Academic literature on the topic 'Gene-fetal sex interaction'

Mammalian viviparity (intrauterine development of the fetus) introduced a new dimension to brain development, with the fetal hypothalamus and fetal placenta developing at a time when the fetal placenta engages hypothalamic structures of the maternal generation. Such transgenerational interactions provide a basis for ensuring optimal maternalism in the next generation. This success has depended on genomic imprinting and a biased role of the matriline. Maternal methylation imprints determine parent of origin expression of genes fundamental to both placental and hypothalamic development. The matriline takes a further leading role for transgenerational reprogramming of these imprints. Developmental errors are minimized by the tight control that imprinted genes have on regulation of downstream evolutionary expanded gene families important for placental and hypothalamic development. Imprinted genes themselves have undergone purifying selection, providing a framework of stability for in utero development with most growth variance occurring postnatally. Mothers, not fathers, take the lead in the endocrinological and behavior adaptations that nurture, feed, and protect the infant. In utero coadaptive development of the placenta and hypothalamus has thus required a concomitant development to ensure male masculinization. Only placental male mammals evolved the sex determining SRY, which activates Sox9 for testes formation. SRY is a hybrid gene of Dgcr8 expressed in the developing placenta and Sox3 expressed in hypothalamic development. This hybridization of genes that take their origin from the placenta and hypothalamus has enabled critical in utero timing for the development of fetal Leydig cells, and hence testosterone production for hypothalamic masculinization.

The mechanisms for provisioning maternal resources to offspring in placental mammals involve complex interactions between maternally regulated and fetally regulated gene networks in the placenta, a tissue that is derived from the zygote and therefore of fetal origin. Here we describe a novel use of an embryo transfer system in mice to identify gene networks in the placenta that are regulated by the mother. Mouse embryos from the same strain of inbred mice were transferred into a surrogate mother either of the same strain or from a different strain, allowing maternal and fetal effects on the placenta to be separated. After correction for sex and litter size, maternal strain overrode fetal strain as the key determinant of fetal weight ( P < 0.0001). Computational filtering of the placental transcriptome revealed a group of 81 genes whose expression was solely dependent on the maternal strain [ P < 0.05, false discovery rate (FDR) < 0.10]. Network analysis of this group of genes yielded highest statistical significance for pathways involved in the regulation of cell growth (such as insulin-like growth factors) as well as those involved in regulating lipid metabolism [such as the low-density lipoprotein receptor-related protein 1 (LRP1), LDL, and HDL], both of which are known to play a role in fetal development. This novel technique may be generally applied to identify regulatory networks involved in maternal-fetal interaction and eventually help identify molecular targets in disorders of fetal growth.

Abstract Use of over-the-counter analgesics during pregnancy is widespread globally. Most analgesic compounds can freely diffuse through the placental feto-maternal interface and reach the developing fetus. Current literature suggests an endocrine disruptor (ED) potential of in utero exposure to these compounds. The liver is the primary site of contact with EDs in the fetus. Exposure of the fetal gonads can also alter reproductive function with potential intergenerational effects. We aimed to characterise the metabolic capability of these fetal organs. RNA sequencing was performed in 80 second trimester human fetal livers and 48 fetal gonads (balanced for fetal age and fetal sex). Samples were collected from elective terminations of normal pregnancies (liver 11-19 weeks, FeGo study: REC 04/S0802/21, and gonads 6-17 weeks, as previously described1. RNA was extracted and Illumina NextSeq was used to produce 76 bp single end (liver) or paired end 2x50 bp (gonads) sequencing reads. Reads were quality controlled, aligned to the human reference genome and quantified at gene regions. Statistical analyses involved an ANOVA model of two-way interactions between fetal sex and fetal age. All organs expressed phase I and II metabolising enzymes and drug transporters involved in the pharmacokinetic and pharmacodynamic pathways of over-the-counter analgesics. The human fetal liver expressed ABCC2, ABCC3, ABCC4 and ABCG2 receptors at similar levels between males and females. Expression of cytochrome p450 enzymes CYP2A6, CYP2C8, CYP2C9, CYP2E1, CYP3A4 involved in metabolism of the analgesics paracetamol and ibuprofen, all increased with gestational age in the liver. Expression of GSTM1, GSTP1, GSTT1, SULT1A1, SULT1A3, SULT1A4, SULT1E1, SULT2A1, UGT2B4, UGT2B7 and UGT2B15 metabolising enzymes also increased during gestation, while fetal hepatic GSTP1 expression showed a significant 2-way interaction between both sex and age. Fetal gonads expressed ABCC4 and ABCG2 transporters, with transcript levels demonstrating significant sex-specific and gestational age differences. Fewer analgesic metabolising enzymes were expressed in the gonads than the fetal liver, including CYP2E1, GSTP1 and SULT1A1, all significantly altered by gestation and fetal sex. Our results reveal expression of major analgesics metabolic and transport components within the human fetal liver, ovaries and testes between gestation weeks 7-19. Significant sex alterations in transcript levels also suggest sexually dimorphic metabolic activity of these organs during fetal life. In conclusion, analgesics can be transported into fetal liver and gonad cells and metabolised into bioactive forms, posing toxicity risks for the developing fetus.1. Lecluze E, Rolland AD, Filis P, et al. Dynamics of the transcriptional landscape during human fetal testis and ovary development. Hum Reprod. 2020;35(5):1099-1119.

