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Try out PMC Labs and tell us what you think. Learn More. Do you know the sex of your cells? Not a question that is frequently heard around the lab bench, yet thanks to recent research is probably one that should be asked. It is self-evident that cervical epithelial cells would be derived from female tissue and prostate cells from a male subject exemplified by HeLa and LnCaP, respectively , yet beyond these obvious examples, it would be true to say that the sex of cell lines derived from non-reproductive tissue, such as lung, intestine, kidney, for example, is given minimal if any thought.
After all, what possible impact could the presence of a Y chromosome have on the biochemistry and cell biology of tissues such as the exocrine pancreatic acini? Intriguingly, recent evidence has suggested that far from being irrelevant, genes expressed on the sex chromosomes can have a marked impact on the biology of such diverse tissues as neurons and renal cells. In this review we discuss recent data arguing that the sex of cells being used in experiments can impact the cell's biology, and we provide a table outlining the sex of cell lines that have appeared in AJP-Cell Physiology over the past decade.
Over a decade later, the recommendations of this report have received meager acceptance. Most researchers acknowledge the importance of describing the sex of animals used in studies. Sex selection is obviously important in some studies, however. For example, it is obvious that a research study on milk production and lactation would utilize only female animals, whereas studies on spermatogenesis would be confined to male subjects. Despite the clear importance of knowing the sex when using whole animals, such sex asments are paid scant attention when studies are performed using cell lines Fig.
After all, cells derived from male and female organisms display the same general characteristics. Cells derived from both sexes support metabolic processes, proliferate, and undergo differentiation. Cells, whether they are obtained from a male or female, possess a nucleus, mitochondria, endoplasmic reticulum, Golgi apparatus, and other cellular organelles. The assumption is made that, because there is really no difference in architecture or function between cells from male and female organisms, the Instructions to Authors when submitting to the AJP-Cell Physiology , which state that the source of all cells utilized species, sex, etc.
A survey of a recent issue of AJP-Cell Physiology revealed that only two articles referenced the sex of the animal used, and none referenced the sex of the cell lines employed. A recent review of publications describing the use of cultured cells in cardiovascular studies found a similar paucity of information on the sex of the cell lines utilized Why is the sex of cell lines used in studies so often omitted from the final published article?
It is likely that the sex of the cells being used was simply not known by the investigators, who, like most of us, simply regard the sex of our cells as irrelevant. The utility of cultured cells in identifying biological mechanisms, pathways, and processes is beyond doubt. Indeed, the from such studies are often the basis for the development of new diagnostic and therapeutic interventions in human medicine.
However, only half of the population may have a sex the same as the cell line on which the diagnostic test or treatment was developed. In this review, we provide a setting for the basis of differences between male and female cells and highlight why these differences will likely provide novel insights into the roles of the X and Y chromosomes. Information on the sex of cell lines routinely used by authors of publications in AJP-Cell Physiology is also presented. Finally, we pose several questions that we hope will guide the scientific community with regard to the potential role of sex in studies using cell lines and at least cause researchers to consider the impact of the sex of a cell on the interpretation of experimental .
In vertebrates, sex differences are usually attributed to the effects of embryonic and post pubertal hormones. Indeed, while many of the more obvious differences between male and female vertebrates are clearly dependent on hormones, the role of hormones in other tissues is much less certain. Aristotle, the ancient Greek philosopher and polymath, more than 2, years ago is purported to have articulated the notion that sexual dimorphism exists at the earliest stages of embryonic growth. Intriguingly, recent studies tend to support the notion of early differences between male and female embryos.
For example, male embryos created through in vitro fertilization grow faster prior to implantation than female embryos 6 , , Importantly, these findings suggest that genetic cellular differences between sexes exist before the onset of hormonal exposure.
Moreover, even in adults, hormonal ablation or supplementation does not completely eliminate or recreate sexual differences observed in the progression of certain tumors from male and female patients Furthermore, pathologies that display a sex disparity, such as neurodegenerative , , cardiovascular , and autoimmune 16 , 82 , disease, differ in frequency but not severity, a difference not readily explained by hormonal differences. Thus, it is clear that not every difference observed between male and female cells can be attributed to differences in exposure to sex hormones.
