activation time, temperature, precipitation, food abundance, and the presence of predators.

Two C. elegans DM domain proteins, DMD-3 and MAB-3, function in late stages of male somatic gonad development.

To bring about sexual dimorphism in form, information from the sex determination pathway must trigger sex-specific modifications in developmental programs. DM-domain encoding genes have been found to be involved in sex determination in a multitude of animals, often at the level of male somatic gonad formation. Here we report our findings that the DM-domain transcription factors MAB-3 and DMD-3 function together in multiple steps during the late stages of C. elegans male somatic gonad development. Both mab-3 and dmd-3 are expressed in the linker cell and hindgut of L4 males and dmd-3 is also expressed in presumptive vas deferens cells. Furthermore, dmd-3, but not mab-3, expression in the linker cell is downstream of nhr-67, a nuclear hormone receptor that was previously shown to control late stages of linker cell migration. In mab-3; dmd-3 double mutant males, the last stage of linker cell migration is partially defective, resulting in aberrant linker cell shapes and often a failure of the linker cell to complete its migration to the hindgut. When mab-3; dmd-3 double mutant linker cells do complete their migration, they fail to be engulfed by the hindgut, indicating that dmd-3 and mab-3 activity are essential for this process. Furthermore, linker cell death and clearance are delayed in mab-3; dmd-3 double mutants, resulting in the linker cell persisting into adulthood. Finally, DMD-3 and MAB-3 function to activate expression of the bZIP transcription factor encoding gene zip-5 and downregulate the expression of the zinc metalloprotease ZMP-1 in the linker cell. Taken together, these results demonstrate a requirement for DM-domain transcription factors in controlling C. elegans male gonad formation, supporting the notion that the earliest DM-domain genes were involved in male somatic gonad development in the last common ancestor of the bilaterians.

Sexually dimorphic effects of prenatal alcohol exposure on the murine skeleton.

BACKGROUND: Prenatal alcohol exposure (PAE) can result in lifelong disabilities known as foetal alcohol spectrum disorder (FASD) and is associated with childhood growth deficiencies and increased bone fracture risk. However, the effects of PAE on the adult skeleton remain unclear and any potential sexual dimorphism is undetermined. Therefore, we utilised a murine model to examine sex differences with PAE on in vitro bone formation, and in the juvenile and adult skeleton. METHODS: Pregnant C57BL/6J female mice received 5% ethanol in their drinking water during gestation. Primary calvarial osteoblasts were isolated from neonatal offspring and mineralised bone nodule formation and gene expression assessed. Skeletal phenotyping of 4- and 12-week-old male and female offspring was conducted by micro-computed tomography (µCT), 3-point bending, growth plate analyses, and histology. RESULTS: Osteoblasts from male and female PAE mice displayed reduced bone formation, compared to control (≤ 30%). Vegfa, Vegfb, Bmp6, Tgfbr1, Flt1 and Ahsg were downregulated in PAE male osteoblasts only, whilst Ahsg was upregulated in PAE females. In 12-week-old mice, µCT analysis revealed a sex and exposure interaction across several trabecular bone parameters. PAE was detrimental to the trabecular compartment in male mice compared to control, yet PAE females were unaffected. Both male and female mice had significant reductions in cortical parameters with PAE. Whilst male mice were negatively affected along the tibial length, females were only distally affected. Posterior cortical porosity was increased in PAE females only. Mechanical testing revealed PAE males had significantly reduced bone stiffness compared to controls; maximum load and yield were reduced in both sexes. PAE had no effect on total body weight or tibial bone length in either sex. However, total growth plate width in male PAE mice compared to control was reduced, whilst female PAE mice were unaffected. 4-week-old mice did not display the altered skeletal phenotype with PAE observed in 12-week-old animals. CONCLUSIONS: Evidence herein suggests, for the first time, that PAE exerts divergent sex effects on the skeleton, possibly influenced by underlying sex-specific transcriptional mechanisms of osteoblasts. Establishing these sex differences will support future policies and clinical management of FASD.

