Prenatal Allergen Exposure Perturbs Sexual Differentiation and Programs Lifelong Changes in Adult Social and Sexual Behavior

期刊：

作者：Kathryn M. Lenz, Lindsay A. Pickett, Christopher L. Wright, Anabel Galan, Margaret M. McCarthy

发表时间：2019/03/18

数字识别码： 10.1038/s41598-019-41258-2

原文链接：

Sexual differentiation of the rodent brain occurs during a narrow developmental window that begins prenatally and extends into the early postnatal period. During this “critical period” males are exposed to high levels of androgens that are derived from the testes, and these androgens are converted to estrogens in the brain and subsequently direct brain development in a male-typical pattern1. In the absence of steroid hormones, the brain develops in a female-typical pattern. Sex differences in brain development prepare the brain to direct sex-specific behavioral repertoires necessary for successful reproduction. The preoptic area (POA) is a brain region responsible for both the motivational and consummatory aspects of male sexual behavior2. Our lab and others have focused on how perinatal hormone exposure leads to male-typical development of the POA in rats. Several of the downstream effectors of hormonally-driven sexual differentiation have been identified, and one of the key players of this process is the brain’s immune system3.

Microglia, the primary resident immune cells of the brain, are both targets and effectors of the sexual differentiation process. Males have twice the number of ameboid-shaped microglia in the POA as a result of estradiol exposure in early life4. This higher microglia load leads to higher levels of the pro-inflammatory lipid, prostaglandin E2 (PGE2) in the male compared to the female POA4. PGE2 in turn is responsible for establishing a higher density of dendritic spine synapses in the developing male POA5 which persist into adulthood and positively correlate with the display of male copulatory behavior6. We have recently discovered that another innate immune cell type within the brain, the mast cell, is also a target and effector of sexual differentiation7.

Mast cells are tissue resident granulocytic innate immune cells that are activated by exposure to allergens8. They are distributed throughout the body, mostly at interfaces, but also reside in the brain. They are found inside the blood-brain-barrier but typically cluster at the meninges9. We have found that mast cells are more numerous and more activated within the neuropil of male rat POA during perinatal brain development, and that estradiol acts directly on these mast cells to stimulate the release of histamine7. This histamine is in turn sufficient to activate neighboring microglia and set off the cascade of microglia activation and production of PGE2 that drives male-typical dendritic spine patterning in the POA. In this way, the immune system is indispensable for brain sexual differentiation. In females, pharmacologically activating mast cells leads to masculinization of dendritic spine patterning in the POA as well as the masculinization of copulatory behavior7, suggesting that mast cell activation via non-pharmacological means could shift female sexual development toward a masculinized phenotype.

During this same critical period for brain sexual differentiation, perinatal exposure to many perturbations can independently alter the trajectory of brain development by activating immune cells in the brain. These include stress, infection, inflammation, over or undernutrition, or hypoxia. Maternal conditions or illnesses, such as bacterial and viral infections, preeclampsia, autoimmune disorders, asthma, or allergies, can similarly shape offspring brain and behavioral development10,11,12. But to date, the effects of such early life inflammatory perturbations on sexual differentiation and the establishment of sex differences in brain and behavior have not been explored. Given that our previous studies have indicated that mast cells and microglia are integral to sexual differentiation, we sought to determine whether this essential developmental process is sensitive to prenatal allergic inflammation. We report herein that allergic challenge of pregnant dams impacted the sexual differentiation of both the male and female POA, inducing masculinized brain and behavioral development in female offspring while also dysmasculinizing brain and behavioral development in male offspring.

摘要：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. We 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, specifically organizing the synaptic development of the preoptic area and leading to male-typical sexual behavior in adulthood. Mast cells are known for their roles in allergic responses, thus in this study we sought to determine if exposure to an allergic response of the pregnant female in utero would alter the sexual differentiation of the preoptic area of offspring and resulting sociosexual behavior in later life. Pregnant rats were sensitized to ovalbumin (OVA), bred, and challenged intranasally 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 cell and microglia activation within their brains, downstream dendritic spine patterning on POA neurons, or grown to adulthood to assess behavior and dendritic spines. In utero exposure to allergic inflammation increased mast cell and microglia activation in the neonatal brain, and led to masculinization of dendritic spine density in the female POA. In adulthood, OVA-exposed females showed an increase in male-typical mounting behavior relative to control females. In contrast, OVA-exposed males showed evidence of dysmasculinization, including reduced microglia activation, reduced neonatal dendritic spine density, decreased male-typical copulatory behavior, and decreased olfactory preference for female-typical cues. Together these studies show that early life allergic events may contribute to natural variations in both male and female sexual behavior, potentially via underlying effects on brain-resident mast cells.

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