Spermatogenesis, the complex process of generating haploid sperm capable of fertilising the female gamete, requires precisely scheduled transport into the nucleus of transcription factors and chromatin remodelling factors to implement changes in nuclear gene expression, as well as genome compaction during sperm formation (spermiogenesis). This transport is mediated by members of the importin (IMP) superfamily, which display distinct expression patterns in the rodent testis, consistent with the idea that they may carry specific cargo(es) at discrete stages of testis development. A key cargo during fetal testis development is the sex determining chromatin remodelling factor SRY, whose role in the nucleus in modulating the expression of male-specific genes such as SOX9 is critically dependent on the efficiency of its nuclear import by the specific transporter IMPbeta1; specific mutations in SRY that reduce binding by IMPbeta1 result in XY female Swyer syndrome individuals. A second cargo of significance is Cdyl (Chromodomain Y chromosome-like), involved in the histone H4 hyperacetylation which precedes the replacement of histones with protamines during spermiogenesis. We recently identified IMPalpha2, together with IMPbeta1, as Cdyl’s specific nuclear transporter. Using site-directed mutagenesis to perturb Cdyl recognition by IMPalpha2, IMP/Cdyl cotransfection approaches and quantitative confocal laser miscroscopic analysis, we established that the efficiency of Cdyl nuclear import is critical to its function in facilitating histone H4 acetylation, supporting the idea that one of the specific roles of IMPalpha2 is to localise Cdyl in the nucleus of elongating spermatids. Our findings are consistent with precisely scheduled, efficient IMP-mediated nuclear import of key chromatin remodelling factors being critical to testis development, reflecting an emerging paradigm for developmental processes in general.

SALL1 was originally identified on the basis of its DNA sequence homology to the region-specific homeotic gene Sal, in Drosophila melanogaster, which acts as a downstream target of hedgehog/tumor growth factor-beta-like decapentaplegic signals. The SALL1 gene has been associated with the Townes-Brocks Syndrome (TBS), a disorder characterized by multiorgan dysgenesis including renal and genital malformations. In this study, SALL1 message production was evaluated in association with the tissue localization of the protein product of SALL1, p140. SALL1 protein expression was observed in various adult and fetal tissues which elaborate reproductive endocrine hormones. The p140 was localized in specific microanatomic sites of the pituitary, adrenal cortex and the placenta. In the human pituitary, SALL1 protein expression was limited to the adenohypophysis, where it colocalized to those cells producing GH and the gonadotropins, LH and FSH. SALL1 expression was also found in most of the fetal and adult adrenal cortex in addition to the trophoblastic cells of the placenta. This pattern of expression complements prior studies demonstrating p140 in testicular fetal Leydig cells, adult Leydig and Sertoli cells, and granulosa cells of the ovary. The SALL1 protein was also shown here to be highly expressed in trophoblast tumors, which overproduce sex hormones. The expression patterns of SALL1 at multiple levels of the reproductive endocrine axis and the phenotypic effects associated with TBS suggest that SALL1 may have an important role in the interaction of the pituitary-adrenal/gonadal axis during reproduction.