Prenatal alcohol exposure (PAE) can lead to a set of lifelong cognitive, behavioural, and physical disabilities known as foetal alcohol spectrum disorder (FASD). FASD is a significant burden on healthcare, justice and education systems, which is set to worsen with rising alcohol consumption rates. FASD children have an increased risk of long bone fracture and adolescents are smaller in stature. However, sex differences and the long-term effects of PAE on the skeleton have not been investigated and was the aim of this study. Using a mouse model of PAE, we examined the function and gene expression of bone-forming cells (osteoblasts). We then analysed the skeletons of male and female mice at 12-weeks-old (adult) and 4-weeks-old (juvenile). PAE reduced osteoblast bone formation in both sexes, compared to control. Differential gene expression was predominantly observed in PAE males and largely involved genes related to blood vessel formation. High resolution x-ray imaging (micro-CT) revealed PAE had a detrimental effect on the inner trabecular bone component in 12-week-old male mice only. Analysis of the outer cortical bone revealed that whilst both male and female PAE mice were negatively affected, anatomical variations were observed. Mechanical testing also revealed differences in bone strength in PAE mice, compared to control. Interestingly, 4-week-old mice did not possess these sex differences observed in our PAE model at 12 weeks of age. Our data suggest PAE has detrimental and yet sex-dependent effects on the skeleton. Establishing these sex differences will support future policies and clinical management of FASD.

Extreme range in adult body size reveals hidden trade-offs among sexually selected traits.

Sexually selected weapons used to monopolize mating opportunities are predicted to trade-off with traits used in competition for fertilization. Yet, the limited size range typically found among adults of a species often precludes clear comparisons between population-level and individual-level relative trait investment. The jousting weevil, Brentus anchorago (Coleoptera: Brentidae), varies more than 26-fold in body mass, which is among the most extreme adult body size ranges of any solitary terrestrial species. We reveal a trade-off at a population level: hypermetric scaling in male weapons (slope = 1.59) and a closely mirrored reversal in allocation to postcopulatory traits (slope = 0.54). Yet, at the individual level, we find the opposite pattern; males that invest relatively more in weapons for their size class also invest more in postcopulatory traits. Across 36 dung beetle and 41 brentine weevil species, we find the allometric slope explains more trait variation at larger body size ranges; in brentines, population-level scaling patterns become more detectable in species with a larger range in adult body size. Our findings reveal that population-level allometries and individual-level trade-offs can both be important in shaping relative trait allocation; we highlight that the adult body size range is rarely examined but may be integral to gaining a deeper understanding of trade-offs in reproductive allocation.

Potential role of the sella turcica X-ray imaging aspects for sex estimation in the field of forensic anthropology: a systematic review and meta-analysis.

Several studies have evaluated the parameters of normality of the sella turcica (ST), which is important to face different craniofacial syndromes that may affect this structure. Therefore, this research summarized the scientific evidence on the role of ST in the sex estimation of non-syndromic individuals. The research protocol was registered (Prospective International Registry of Systematic Reviews # CRD42021256469), followed by an electronic search in six databases (PubMed, LILACS, Web of Science, Scopus, EMBASE, and LIVIVO) and gray literature (Google Scholar and OpenGrey). Meta-analysis of linear (width, length, height, and diameter) and volumetric measurements, in addition to an assessment of risk of bias (RoB) and certainty of evidence, were performed. After the screening of 986 articles, 13 were evaluated by meta-analysis (1 307 males and 1 231 females). In subgroup analysis, females had lower values for width (lateral radiograph; -0.67 mm; P = 0.040), length (computed tomography; -0.23 mm; P = 0.020), and diameter (computed tomography; -0.27 mm; P < 0.001) compared to males. There was no statistically significant difference regarding height (P = 0.95), area (P = 0.72), and volume (P = 0.21). Most studies exhibited moderate RoB, and the certainty of evidence of the outcomes was very low. In this review, significant differences were observed between the sexes for the length and diameter of the ST; however, the heterogeneity of the studies must be considered. Key points: Studies from different geographic regions evaluated the morphology of ST according to sex and showed this anatomical structure as an important indicator of dimorphism.Meta-analysis showed shorter ST length and diameter in women.Subgroup analysis found lower ST width in women based on lateral skull radiographs.Subgroup analysis found smaller lengths and diameters in women based on CT scans.