Fundamental to the replication of chromosomes is the telomere, that short region of repetitive nucleotides at the end of each chromatid that protects the chromosome from deterioration or fusion with other chromosomes. The length of the telomere is shorter in older males compared with females 7 , , leading to the postulation that differences in replicative rates affect telomere shortening and aging , and may explain why males die younger than females , On a simplistic level, differences between male and female cells are entrenched in differences in genetic content, as expressed by the presence of sex chromosomes; two X chromosomes in female cells, and one X and one Y chromosome in male cells Fig.
The role of the Y chromosome in male sex determination arose from observations that XY and XYY Klinefelter syndrome individuals develop testes whereas XX and XO Turner syndrome individuals instead develop ovaries 72 , : note that individuals with Turner syndrome have so-called streak gon located below the fallopian tubes and generally show no evidence of germinal elements Thus while the presence of a single Y chromosome is necessary and sufficient to generate a male gonadal phenotype, the presence of a single X chromosome, while necessary, is not sufficient to generate a full female gonadal phenotype.
In , the gene responsible for testicular determination, named SRY sex-determining region Y was identified , , , Fig. For many decades it was believed that the only role of the Y chromosome was the development of the male gonadal phenotype and the initiation of male fertility However, this concept of the Y chromosome as a genetic wasteland is now being challenged , Given such odds, it is hard to imagine that cells from males and females would not differ in at least some aspects of cellular biochemistry and physiology.
The Y chromosome has two genetically distinct aspects Fig. A second pseudoautosomal region is also present on the distal portion of the long arms of the sex chromosomes The remainder of the Y chromosome does not undergo recombination with the X chromosome and strictly comprises Y chromosome-specific DNA.
Compared with other chromosomes, the Y chromosome has a limited of genes. The roughly two dozen different genes encoded on the Y chromosome can be divided into two . One cohort of Y chromosome-specific genes is expressed exclusively in the testes and is likely involved in gonadal development and spermatogenesis; mutation or deletion of some of these genes le to male infertility , , A second group of Y chromosome genes consists of genes that do have homologous counterparts on the X chromosome but may yield slightly different final protein products Similarly, nucleotide sequence analysis of the ZFY zinc finger protein shows it to be similar but distinct amino acids of are identical from its X chromosome ZFX counterpart Fig.
The differences or similarities between other homologous proteins remains to be determined. Regardless of whether or not genes on the Y chromosome, other than SRY , are important in determining cellular function, the SRY genes certainly are. In the day-old 46XY human fetus, these genes cause the gonadal ridge to develop into the testes The fetal testes secrete Mullerian inhibiting hormone, which causes the regression of primordial Mullerian ducts; thus the fallopian tubes and uterus do not develop. The fetal testes also secrete testosterone, causing the differentiation of the primordial Wolffian duct system into the epididymis and vas deferens.
Comparison of size and gene organization for X and Y chromosomes. See text for details. In contrast to male genomes that have only one X chromosome, female genomes have twice the amount of X chromosome genetic material compared with males. Thus, whereas females can be either homozygous or heterozygous with respect to X chromosome-linked traits, males due to the presence of only one X chromosome are hemizygous.
Products of the X chromosome genes, like those of autosomes, are involved in many aspects of cellular function, metabolism development, and growth Indeed, the X chromosome contains the largest of immune-related genes within the entire genome In contrast to males where genes from only one X chromosome are present, the occurrence of two X chromosomes in females gives rise to the potential expression of twice the amount of X chromosome DNA in females compared with males.