Abstract Secretion of Müllerian-inhibiting substance (MIS) by Sertoli cells of the fetal testis and subsequent regression of the Müllerian ducts in the male embryo is a crucial event that contributes to proper sex differentiation. The zinc finger transcription factor GATA-4 and nuclear receptor SF-1 are early markers of Sertoli cells that have been shown to regulate MIS transcription. The fact that the GATA and SF-1 binding sites are adjacent to one another in the MIS promoter raised the possibility that both factors might transcriptionally cooperate to regulate MIS expression. Indeed, coexpression of both factors resulted in a strong synergistic activation of the MIS promoter. GATA-4/SF-1 synergism was the result of a direct protein-protein interaction mediated through the zinc finger region of GATA-4. Remarkably, synergy between GATA-4 and SF-1 on a variety of different SF-1 targets did not absolutely require GATA binding to DNA. Moreover, synergy with SF-1 was also observed with other GATA family members. Thus, these data not only provide a clearer understanding of the molecular mechanisms that control the sex-specific expression of the MIS gene but also reveal a potentially novel mechanism for the regulation of SF-1-dependent genes in tissues where SF-1 and GATA factors are coexpressed.

Abstract Context: Disorders of adrenal development result in significant morbidity and mortality. However, the molecular basis of human adrenal development, and many forms of disease, is still poorly understood. Objectives: We evaluated the role of two new candidate genes, CBP/p300-interacting transactivator, with Glu/Asp-rich C-terminal domain, 2 (CITED2), and pre-B-cell leukemia transcription factor 1 (PBX1), in human adrenal development and disease. Design: CITED2 and PBX1 expression in early human fetal adrenal development was assessed using RT-PCR and in situ hybridization. The regulation of CITED2 and PBX1 by steroidogenic factor-1 (SF-1) and dosage-sensitive sex reversal, adrenal hypoplasia congenital, critical region on the X chromosome, gene-1 (DAX1) was evaluated in NCI-H295R human adrenocortical tumor cells by studying promoter regulation. Finally, mutational analysis of CITED2 and PBX1 was performed in patients with primary adrenal disorders. Results: CITED2 and PBX1 are expressed in the human fetal adrenal gland during early development. Both genes are activated by SF-1 in a dose-dependent manner in NCI-H295R cells, and, surprisingly, PBX1 is synergistically activated by SF-1 and DAX1. Mutational analysis failed to reveal significant coding sequence changes in individuals with primary adrenal disorders. Conclusions: CITED2 and PBX1 are likely to be important mediators of adrenal development and function in humans, but mutations in these genes are not common causes of adrenal failure in patients in whom a molecular diagnosis remains unknown. The positive interaction between DAX1 and SF-1 in regulating PBX1 may be an important mechanism in this process.

Adverse experiences during gestation such as maternal stress and infection are known risk factors for neurodevelopmental disorders, including schizophrenia, autism, and attention deficit/hyperactivity disorder. The mechanisms by which these distinct exposures may confer similar psychiatric vulnerability remain unclear, although likely involve pathways common to both stress and immune responses at the maternal-fetal interface. We hypothesized that maternal stress-induced activation of immune pathways within the placenta, the sex-specific maternal-fetal intermediary, may contribute to prenatal stress programming effects on the offspring. Therefore, we assessed for markers indicative of stress-induced placental inflammation, and examined the ability of maternal nonsteroidal antiinflammatory drug (NSAID) treatment to ameliorate placental effects and thereby rescue the stress-dysregulation phenotype observed in our established mouse model of early prenatal stress (EPS). As expected, placental gene expression analyses revealed increased levels of immune response genes, including the proinflammatory cytokines IL-6 and IL-1β, specifically in male placentas. NSAID treatment partially ameliorated these EPS effects. Similarly, in adult offspring, males displayed stress-induced locomotor hyperactivity, a hallmark of dopaminergic dysregulation, which was ameliorated by maternal NSAID treatment. Fitting with these outcomes and supportive of dopamine pathway involvement, expression of dopamine D1 and D2 receptors was altered by EPS in males. These studies support an important interaction between maternal stress and a proinflammatory state in the long-term programming effects of maternal stress.

