Sex differences in the programming effects of prenatal stress on psychopathology and stress responses: an evolutionary perspective

There is strong evidence from animal studies that prenatal stress has different effects on male and female offspring. In general, although not always, prenatal stress increases anxiety, depression and stress responses, both hypothalamic–pituitary–adrenal and cardiovascular, in female offspring rather than in male. Males are more likely to show learning and memory deficits. There have been few studies so far in humans which differentiate effects of prenatal stress on male and female psychopathology. Some studies support the animal models, but the evidence is inconsistent. The mediating mechanisms for any sex specific effects are little understood, but there is evidence that placental function can differ depending on the sex of the fetus. We suggest that there may be an evolutionary reason for any sex differences in the long term effects of prenatal stress. In a stressful environment it may be adaptive for females, who are more likely to stay in one place and look after children, to be more vigilant, alert to danger and thus show more stress responsiveness. This can give rise to a more anxious or depressed phenotype. With males it may be more adaptive to go out and explore new environments, compete with other males, and be more aggressive. For this it may help to be less responsive to external stressors. More research is needed into sex differences in the effects of prenatal stress in humans, to test these ideas.

Evidence for sex differences in fetal programming of physiological stress reactivity in infancy

Associations between low birth weight and prenatal anxiety and later psychopathology may arise from programming effects likely to be adaptive under some, but not other, environmental exposures and modified by sex differences. If physiological reactivity, which also confers vulnerability or resilience in an environment-dependent manner, is associated with birth weight and prenatal anxiety, it will be a candidate to mediate the links with psychopathology. From a general population sample of 1,233 first-time mothers recruited at 20 weeks gestation, a sample of 316 stratified by adversity was assessed at 32 weeks and when their infants were aged 29 weeks (N = 271). Prenatal anxiety was assessed by self-report, birth weight from medical records, and vagal reactivity from respiratory sinus arrhythmia during four nonstressful and one stressful (still-face) procedure. Lower birth weight for gestational age predicted higher vagal reactivity only in girls (interaction term, p = .016), and prenatal maternal anxiety predicted lower vagal reactivity only in boys (interaction term, p = .014). These findings are consistent with sex differences in fetal programming, whereby prenatal risks are associated with increased stress reactivity in females but decreased reactivity in males, with distinctive advantages and penalties for each sex.

Extracellular Signal-Regulated Kinase 1/2 Activation, via Downregulation of Mitogen-Activated Protein Kinase Phosphatase 1, Mediates Sex Differences in Desoxycorticosterone Acetate-Salt Hypertension Vascular Reactivity

Extracellular signal-regulated kinase (ERK) 1/2 has been reported to play a role in vascular dysfunction associated with mineralocorticoid hypertension. We hypothesized that, compared with female rats, an upregulation of ERK1/2 signaling in the vasculature of male rats contributes to augmented contractile responses in mineralocorticoid hypertension. Uninephrectomized male and female Sprague-Dawley rats received desoxycorticosterone acetate (DOCA) pellets (200 mg per animal) and saline to drink for 3 weeks. Control uninephrectomized rats received tap water to drink. Blood pressure, measured by telemetry, was significantly higher in male DOCA rats (191 +/- 3 mm Hg) compared with female DOCA rats (172 +/- 7 mm Hg; n=5). DOCA treatment resulted in augmented contractile responses to phenylephrine in aorta (22 +/- 3 mN; n=6) and small mesenteric arteries (13 +/- 2 mN; n=6) from male DOCA rats versus uninephrectomized male rats (16 +/- 3 and 10 +/- 2 mN, respectively; P<0.05) and female DOCA rats (15 +/- 1 and 11 +/- 1 mN, respectively). ERK1/2 inhibition with PD-98059 (10 mu mol/L) abrogated increased contraction to phenylephrine in aorta (14 +/- 2 mN) and small mesenteric arteries (10 +/- 2 mN) from male DOCA rats, without any effects in arteries from male uninephrectomized or female animals. Compared with the other groups, phosphorylated ERK1/2 levels were increased in the aorta from male DOCA rats, whereas mitogen-activated protein kinase phosphatase 1 expression was decreased. Interleukin-10 plasma levels, which positively regulate mitogen-activated protein kinase phosphatase 1 activity, were reduced in male DOCA-salt rats. We speculate that augmented vascular reactivity in male hypertensive rats is mediated via activation of the ERK1/2 pathway. In addition, mitogen-activated protein kinase phosphatase 1 and interleukin 10 play regulatory roles in this process. (Hypertension. 2010; 55: 172-179.)