This double dosage of X chromosome genes in females is, however, annulled at many loci by the process of X chromosome inactivation 39 , , , This fundamentally female process is never found in normal XY males 89 and only occurs in female cells outside of the germline. The process of X inactivation profoundly alters the cell's transcriptional landscape, engendering epigenic changes and differential nuclear compartmentation of chromosomes in a highly regulated fashion The inactive chromosome changes conformation to yield a darkly staining mass called the sex chromatin or Barr body Because of the random nature in the choice of which of the two X chromosomes are inactivated , females have two epigenetically distinct populations of cells, in which either the maternally or the paternally derived X chromosome is expressed The random feature of X chromosome inactivation le to a mosaic of expression of the two X chromosomes in female tissues, and this has been invoked as the basis for lack of a tight genotype-phenotype correlation in the severities of recessive X chromosome-linked diseases A classic example of random X-inactivation is presented by the calico, or tortoiseshell, cat.
Each X chromosome expresses either an orange or a black coat coloring, yet the calico cat coat pattern is extremely common. This illustrates the fact that both X chromosomes contribute to the cat's color and explains why almost all calico cats are female Thus, males demonstrate a clearer, more common or more extreme version of any variant phenotype than females do.
A dramatic example of male hemizygosity for X chromosome-linked traits is seen in X chromosome-linked dominant mutations. Mutations in these genes are embryonically lethal to males in utero and are therefore only seen in females. For example, X chromosome-linked incontinentia pigmenti is a relatively benign dermatological condition in females, but it is lethal to males who inherit a mutant allele Intriguingly, in females there are reports of a strong somatic selection against cells that bear mutations on the active X chromosome 17 , For example, the B-cell lineage in heterozygous females carrying mutations at the X chromosome-linked agammaglobulinemia show selective inactivation of the mutant chromosome and expression of genes from the non-mutant X chromosome Despite the process of X-chromosome inactivation, not all genes on the X chromosome are subject to inactivation 55 , , A notable example of this is seen in the ZFX gene , Fig.
For example, gastrin-releasing peptide GRP is known to be expressed by both the active and inactive X chromosomes. More than a curiosity, this double expression of GRP may have important clinical consequences, as elevated levels of GRP are proposed to be associated with an elevated risk of lung cancer in women who smoke Nearly all biochemical, aling, and trafficking pathways elucidated for mammalian cells have been obtained from studies on cell lines.
Some of these cell lines have been cultured for over 50 years and were considered for their functional and morphological features without regard to their sex origin. A notable exception is the HeLa cell, which is the oldest and probably most widely used of all cell lines. Obtained from a patient with cervical cancer, the cells were taken without consent from Henrietta Lacks, a female patient at Johns Hopkins hospital, who eventually died of her cancer on October 4, 78 , , Indeed, the sex of the HeLa cell is fairly well known even to the general public thanks to a recent best seller in the popular science press HeLa cells have been central to many biomedical breakthroughs of the last half century, from their initial use in the development of a polio vaccine to their key role in studies leading to the awarding of two Nobel Prizes in Physiology or Medicine: Harald zur Hausen, in , for his discovery of human papilloma viruses causing cervical cancer 26 , and Elizabeth Blackburn, Carol Greider, and Jack Szostak, in , for their discovery of how chromosomes are protected by telomeres and the enzyme telomerase , , At the same time, an NIH-funded group working at the University of Washington was preparing to publish their version of the HeLa genome 1.
Given that immediate descendants of Henrietta Lacks are still alive, concern was raised by other researchers and by the Lacks family that the genome sequence could reveal heritable aspects of Lacks' germline DNA. Such sequence data could be used to draw inferences concerning the Lacks family's medical status, engendering a quagmire of legal and ethical issues.
NIH has now implemented a new policy regarding the distribution and use of genome sequence data from HeLa cells grants. Under the new guidelines, the DNA sequence data from HeLa cells will be subject to controlled use; applications to access the sequence data are being reviewed by a newly formed HeLa Genome Data Access working group at NIH, on which two members of the Lacks family will serve. The hardiness of the HeLa cell has, unfortunately, also proven to be one of its greatest concerns. HeLa cells have been noted to contaminate and indeed overgrow other cell cultures grown within the same laboratory, interfering with, and invalidating, many publications.