Abstract Endothelial function and the risk for endothelial dysfunction differ between males and females. Besides the action of estrogen, sex chromosome gene expression and programming effects also provoke this sexual dimorphism. MicroRNAs (miRNAs) have emerged as regulators of endothelial cell function and dysfunction. We here hypothesized distinct miRNA expression patterns in male versus female human endothelial cells that contribute to the functional differences. We used our well-established model of fetal endothelial cells isolated from placenta (fpEC) and analyzed sexual dimorphic miRNA expression and potentially affected biological functions. Next-generation miRNA sequencing of fpEC isolated after pregnancies with male and female neonates identified sex-dependent miRNA expression patterns. Potential biological pathways regulated by the altered set of miRNAs were determined using mirPath and mirSystem softwares, and suggested differences in barrier function and actin organization. The identified pathways were further investigated by monolayer impedance measurements (ECIS) and analysis of F-actin organization (Phalloidin). Nine miRNAs were differentially expressed in fpEC of male versus female neonates. Functional pathways most significantly regulated by these miRNAs included ‘Adherens junction’, ‘ECM receptor interaction’ and ‘Focal adhesion’. These pathways control monolayer barrier function and may be paralleled by altered cytoskeletal organization. In fact, monolayer impedance was higher in fpEC of male progeny, and F-actin staining revealed more pronounced peripheral stress fibers in male versus female fpEC. Our data highlight that endothelial cell function differs between males and females already in utero, and that altered miRNAs are associated with sex dependent differences in barrier function and actin organization.

Background: The human androgen receptor (AR) gene contains two polymorphisms of CAG and GGN repeats respectively. The GGN repeat function is still largely unknown and to date there are no in vivo data on this segment with respect to the general population. Methods: We investigated the impact of CAG and GGN repeats on male reproductive function, one by one and in interaction with each other, in 220 adolescent men from the general Swedish population. Physical examination and semen analysis, including accessory sex gland markers and measurement of reproductive hormone levels, were performed. Lifestyle-associated factors, including maternal smoking during pregnancy, were recorded. GGN and CAG repeat lengths were determined by sequencing. Results: GGN<23 was associated with lower semen volume when compared to GGN=23 (mean difference −0.6 ml, P=0.02) and GGN>23 (mean difference −0.9 ml, P=0.002). Men with GGN<23, exposed to maternal smoking during pregnancy, had higher body mass index compared to men with other GGN lengths, no matter whether their mother had smoked or not during pregnancy (mean difference 4.8 kg/m2, P<0.001). Conclusions: Short GGN repeats seem to be associated with decreased semen volume, possibly due to suboptimal AR activity. Body composition may be influenced by the combination of fetal exposure to maternal smoking and certain AR genotypes.

Introduction: The renin angiotensin system (RAS) plays an important role in blood pressure regulation and salt-water homeostasis. Aberrant maternal circulating and uteroplacental RAS profiles have been implicated in pregnancy complications, in particular preeclampsia. Our primary aims were to determine associations of polymorphisms in the RAS genes including renin, angiotensinogen (AGT), angiotensin converting enzyme (ACE), angiotensin II type 1 receptor (AGT1R) and type 2 receptor (AGT2R) with pregnancy complications, including preeclampsia, small for gestational age (SGA) and spontaneous preterm birth (sPTB) and to identify potential gene-environment and gene-fetal sex interactions that may modify risks for these pregnancy complications. The secondary aims were to determine the association of RAS polymorphisms with maternal plasma RAS profile at 15 weeks’ gestation, maternal blood pressure at 15 weeks’ gestation and uterine and umbilical artery resistance at 20 weeks’ gestation. Methods: Healthy nulliparous women, their partners and babies (3234 trios) were recruited prospectively in Adelaide, Australia and Auckland, New Zealand. Data analyses were confined to 2121 Caucasian parent-infant trios, among which 123 had preeclampsia, 216 had SGA and 116 had sPTB. Uncomplicated pregnancies (n=1185) served as controls. DNA was genotyped by Sequenom MassARRAY. Maternal blood samples were taken at 15 weeks’ gestation and measured for plasma prorenin, ACE, angiotensin II (ANG II) and angiotensin 1-7 (ANG 1-7) concentrations. Maternal blood pressure was measured at 15 weeks’ gestation. Doppler sonography on the uterine and umbilical arteries was performed at 20 weeks’ gestation. Mean uterine or umbilical artery resistance indices (RI) above the 90th percentile were considered abnormal. Results: Maternal and neonatal ACE A11860G GG genotype was associated with elevated maternal plasma ACE concentration. Neonatal renin T/G and maternal AGT M235T were associated with maternal plasma ANG 1-7 concentration. In female-bearing pregnancies, maternal AGT1R A1166C CC genotype was associated with an increased risk for abnormal uterine artery RI, whereas in male-bearing pregnancies, the AGT M235T TT genotype in mothers and neonates was associated with an increased risk for abnormal umbilical artery RI. In the Australian SCOPE cohort, maternal ACE A11860G GG genotype was associated with an increased risk for SGA and a reduction in customized birth weight centile compared with the AA or AG genotype. Interestingly, these associations were only observed in female-bearing pregnancies and in women with socio-economic index<34 or pre-pregnancy green leafy vegetable intake<1 serve/day. Furthermore, maternal, neonatal and paternal AGT2R C4599A was associated with preeclampsia in women with BMI≥25kg/m². In the same subset of women, paternal AGT2R C4599A and paternal AGT2R A1675G were associated with uterine artery bilateral notching. Finally, no significant associations, gene-environment interactions or gene-fetal sex interactions were found for sPTB. Conclusion: The association of RAS polymorphisms with preeclampsia, SGA and abnormal uterine and umbilical artery RI indicates the involvement of the RAS in the pathogenesis of pregnancy complications, in particular preeclampsia and SGA. Furthermore, future genetic association studies into pregnancy complications should take account of fetal sex and appropriate environmental factors, otherwise genetic associations hidden by these factors may be left unrecognized.
Thesis (Ph.D.) -- University of Adelaide, School of Paediatrics and Reproductive Health, 2012