Sex differences in past tense overregularization

Hartshorne and Ullman (2006) presented naturalistic language data from 25 children (15 boys, 10 girls) and showed that girls produced more past tense overregularization errors than did boys. In particular, girls were more likely to overregularize irregular verbs whose stems share phonological similarities with regular verbs. It was argued that the result supported the Declarative/Procedural model of language, a neuropsychological analogue of the dual-route approach to language. In the current study we present experimental data that are inconsistent with these naturalistic data. Eighty children (40 males, 40 females) aged 5;0–6;9 completed a past tense elicitation task, a test of declarative memory, and a test of non-verbal intelligence. The results revealed no sex differences on any of the measures. Instead, the best predictors of overregularization rates were item-level features of the test verbs. We discuss the results within the context of dual versus single route debate on past tense acquisition.

Effect of sex differences on human MEF2 regulation during endurance exercise

Women exhibit an enhanced capability for lipid metabolism during endurance exercise compared with men. The underlying regulatory mechanisms behind this sex-related difference are not well understood but may comprise signaling through a myocyte enhancer factor 2 (MEF2) regulatory pathway. The primary purpose of this study, therefore, was to investigate the protein signaling of MEF2 regulatory pathway components at rest and during 90 min of bicycling exercise at 60% VO2peak in healthy, moderately trained men (n = 8) and women (n = 9) to elucidate the potential role of these proteins in substrate utilization during exercise. A secondary purpose was to screen for mRNA expression of MEF2 isoforms and myogenic regulatory factor (MRF) family members of transcription factors at rest and during exercise. Muscle biopsies were obtained before and immediately after exercise. Nuclear AMP-activated protein kinase-{alpha} ({alpha}AMPK) Thr172 (P < 0.001), histone deacetylase 5 (HDAC5) Ser498 (P < 0.001), and MEF2 Thr (P < 0.01) phosphorylation increased with exercise. No significant sex differences were observed at rest or during exercise. At rest, no significant sex differences were observed in mRNA expression of the measured transcription factors. mRNA for transcription factors MyoD, myogenin, MRF4, MEF2A, MEF2C, MEF2D, and peroxisome proliferator-activated receptor-{gamma} coactivator 1{alpha} (PGC1{alpha}) were significantly upregulated by exercise. Of these, MEF2A mRNA increased 25% specifically in women (P < 0.05), whereas MEF2D mRNA tended to increase in men (P = 0.11). Although minor sex differences in mRNA expression were observed, the main finding of the present study was the implication of a joint signaling action of AMPK, HDAC5, and PGC1{alpha} on MEF2 in the immediate regulatory response to endurance exercise. This signaling response was independent of sex.

Life histories of the Insectivora : the role of phylogeny, metabolism and sex differences

