Sexual differentiation is the early life process by which the brain is prepared for male or female typical behaviors, and is directed by sex chromosomes, hormones and early life experiences. Scientists have recently found that innate immune cells residing in the brain, including microglia and mast cells, are more numerous in the male than female rat brain. Neuroimmune cells are also key participants in the sexual differentiation process. A single allergic reaction during pregnancy prompts sexual-development changes in the brains of offspring that last a lifetime. That is the conclusion of a new research. Female rats born to mothers exposed to an allergen during pregnancy acted more characteristically “male” – mounting other female rodents, for instance – and had brains and nervous systems that looked more like those seen in typical male animals. The male offspring also showed a tendency toward more female characteristics and behaviors, though the changes were not as significant.
Previous research has shown that insults to the immune system, including stress, infection and malnutrition, can change brain development. Sexual development occurs on a spectrum and, in and of themselves, these shifts in sexual behavior after allergy exposure are not particularly troubling. They do help researchers understand the interplay between allergensand brain development, however, and highlight that early life immune activation could be a source of normal variations in female behavior, which haven’t been as well-studied. And these types of brain changes as a response to an allergen could mean changes in other areas of concern, such as cognitive development. This new research highlights the important role allergies could play. Scientists compared the allergic reaction in the study to an asthma attack – something that prompts a more-robust immune response than low-grade seasonal allergies but less severe than an allergic attack that would require an antidote like epinephrine.
In the experiments, pregnant rats were sensitized to ovalbumin (OVA), bred and challenged intra-nasally with OVA on gestational day 15, which produced robust allergic inflammation, as measured by elevated immunoglobulin E. Offspring of these challenged mother rats were assessed relative to control rats in the early neonatal period for mast cells and microglia activation within their brains, downstream dendritic spine patterning on POA neurons, or grown to adulthood to assess behavior and dendritic spines. The study builds on Lenz’s previous work, which found changes in immune cells called microglia and mast cells in an area of the brain called the pre- optic area, a region of the hypothalamus involved in sexual behavior. According to scientists, it’s possible these changes could also contribute to things like impaired decision-making, attention and hyperactivity. Mother animals in the study were either exposed once to an allergen derived from eggs or unexposed. Then, the research team studied their pups into adulthood.
Females born to mothers that had an allergic reaction during pregnancy exhibited higher levels of behavior normally attributed to males. They mounted other females more often and were as quick to mount another female as typical male rats. They also were drawn to bedding that smelled like other females. Furthermore, they had increases in brain cells called mast cells and <strong>microglia</strong> and evidence of more synapses in the brain – changes that researchers would expect in a male rat. Males born to the allergy-exposed mothers behaved less like typical male rats. They had less interest in mounting and less interest in female bedding. The researchers also saw less activation of microglia and fewer synapses – both of which point to a change in the rats as a result of the allergen exposure that made them more like females. The study, therefore, shows for the first time that an allergic reaction in a mother could affect the sexual development of its offspring. This allergic response is enough to make the female brain look like a male’s brain, and that’s something that endures throughout its entire life.
Dr. Lenz, Kathryn Lenz, the study’s lead author and an assistant professor of Psychology at The Ohio State University, thoroughly explained: “Most of the scientific literature on immune activation during and outcomes in offspring has focused on autism and schizophrenia. This is the first time we’re seeing this kind of connection with altered sexual development. Interestingly, there’s some research out there to show an increase in gender variance and gender-identity differences in people with autism. It suggests that something about sexual development is different in people with autism. Oftentimes, we are focused on male animals because they appear to be more sensitive to environment changes and also have a higher incidence of conditions such as ADHD and autism. We often frame what we understand about the female brain and female behavior in relation to males. Study of female sexual development has just really been neglected. Even though we know there’s wide variety in girls’ and women’s behavior, we don’t really understand what contributes to those variations. Though it’s too soon to draw connections between what has been seen in the rats and human development, it may be worthwhile to explore further how medications and other factors during pregnancy may contribute to developmental changes in the fetus”.
- Edited by Dr. Gianfrancesco Cormaci, PhD, specialist in Clinical Biochemistry.
Lux H et al. Occup Environ Med. 2019; 76(4):269-278.
Barrientos RM et al. Brain Behav Immun. 2019 Mar 11.
Lenz KM et al. J Neuroscience 2018; 38(37):8044-8059.
Haim A et al. Brain Behav Immun. 2017 Jan; 59:67-78.
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