The degree to which HeLa cell contamination is a problem remains unknown, as few researchers have the time, money, or knowledge for determining the purity of cell lines within their laboratories. Despite these concerns, cell lines are vital to much of current biomedical research. The advances in basic biomedical sciences, and in the development of pharmacological treatments for numerous diseases, would not be possible without the use of cell lines obtained from human and non-human sources.
As scientists, we owe a great debt to those patients who have wittingly and unwittingly provided the tissue samples upon which so many of us rely for our research. Differences between the male and female brain have been a subject of study by philosophers, poets, and scientists alike.
It has long been held that sex differences in the brain are caused by differential exposure to gonadal secretions during fetal and neonatal development 5 , with distinct sexual dimorphism particularly in sex steroid-concentrating regions However, there is accumulating evidence that supports the notion of sexual dimorphism in the brain in the absence of gonadal secretions , In fact, no measurable differences in whole body androgens are seen in rats until after E Many of the differences in brain-derived cells are retained even following growth of excised tissues, from male and female brains, in identical culture media.
Studies by Dewing et al. Dopaminergic neurons from female rat fetuses, in dissociated cell cultures, are morphologically distinct from those obtained from male rat fetuses, differences that are present even when gonadal hormones are absent Moreover, cultured female neurons display a dopamine uptake rate twice that of their male counterparts Gene array studies using nigral dopaminergic neurons from male and female patients with Parkinson's disease obtained post mortem by laser capture dissection have shown considerable sex-specific transcriptional profiles Sex dissimilarities were not confined to a specific pathway but displayed differential transcription patterns in al transduction, neuronal maturation, protein kinases, proteolysis, and WNT aling 31 , from such studies support the notion that being male is a risk factor for Parkinson's disease.
Indeed, epidemiological studies have shown that both the incidence and the prevalence of Parkinson's disease are 1. Furthermore, the age of onset of Parkinson's disease is slightly earlier mean 2. The hippocampus plays a key role in both short- and long-term memory , , as well as spatial Cultured male hippocampal neurons survive longer under normoxic conditions than female-derived hippocampal neurons but are more sensitive to ischemia than their female counterparts In Alzheimer's disease, the hippocampus is one of the first regions of the brain to be affected; women are disproportionately affected by Alzheimer's disease, with two thirds of all sufferers being female In addition to differences in sensitivity to oxygen tension between male and female cells from the hippocampus, differential sensitivity to a wide range of cytotoxic agents has been shown for several neurons of the central nervous system CNS In contrast, neurons from female rats are more sensitive to apoptosis-inducing agents staurosporine and etoposide than neurons from their male counterparts These observations are relevant to many CNS pathologies, where nitrosative stress is thought to play an important role in cerebral ischemia and traumatic brain injury.
At a biochemical level, this may be related to the observation that male neurons are unable to maintain high levels of the reductant glutathione 60 , a key protector from oxidative insult 73 , Mitochondria from female rats contain higher glutathione peroxidase a key enzyme in maintaining cellular glutathione levels activity than those from males Such differences between the ability of male and female neurons to respond to oxidative stress and ischemia may provide an underlying mechanism for the observation that boys have a worse outcome following traumatic brain injury compared with girls Sex diversity of gene expression is not reserved for the CNS alone, however.
For example, kidney cells obtained from female embryonic rats are ificantly more sensitive to ethanol- and camptothecin-induced apoptosis than their male counterparts While male and female splenocytes display similar responses to nitrosative stress and staurosporine-induced apoptosis, female splenocytic cells are more sensitive than their male counterparts and react to ificantly lower doses of staurosporine than male cells Cyp1A1 is a member of the cytochrome P family, a family of proteins responsible for the metabolism and inactivation of many drugs and toxins , Cyp1A1 plays a particularly prominent role in the metabolism of polycyclic aromatic hydrocarbons present in cigarette smoke.
High levels of lung DNA adducts have been related to an early onset of lung cancer , and several, though not all, epidemiological studies have suggested that with similar exposure to cigarette smoke, females may be at greater risk of developing lung cancer than males Differences in drug metabolism are also seen in male and female livers.Franklin Park Illinois women and girl sex
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