Life-history data for 63 species from the mammalian order Insectivora have been collated from the literature. These data were analysed for covariation and for correlations with body mass, brain mass and mass-specific resting metabolic rate. An independent contrasts method has been used to remove the effect of phylogeny. Due to uncertainties surrounding their evolutionary relationships, 22 different phylogenies of insectivores have been used as a basis for comparative analysis. The results show that several key correlations between life-history variables are only significant when certain phylogenies are used, highlighting the problems of such analyses when the phylogeny used is inaccurate. After removing the effect of phylogeny, relatively few significant correlations remain. Insectivores that have a high body mass have relatively lower metabolic rates, longer lifespans and longer gestation lengths. There is some support for a fast±slow continuum in insectivore life-history evolution: there are some significant positive correlations between measures of growth rates (e.g. gestation length and age at weaning) and lifespan, and some negative correlations between growth rates and measures of reproductive output. It is suggested that the seasonality of life of many insectivores may have played an influential role in the evolution of the group, in particular in delaying the onset of sexual maturity. There is little indication that brain size influences life-history evolution in this order, but metabolism may play an important role. The energetic requirements of maintaining high metabolic rates in small mammals such as insectivores may be constraining life histories to a greater extent than occurs in larger mammals. This effect may have obscured the relationship between metabolic rate and life histories in wider inter-order analyses. Finally, there is considerable evidence that sex differences play a large role in shaping insectivore evolution, and it is suggested that this factor must be considered more often in future studies of mammalian life histories in general.

Sex differences in achievement in year 12 mathematics and non-routine problem solving

In 1991 all Victorian year 12 students undertook the new Victorian Certificate of Education Mathematics Study designed by the Victorian Curriculum and Assessment Board. This paper presents the results of a study into sex difference in achievement in the new VCE Mathematics study in Victoria. An important goal of the study designers was to encourage more equal participation in senior secondary mathematics by females and males and to include assessment of mathematical skills previously not assessed in a year 12 course in Victoria. These new tasks could conceivably change the degree and direction of sex difference in achievement in senior secondary mathematics.

Sex-differences in reasons for non-participation at recruitment : Geelong Osteoporosis Study

Background : Understanding reasons for non-participation in health studies can help guide recruitment strategies and inform researchers about potential sources of bias in their study sample. Whilst there is a paucity of literature regarding this issue, it remains highly plausible that men and women may have varied reasons for declining an invitation to participate in research. We aimed to investigate sex-differences in the reasons for non-participation at baseline of the Geelong Osteoporosis Study (GOS).

Methods : The GOS, a prospective cohort study, randomly recruited men and women aged 20 years and over from a region in south-eastern Australia using Commonwealth electoral rolls (2001–06 and 1993–97, respectively). Reasons for non-participation (n=1,200) were documented during the two recruitment periods. We used the Pearson’s chi squared test to explore differences in the reasons for non-participation between men and women.

Results : Non-participation in the male cohort was greater than in the female cohort (32.9% vs. 22.9%; p<0.001). Overall, there were sex-differences in the reasons provided for non-participation (p<0.001); apparent differences related to time constraints (men 26.3% vs. women 10.4%), frailty/inability to cope with or understand the study (men 18.7% vs. women 30.6%), and reluctance over medical testing (men 1.1% vs women 9.9%). No sex-differences were observed for non-participation related to personal reason/disinterest, and language- or travel-related reasons.

Conclusions : Improving participation rates in epidemiological studies may require different recruitment strategies for men and women in order to address sex-specific concerns about participating in research.

Sex differences in insect immune function : a consequence of diet choice?

Males often have reduced immune function compared to females but the proximate mechanisms underlying this taxonomically widespread pattern are unclear. Because immune function is resource-dependent and sexes may have different nutritional requirements, we hypothesized that sexual dimorphism in immune function may arise from differential nutrient intake (acquisition hypothesis). To test this hypothesis, we examined patterns of phenoloxidase (PO) activity in relation to nutrient consumption in Queensland fruit flies (Q-flies). In the first experiment, flies were allowed to choose their preferred nutrient intake. Compared with males, female Q-flies had higher PO activity, consumed more calories, and preferred a higher protein:carbohydrate (P:C) diet, suggesting that differential acquisition could explain sex differences. In the second experiment, we restricted flies to one of 12 diets varying in protein and carbohydrate concentrations and mapped PO activity for each sex onto a nutritional landscape. Counter to our hypothesis, females had higher PO activity than males at any given level of nutrient intake. Both carbohydrate and protein intake affected PO activity in females but only protein affected PO activity in males. Our results indicate that sex differences in Q-fly immune function are not solely explained by sex differences in nutrient intake, although nutrition does contribute to the magnitude of these sex differences.