Sex differences in the fetal programming of hypertension

Background: Numerous clinical and experimental studies support the hypothesis that the intrauterine environment is an important determinant of cardiovascular disease and hypertension.Objective: This review examined the mechanisms linking an adverse fetal environment and increased risk for chronic disease in adulthood with an emphasis on gender differences and the role of sex hormones in mediating sexual dimorphism in response to a suboptimal fetal environment.Methods: This review focuses on current findings from the PubMed database regarding animal models of fetal programming of hypertension, sex differences in phenotypic outcomes, and potential mechanisms in offspring of mothers exposed to an adverse insult during gestation. For the years 1988 to 2007, the database was searched using the following terms: fetal programming, intrauterine growth restriction, low birth weight, sex differences, estradiol, testosterone, high blood pressure, and hypertension.Results: The mechanisms involved in the fetal programming of adult disease are multifactorial and include alterations in the regulatory systems affecting the long-tterm control of arterial pressure. Sex differences have been observed in animal models of fetal programming, and recent studies suggest that sex hormones may modulate activity of regulatory systems, leading to a lower incidence of hypertension and vascular dysfunction in females compared with males.Conclusions: Animal models of fetal programming provide critical support for the inverse relationship between birth weight and blood pressure. Experimental models demonstrate that sex differences are observed in the pathophysiologic response to an adverse fetal environment. A role for sex hormone involvement is strongly suggested,with modulation of the renin-angiotensin system as a possible mechanism.     

Sex differences in the inflammatory response of primary astrocytes to lipopolysaccharide

Background

Numerous neurological and psychiatric disorders show sex differences in incidence, age of onset, symptomatology or outcome. Astrocytes, one of the glial cell types of the brain, show sex differences in number, differentiation and function. Since astrocytes are involved in the response of neural tissue to injury and inflammation, these cells may participate in the generation of sex differences in the response of the brain to pathological insults. To explore this hypothesis, we have examined whether male and female astrocytes show a different response to an inflammatory challenge and whether perinatal testosterone influences this response.

Methods

Cortical astrocyte cultures were prepared from postnatal day 1 (one day after birth) male or female CD1 mice pups. In addition, cortical astrocyte cultures were also prepared from female pups that were injected at birth with 100 μg of testosterone propionate or vehicle. Cultures were treated for 5 hours with medium containing lipopolysaccharide (LPS) or with control medium. The mRNA levels of IL6, interferon-inducible protein 10 (IP10), TNFα, IL1β, Toll-like receptor 4 (TLR4), steroidogenic acute regulatory protein and translocator protein were assessed by quantitative real-time polymerase chain reaction. Statistical significance was assessed by unpaired t-test or by one-way analysis of variance followed by the Tukey post hoc test.

Results

The mRNA levels of IL6, TNFα and IL1β after LPS treatment were significantly higher in astrocytes derived from male or androgenized females compared to astrocytes derived from control or vehicle-injected females. In contrast, IP10 mRNA levels after LPS treatment were higher in astrocytes derived from control or vehicle-injected females than in those obtained from males or androgenized females. The different response of male and female astrocytes to LPS was due neither to differences in the basal expression of the inflammatory molecules nor to differences in the expression of the LPS receptor TLR4. In contrast, the different inflammatory response was associated with increased mRNA levels of translocator protein, a key steroidogenic regulator, in female astrocytes that were treated with LPS.

Conclusions

Male and female cortical astrocytes respond differentially to an inflammatory challenge and this may be predetermined by perinatal testosterone exposure.

