Female Mice Deficient in Alpha-Fetoprotein Show Female-Typical Neural Responses to Conspecific-Derived Pheromones

Abstract

The neural mechanisms controlling sexual behavior are sexually differentiated by the perinatal actions of sex steroid hormones. We recently observed using female mice deficient in alpha-fetoprotein (AFP-KO) and which lack the protective actions of AFP against maternal estradiol, that exposure to prenatal estradiol completely defeminized the potential to show lordosis behavior in adulthood. Furthermore, AFP-KO females failed to show any male-directed mate preferences following treatment with estradiol and progesterone, indicating a reduced sexual motivation to seek out the male. In the present study, we asked whether neural responses to male- and female-derived odors are also affected in AFP-KO female mice. Therefore, we compared patterns of Fos, the protein product of the immediate early gene, c-fos, commonly used as a marker of neuronal activation, between wild-type (WT) and AFP-KO female mice following exposure to male or estrous female urine. We also tested WT males to confirm the previously observed sex differences in neural responses to male urinary odors. Interestingly, AFP-KO females showed normal, female-like Fos responses, i.e. exposure to urinary odors from male but not estrous female mice induced equivalent levels of Fos protein in the accessory olfactory pathways (e.g. the medial part of the preoptic nucleus, the bed nucleus of the stria terminalis, the amygdala, and the lateral part of the ventromedial hypothalamic nucleus) as well as in the main olfactory pathways (e.g. the piriform cortex and the anterior cortical amygdaloid nucleus), as WT females. By contrast, WT males did not show any significant induction of Fos protein in these brain areas upon exposure to either male or estrous female urinary odors. These results thus suggest that prenatal estradiol is not involved in the sexual differentiation of neural Fos responses to male-derived odors.

Absence of Female-Typical Pheromone-Induced Hypothalamic Neural Responses and Kisspeptin Neuronal Activity in α-Fetoprotein Knockout Female Mice

“…Finally, our results are in contrast with a previous study in our lab evaluating the central responses of female AfpKO after exposure to male urine (33). In the Brock et al study (33), a normal, female-typical Fos response to male odors was observed in the main and accessory olfactory pathways of AfpKO females.…”

“…In the Brock et al study (33), a normal, female-typical Fos response to male odors was observed in the main and accessory olfactory pathways of AfpKO females. The type of olfactory stimulation used might explain the discrepancy between the previous (33) and the current study.…”

“…The type of olfactory stimulation used might explain the discrepancy between the previous (33) and the current study. Brock et al (33) applied urine (from intact male or estrous female) directly onto the nose, whereas in the present study, we exposed the experimental subjects to bedding soiled by intact males or estrous females. Although mouse urine seemed to be the major source of pheromones in mice, other natural sources of pheromones exist, such as the extraorbital lacrimal gland, which secrete and release potential pheromonal compounds in tears (34).…”

Cyp1b1 deletion and retinol deficiency coordinately suppress mouse liver lipogenic genes and hepcidin expression during post-natal development

“…R-Cyp1b1−/− responses that are not retained from the normal Cyp1b1−/− mice are highlighted by large increases in Afp and Igf2 . Each response may be functionally important since Afp sequesters estradiol (Brock et al, 2012), a potential substrate for Cyp1b1 , while Igf2 replaces Igf1 during early development (Lee et al, 2014). …”

Cyp1b1 affects external control of mouse hepatocytes, fatty acid homeostasis and signaling involving HNF4α and PPARα

“…The loss of Afp between birth and weaning is also appreciably delayed leading to extensive perinatal expression. Afp sequesters estradiol and potentially diminishes perinatal effects of estradiol on development [56]. …”