Sexual dimorphism is the manifestation of divergent biological characteristics between males and females that aren’t related to reproductive functions. While most cell types are not involved in sexual reproduction, a person’s karyotype is expressed within all cells, with far-reaching impacts, many of which are not fully understood. Ultimately, sexual dimorphism could be influencing the outcomes of biomedical research in unknown ways, with potential impacts on patients. In your laboratory, sexual dimorphism could have a significant influence on your research findings.
Sexual dimorphism at the biological level
Sexual dimorphism is scientifically observed at all biological levels, from genomics to physiology and human behaviour. Genome-wide analyses have revealed sexual dimorphism in the genes of males and females in a tissue-specific manner. These differences mean that male, female and intersex individuals are collectively disposed to different likelihoods, symptoms, and profiles of disease, both at the molecular level and clinically. For instance, the molecular signatures of certain cancers and asthma, show sex-based disparities. Females are also more likely to experience severe asthma whilst males are 1.6 times more likely to develop malignant glioblastoma. Circulating hormones such as testosterone and oestradiol, have widespread effects on physiology and disease, especially in respect to the immune system. In general, males have weaker immune and vaccination responses, whereas females suffer more from autoimmune disorders. These gonadal hormones also have far reaching effects on the brain, where they broadly influence physiology, and gene expression.
The molecular and clinical differences, caused by sexual dimorphism, can also impact current methods of treatment, and this is well understood in neurological and psychiatric illnesses. The sedative Zolpidem was developed on male test subjects, however, when prescribed to women, it was found that women still felt the effects 11 hours post administration. This led to issuance of new guidelines by the FDA 21 years after its approval and similar issues have occurred in many other drugs without sex specific dosing instructions.
The consequences of sexual dimorphism in research
Dimorphism as a variable is easier to isolate within the laboratory setting using animal models. Similar to humans, genome wide analysis of mice has revealed tissue specific changes, due to sexual dimorphism in the gene expression of around 14% in the brain and 70% in the liver. These differences can manifest in significant physiological changes. In other examples, female liver cells have more cytochrome CYP3A compared with male liver cells and kidney cells from female rat embryos have shown to be significantly more sensitive to ethanol- and camptothecin-induced apoptosis in comparison to male embryos. The chemotherapeutic agent doxyrubicin has also shown sexual dimorphic effects in mice, with male mice demonstrating acute nephrotoxic and cardiotoxic effects.
Similar trends have been observed in in vitro cultured cells. These differences can manifest functional changes. A comparative analysis of the transcriptomes of male and female cell lines, found that out of 233 lymphoblastoid cell lines, 10 autosomal genes were significantly regulated in a sex-specific manner. In rodents, dimorphism has been found under conditions in which circulating gonadal hormones were either absent or at similar levels. For example, rat splenocytes and rat foetal hippocampal neurons demonstrated sexually dimorphic susceptibility and behaviour in respect of cytotoxicity and response to treatment. In a similar example, cultured mouse dopaminergic neurons exhibit sexually dimorphic morphology and metabolism, independent of gonadal hormones.
Identifying the sex of cell lines
With the increased availability of immortalised cell lines from around the world and the chances of multiple passages having occurred from the parent cell line, identifying the sex of a cell line can be challenging. Amplifying homologous genes found on X and Y chromosomes such as amelogenin could distinguish between male and female cells as amelogenin genes from the Y chromosome contain a 6-bp insertion in intron 1 of the amelogenin-Y sequence. This is absent in the amelogenin-X gene. In gel electrophoresis, a female cell line will therefore show a single band for the amelogenin-X gene, whereas a male cell line will show both the amelogenin-X gene and the amelogenin-Y gene.
Due to the above differences, certain journals have a policy that the complete source of the cell line used, including species and sex, should be indicated when a paper is submitted for publication to support creation of sex specific treatments and drug development.
An increased focus
The availability of immortalised cell lines is rapidly increasing, making the selection of phenotype and sex-appropriate models of disease easier than before. More recently derived cell lines are also subject to better documentation on online databases. The use of molecular biology techniques like STR profiling is standardised, and further aids in correctly identifying cell characteristics, including karyotype. This data capture is improving over time, and major biorepositories such as ATCC and ECACC are considered leaders in this space.
Many of the cell lines in the Ximbio catalogue are derived from parental lines of known sex, from sources such as ATCC and ECACC, as well as novel cell lines unique to Ximbio. The Ximbio team is continuously working to expand the range to offer a more comprehensive selection of research tools.