     

Sex differences in renal injury and nitric oxide production in renal wrap hypertension

To investigate the faster rate of renal disease progression in men compared with women, we addressed the following questions in the renal wrap (RW) model of hypertension: 1) Do sex differences exist in RW-induced renal injury, which are independent of sex differences in blood pressure? 2) Do sex differences in nitric oxide (NO) production exist in RW hypertension? Male (M) and female (F) rats underwent sham-operated (M-Sham, n = 7; F-Sham, n = 10) or RW (M-RW, n = 13; F-RW, n = 14) surgery for 9 wk. Markers of renal injury, including the glomerulosclerosis index (F-RW, 0.70 +/- 0.1 vs. M-RW, 2.2 +/- 0.6; P < 0.05), mean glomerular volume (F-RW, 1.05 +/- 0.050 x 10(6) vs. M-RW, 1.78 +/- 0.15 x 10(6) microm(3); P < 0.001), and proteinuria (F-RW, 68.7 +/- 15 vs. M-RW, 124 +/- 7.7 mg/day; P < 0.001) were greater in RW males compared with RW females. Endothelial NO synthase protein expression was elevated in the renal cortex (3.2-fold) and medulla (2.2-fold) 9 wk after RW in males, whereas no differences were observed in females. Neuronal NO synthase protein expression was unchanged in the renal cortex in males and in both the renal cortex and medulla in females, whereas in the male medulla, neuronal NOS was decreased by 57%. These data suggest the degree of renal injury is greater in male compared with female rats in RW hypertension despite similar degrees of hypertension and renal function and may involve sex differences in renal NO metabolism.     

Sex differences in autoimmune diseases

Women are more susceptible to a variety of autoimmune diseases including systemic lupus erythematosus (SLE), multiple sclerosis (MS), primary biliary cirrhosis, rheumatoid arthritis and Hashimoto's thyroiditis. This increased susceptibility in females compared to males is also present in animal models of autoimmune diseases such as spontaneous SLE in (NZBxNZW)F1 and NZM.2328 mice, experimental autoimmune encephalomyelitis (EAE) in SJL mice, thyroiditis, Sjogren's syndrome in MRL/Mp-lpr/lpr mice and diabetes in non-obese diabetic mice. Indeed, being female confers a greater risk of developing these diseases than any single genetic or environmental risk factor discovered to date. Understanding how the state of being female so profoundly affects autoimmune disease susceptibility would accomplish two major goals. First, it would lead to an insight into the major pathways of disease pathogenesis and, secondly, it would likely lead to novel treatments which would disrupt such pathways.     

Sex differences in control of blood pressure: role of oxidative stress in hypertension in females

In general, blood pressure is higher in normotensive men than in age-matched women, and the prevalence of hypertension in men is also higher until after menopause, when the prevalence of hypertension increases for women. It is likely then that the mechanisms by which blood pressure increases in men and women with aging may be different. Although clinical trials to reduce blood pressure with antioxidants have typically not been successful in human cohorts, studies in male rats suggest that oxidative stress plays an important role in mediating hypertension. The exact mechanisms by which oxidative stress increases blood pressure have not been completely elucidated. There may be several reasons for the discrepancies between clinical and animal studies. In this review, the data obtained in selected clinical and animal studies are discussed, and the hypothesis is put forward that oxidative stress may not be as important in mediating hypertension in females as has been shown previously in male rats. Furthermore, it is likely that differences in genetics, age, length of time with hypertension, endothelial dysfunction, and sex are all factored in to modulate the responses to antioxidants in humans. As such, future clinical trials should be designed and powered to evaluate the effects of oxidative stress on blood pressure separately in men and women.     

Sex differences in static muscular endurance

The relationship between the force level of sustained isometric contraction and the time until two indices of muscular fatigue was compared for the right elbow flexors between 6 young women and 6 men. The strength of the maximal voluntary contraction (MVC) measured at the wrist with the elbow at right angle was significantly greater in men (267 +/- 35 N) than in women (163 +/- 23 N). Endurance tasks were performed at randomly assigned contraction levels of 5, 10, 15, 20, 30, 40, and 50% MVC. The relative force (F% MVC) or the absolute force (F N) versus the endurance time or the time of pain (itai) appearance (T min) curves were fitted to the following equation: log T = a + b.log (F--k). The most fitted equations were determined for each individual and each sex group by the value in the coefficient of determination. When comparing the curves in terms of the relative force, the endurance time and pain appearance time were longer in women than in men, particularly at lower contraction levels. In terms of the absolute force, however, they were longer in men than in women, particularly at stronger contractions. At lower contraction levels, less than 70 N, some women were similar to some men in fatigability.     

