Toll-Like Receptor 4 and Brain Sexual Dimorphism

There is a protein that encodes in TOLL; CD284; TLR-4; ARMD10 belongs to the Toll-like receptor family which plays a fundamental role in recognizing pathogens as well as innate immunity (Buettner, N., & Thimme, 2019). The Drosophila conserves the TLRs to human beings and also share both structural and functional similarities. They tend to recognize the molecular patterns with pathogens on infectious agents. They also mediate the production of cytokines that are necessary for development and effective immunity. The various TLRs show distinct pattern of expression (Hooper eta al., 2018). Transduction events induced by lipopolysaccharide implicates the receptor in signal transduction events found in most gram-negative bacteria. The mutations of the gene present differences in LPS responsiveness. There are also multiple transcript variants that encode different isoforms in this gene.

Sexual Differentiation of the Developing Brain

In sex determination in mammas, either male or female, relies on the presentation of Y chromosome gene (Kaidonis et al., 2018). Sry is a code for a protein called testis whose determining factor is due to its role in the testular development. When Sry is absent, like in XX persons, the potential gonad grows and becomes and ovary. The process of the gonadal differentiation takes place quickly and during the early development (Villa et al., 2016). On the other hand, other phenotypic traits associated with sex occur following gonadal development. There are other factors included in gonadal development like phenotypic sex of the brain (Lenz & McCarthy, 2015). Like the primordial gonad, is bi-potential before one becomes either female or male. For a period of 5 decades, scientists have investigated factors such as origins, mechanisms, as well as the impact of sexual differentiation of the brain and established fundamental principles.

Gonadal Steroids in Males Masculinize

According to research, indicates that gonadal steroids in males makes the brain masculine in the early developmental stages and the male becomes active my mid late gestation period except for spermatogenesis (Kaidonis et al., 2018). When it comes to rodents, it appears that there is a surge in fetal testis androgen production that begins in the last few days of gestation and endures shortly after birth. In primates, the production of androgen takes place earlier from the closing of the first trimester and into second with another surge at birth. After gaining access to the brain, testosterone T goes through either aromatization to estradiol (E2) or 5-α reduces to dihyrdotestosterone (DHT). There is inducement of masculine endpoints by both T and DHT (Buettner, N., & Thimme, 2019). However, but it is E2 that acts as the main the dominant masculinizing hormone in the rodent brain.

The gender based differences in the incidence as well as the severity of bacterial sepsis makes the male individuals to be more susceptible to septic shock as opposed to the females (Villa et al., 2016). Nonetheless, the mechanisms that call for this sexual dimorphism are not clear. Studies confirm that males produce more inflammatory cytokine IL-6 and acute phase protein LPS-binding protein (LBP) than females after vivo lipopolysaccharide (LPS) exposure.  According to verification, show that LPS-challenged from male macrophages have higher levels of IL-1beta and lower levels of PGE(2) than other treated female derived cells in the same way (Lenz & McCarthy, 2015).  It is important to note that the male-derived macrophages produce a considerable amount of inflammatory chemokine IP-10  after LPS challenge their female counterparts.

The confirmation of the critical role of E2 in the brain masculinization comes from different sources. There are studies where newborn females are masculinized through treatment by using exogenous hormones to copy the levels that males experiences. In studies where males fail to masculinize due to the ablation of estrogen receptors. According to the naturally occurring masculinization process in males, one can prevent the process through treatment by using inhibitors of aromatase enzyme or antagonists of the estrogen receptor (ER) (Buettner, N., & Thimme, 2019). It is significant to note that in both males and females the treatment must take place in a narrowly defined critical or sensitive period. The period marks the beginning of onset androgen production by the fetal testis and ends at the time in which the exogenous treatments lose their effectiveness by either inducing or preventing the process of masculinization. I rodents, it marks the end of the first week of life. When it comes to primates like human beings, the sensitive period is mostly during prenatal

Early Life Programming Permanently Alters Brain and Behavior

Gonadal steroids actions during the perinatal sensitive period are organizational but significant in the programing life in the early stages (Hooper eta al., 2018). As compared to nutritional status, trauma, or stress, can influence the sensitivity of the adults permanently when it comes to various challenges. The early hormone exposure determines the sensitivity of the adult brain to additional hormone that takes place after puberty (Klein & Flanagan, 2016). However, for instance in this case, the aim is that the adult hormone exposure matches with the conditions perinatal. As such, high testosterone hormone in adult male is a catalyst for male reproductive physiology- the pulsatile luteinizing hormone release (Lenz & McCarthy, 2015). Similarly, the development of feminized brains reacts to cyclical changes in estrogen and Progestins in the adult stage with female reproductive physiology such as ovulation and inducing luteinizing hormone surges and behavior (Lenz & McCarthy, 2015). if the profile of the adult hormone profile does nit balance with the perinatal profile, the animal will be blind to the inducing effects of the hormones.

According to research, the masculinization of sexual behavior in the rodent has provided a high value for mode system when it comes to investigating early life programming effects of gonadal steroids (Lenz & McCarthy, 2015). We are aware that periotic area-POA is a critical brain area responsible for male sexual behavior and has marked neuroanatomical sex differences. These have a much larger dimorphic nucleus that is more stellate as well as ramified astrocytes. It is also twice as great in density of the dendritic spine as observed in the female POA (Hooper eta al., 2018). The Elucidating mechanism in which steroids use to balance neuronal cell death astrocyte differentiation as well as synaptogenesis has more value than just the sexual differentiation of reproductive behavior and it also produces fundamental principles in brain development.

In conclusion, according to research, there is an original role for microglia in regulating synaptic pattering selectively in primate males and females. This demonstrates that despite resting macrophage levels of mRNA encoding Toll-like receptor 4(TLR4) as well as it co-receptor CD14 are not far apart in differences between genders. When looking at the male-derived macrophages surface cells, show higher levels of the protein. They tend to elevate circulating levels of LBP as well as constitute higher cell surface expression of TLR4 and CD14 ON macrophages in males. As a result, they could cause sexual dimorphism in LPS induced inflammatory mediator production as well as greater susceptibility of males when it comes to bacterial sepsis.


Buettner, N., & Thimme, R. (2019, March). Sexual dimorphism in hepatitis B and C and 

hepatocellular carcinoma. In Seminars in immunopathology (Vol. 41, No. 2, pp. 203-211). Springer Berlin Heidelberg.

Cowell, W. J., & Wright, R. J. (2017). Sex-specific effects of combined exposure to chemical 

and non-chemical stressors on neuroendocrine development: a review of recent findings and putative mechanisms. Current environmental health reports4(4), 415-425.

Hooper, M. J., Wang, J., Browning, R., & Ash, J. D. (2018). Damage-associated molecular 

pattern recognition is required for induction of retinal neuroprotective pathways in a sex-dependent manner. Scientific reports8(1), 9115.

Kaidonis, G., Rao, A. N., Ouyang, Y. B., & Stary, C. M. (2018). Elucidating sex differences in 

response to cerebral ischemia: immunoregulatory mechanisms and the role of microRNAs. Progress in neurobiology.

Klein, S. L., & Flanagan, K. L. (2016). Sex differences in immune responses. Nature Reviews 

Immunology16(10), 626.

Lenz, K. M., & McCarthy, M. M. (2015). A starring role for microglia in brain sex 

differences. The Neuroscientist21(3), 306-321.

Villa, A., Vegeto, E., Poletti, A., & Maggi, A. (2016). Estrogens, neuroinflammation, and 

neurodegeneration. Endocrine reviews37(4), 372-402.

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