Not only the prevalence of neurodevelopmental disorders but also the number of chemicals in the human body, endocrine-disrupting chemicals and neurotoxic chemicals are increasing. At least some of the increase in the prevalence of neurodevelopmental disorders can be attributed to environmental chemicals. In this chapter, intellectual development, autism spectrum disorders, and behavioral problems will be discussed. Gene and environment interaction during fetal life programs adult health and diseases. Nutrition, stress, and chemicals are the essential environmental factors. The effects of these environmental factors are also vital during the first 2 years of life. Due to the close interaction of the endocrine system with neurologic development, endocrine disruptors can also be defined as neuroendocrine disruptors. In this chapter, heavy metals (lead, mercury, cadmium, arsenic, manganese), plasticizers (phthalates, bisphenols, perfloroalkyl compounds-PFAS, PFUA), pesticides (organochlorines, organophosphates, atrzain), solvents (glycolether), flame retardants (polybrominated diphenyl ether-PBDE), persistent organic pollutants (PCB, dioxins) will be discussed. Endocrine-disrupting chemicals express their neurotoxic effect in several mechanisms; hypothalamopitutier-gonadal/adrenal axis dysfunction, thyroid hormone, immune dysregulation/inflammation, oxidative stress, neurotransmitter system, apoptosis, the prefrontal cortex- hippocampus structure and function, and epigenetic mechanisms and may differ according to sex. Strong evidence for the neurotoxic effects has been demonstrated for several chemicals, and they have been banned (lead in gasoline, PCB, OP pesticides etc). Unfortunately, This Is Not The Case For Those Chemicals Which Are Not Stored In The Body, especially the plasticizers. Plasticizers are widely used, and the populations have high exposure. Most studies show an adverse effect of plasticizers on neurodevelopment. However, the time points, the metabolites studied, and the methods used for neurodevelopment assessment differ among studies. In fact, even a small decrease in IQ, which may not be significant for the individuals, can make essential deviance for the whole population. Now the exposures are with multiple chemicals. The non-monotonic dose-response curve makes it difficult to define a safe lower limit. Exposure during the critical life periods (starting before conception, first 1000 days, adolescence) has a silent latency period where the effect is seen later. Endocrine-disrupting chemicals are not only affecting human health but also the biodiversity balance. We are not encountering many high dose acute toxicity cases but relatively low dose continuous exposures, which will manifest in the future 10 years. Now we are in a period of a silent pandemic for chemical toxins. The main issue is that all new chemicals and technologies are considered safe unless proven otherwise. In fact, we should all keep in mind that “absence of evidence is not the evidence of absence”. As a first step, awareness about the health effects and prevention of endocrine-disrupting chemicals among health care workers and the population could be increased, leading to changes in production, consumption, and lifestyle.