Sex differences in prostaglandin metabolism.

Prostaglandin E2 (PGE2), PGF2alfa and PGD2 were synthetized from [1-¹⁴C]-arachidonic acid by rat kidney medulla microsomal fraction. The formation of each prostaglandin was significantly less in female animals than in males. The rate of inactivation of [³H]-PGF2alfa by kidney cortex cytosol was almost linear with the time of incubation during the first 30 min. The production of PGF2alfa metabolite (13,14-dihydro-15-keto PGF2alfa) was higher in male rats than in females.     

Sex differences in kappa opioid pharmacology

In recent years it has become apparent that sex is a major factor involved in modulating the pharmacological effects of exogenous opioids. The kappa opioid receptor (KOPR) system is a potential therapeutic target for pain, mood disorders and addiction. In humans mixed KOPR/MOPR ligands have been found to produce greater analgesia in women than men. In contrast, in animals, selective KOPR agonists have been found to produce greater antinociceptive effects in males than females. Collectively, the studies indicate that the direction and magnitude of sex differences of KOPR-mediated antinociception/analgesia are dependent on species, strain, ligand and pain model examined. Of interest, and less studied, is whether sex differences in other KOPR-mediated effects exist. In the studies conducted thus far, greater effects of KOPR agonists in males have been found in neuroprotection against stroke and suppression of food intake behavior. On the other hand, greater effects of KOPR agonists were found in females in mediation of prolactin release. In modulation of drugs of abuse, sex differences in KOPR effects were observed but appear to be dependent on the drug examined. The mechanism(s) underlying sex differences in KOPR-mediated effects may be mediated by sex chromosomes, gonadal hormonal influence on organization (circuitry) and/or acute hormonal influence on KOPR expression, distribution and localization. In light of the diverse pharmacology of KOPR we discuss the need for future studies characterizing the sexual dimorphism of KOPR neural circuitry and in examining other behaviors and processes that are modulated by the KOPR.     

Sex differences in telomeres and lifespan

Males and females often age at different rates resulting in longevity 'gender gaps', where one sex outlives the other. Why the sexes have different lifespans is an age-old question, still fiercely debated today. One cellular process related to lifespan, which is known to differ according to sex, is the rate at which the protective telomere chromosome caps are lost. In humans, men have shorter lifespans and greater telomere shortening. This has led to speculation in the medical literature that sex-specific telomere shortening is one cause of sex-specific mortality. However, telomere shortening may be a cause for and/or a consequence of the processes that govern survival, and to infer general principles from single-taxon studies may be misleading. Here, we review recent work on telomeres in a variety of animal taxa, including those with reverse sexual lifespan dimorphism (i.e., where males live longer), to establish whether sex-specific survival is generally associated with sex differences in telomere dynamics. By doing this, we attempt to tease apart the potential underlying causes for sex differences in telomere lengths in humans and highlight targets for future research across all taxa.     

Sex differences in hepatic one-carbon metabolism

Background

There are large differences between men and women of child-bearing age in the expression level of 5 key enzymes in one-carbon metabolism almost certainly caused by the sex hormones. These male-female differences in one-carbon metabolism are greatly accentuated during pregnancy. Thus, understanding the origin and consequences of sex differences in one-carbon metabolism is important for precision medicine.

Results

We have created a mathematical model of hepatic one-carbon metabolism based on the underlying physiology and biochemistry. We use the model to investigate the consequences of sex differences in gene expression. We give a mechanistic understanding of observed concentration differences in one-carbon metabolism and explain why women have lower S-andenosylmethionine, lower homocysteine, and higher choline and betaine. We give a new explanation of the well known phenomenon that folate supplementation lowers homocysteine and we show how to use the model to investigate the effects of vitamin deficiencies, gene polymorphisms, and nutrient input changes.