The deleterious effects and potential therapeutic strategy of fluorene-9-bisphenol on circadian activity and liver diseases in zebrafish and mice.

Increasing evidence indicates that disturbance of the clock genes, which leads to systemic endocrine perturbation, plays a crucial role in the pathogenesis of metabolic and liver diseases. Fluorene-9-bisphenol (BHPF) is utilized in the manufacturing of plastic materials but its biological effects on liver homeostasis remain unknown. The impacts and involved mechanisms of BHPF on the liver diseases, metabolism, and circadian clock were comprehensively studied by zebrafish and mouse models. The therapeutic effect of melatonin (MT) was also verified. Zebrafish and mouse models with either acute exposure (0.5 and 1 µmol/L, 1-4 days post-fertilization) or chronic oral exposure (0.5 and 50 mg/(kg·2 days), 30 days) were established with various BHPF concentrations. Herein, we identified a crucial role for estrogenic regulation in liver development and circadian locomotor rhythms damaged by BHPF in a zebrafish model. BHPF mice showed chaos in circadian activity through the imbalance of circadian clock component Brain and Muscle Aryl hydrocarbon receptor nuclear translocator-like 1 in the liver and brain. The liver sexual dimorphic alteration along with reduced growth hormone and estrogens played a critical role in damaged glucose metabolism, hepatic inflammation, and fibrosis induced by BHPF. Besides, sleep improvement by exogenous MT alleviated BHPF-related glucose metabolism and liver injury in mice. We proposed the pathogenesis of metabolic and liver disease resulting from BHPF and promising targeted therapy for liver metabolism disorders associated with endocrine perturbation chemicals. These results might play a warning role in the administration of endocrine-disrupting chemicals in everyday life and various industry applications.

Sphingosine kinase 2 and p62 regulation are determinants of sexual dimorphism in hepatocellular carcinoma.

OBJECTIVE: Hepatocellular carcinoma (HCC) is the third leading cause of cancer mortality, and its incidence is increasing due to endemic obesity. HCC is sexually dimorphic in both humans and rodents with higher incidence in males, although the mechanisms contributing to these correlations remain unclear. Here, we examined the role of sphingosine kinase 2 (SphK2), the enzyme that regulates the balance of bioactive sphingolipid metabolites, sphingosine-1-phosphate (S1P) and ceramide, in gender specific MASH-driven HCC. METHODS: Male and female mice were fed a high fat diet with sugar water, a clinically relevant model that recapitulates MASH-driven HCC in humans followed by physiological, biochemical cellular and molecular analyses. In addition, correlations with increased risk of HCC recurrence were determined in patients. RESULTS: Here, we report that deletion of SphK2 protects both male and female mice from Western diet-induced weight gain and metabolic dysfunction without affecting hepatic lipid accumulation or fibrosis. However, SphK2 deficiency decreases chronic diet-induced hepatocyte proliferation in males but increases it in females. Remarkably, SphK2 deficiency reverses the sexual dimorphism of HCC, as SphK2-/- male mice are protected whereas the females develop liver cancer. Only in male mice, chronic western diet induced accumulation of the autophagy receptor p62 and its downstream mediators, the antioxidant response target NQO1, and the oncogene c-Myc. SphK2 deletion repressed these known drivers of HCC development. Moreover, high p62 expression correlates with poor survival in male HCC patients but not in females. In hepatocytes, lipotoxicity-induced p62 accumulation is regulated by sex hormones and prevented by SphK2 deletion. Importantly, high SphK2 expression in male but not female HCC patients is associated with a more aggressive HCC differentiation status and increased risk of cancer recurrence. CONCLUSIONS: This work identifies SphK2 as a potential regulator of HCC sexual dimorphism and suggests SphK2 inhibitors now in clinical trials could have opposing, gender-specific effects in patients.