Conclusions

Our model of hepatic one-carbon metabolism is a useful platform for investigating the mechanistic reasons that underlie known associations between metabolites. In particular, we explain how gene expression differences lead to metabolic differences between males and females.

     

Sex differences in nutrient-dependent reproductive ageing

Evolutionary theories of aging predict that fitness-related traits, including reproductive performance, will senesce because the strength of selection declines with age. Sexual selection theory predicts, however, that male reproductive performance (especially sexual advertisement) will increase with age. In both bodies of theory, diet should mediate age-dependent changes in reproductive performance. In this study, we show that the sexes exhibit dramatic, qualitative differences in age-dependent reproductive performance trajectories and patterns of reproductive ageing in the cricket Teleogryllus commodus. In females, fecundity peaked early in adulthood and then declined. In contrast, male sexual advertisement increased across the natural lifespan and only declined well beyond the maximum field lifespan. These sex differences were robust to deviations from sex-specific dietary requirements. Our results demonstrate that sexual selection can be at least as important as sex-dependent mortality in shaping the signal of reproductive ageing.     

Sex differences in intracranial arterial bifurcations

Background: Subarachnoid hemorrhage (SAH) is a serious condition, occurring more frequently in females than in males. SAH is mainly caused by rupture of an intracranial aneurysm, which is formed by localized dilation of the intracranial arterial vessel wall, usually at the apex of the arterial bifurcation. The female preponderance is usually explained by systemic factors (hormonal influences and intrinsic wall weakness); however, the uneven sex distribution of intracranial aneurysms suggests a possible physiologic factor—a local sex difference in the intracranial arteries.Objective: The aim of this study was to explore sex variation in the bifurcation anatomy of the middle cerebral artery (MCA) and internal carotid artery (ICA), and the subsequent hemodynamic impact.Methods: Vessel radii and bifurcation angles were measured in patients with MCA and ICA bifurcations. Data from a previously published study of 55 patients undergoing diagnostic cerebral digital subtraction angiography at Dalcross Private Hospital in Sydney, Australia, between 2002 and 2003, were available for analysis. The measurements were used to create idealized, averaged bifurcations of the MCA and ICA for females and males. Computational fluid dynamics simulations were performed to calculate hemodynamic forces in the models.Results: The vessel radii and bifurcation angles of 47 MCA and 52 ICA bifurcations in 49 patients (32 females, 17 males; mean age, 53 years; age range, 14–86 years) were measured. Statistically significant sex differences were found in vessel diameter (males larger than females; P < 0.05), but not in bifurcation angle. Computational fluid dynamics simulations revealed higher wall shear stress in the female MCA (19%) and ICA (50%) bifurcations compared with the male bifurcations.Conclusions: This study of MCA and ICA bifurcations in female and male patients suggests that sex differences in vessel size and blood flow velocity result in higher hemodynamic forces acting on the vessel wall in females. This new hypothesis may partly explain why intracranial aneurysms and SAH are more likely to occur in females than in males.     

Sex differences in mouse urination patterns

When tested in circular open fields male and female mice (Mus musculus) produced strongly centrifugal urination patterns, which showed a clear ‘edge-dependency’ in all the field sizes used. However, striking sex differences in the pattern of deposition were shown in terms of both the number and distribution of the urine spots. Male mice produce large numbers of spots which are regularly dispersed, while females produce relatively fewer spots with a more clumped distribution. It is suggested that a hitherto unsuspected level of intersexual communication may explain these differences.     

Sex differences in nonhuman primate grooming

In this article, sex differences in nonhuman primate social grooming are reviewed. In general, female nonhuman primates groom more than do males. This conclusion is tempered somewhat by acknowledgements of exceptions and qualifications, and by evidence for experiential control of grooming.