Bruce effect

The Bruce effect, or pregnancy block,^[1]^[2] is the tendency for female rodents to terminate their pregnancies following exposure to the scent of an unfamiliar male.^[3] The effect was first noted in 1959 by Hilda M. Bruce,^[4] and has primarily been studied in laboratory mice (Mus musculus).^[1] In mice, pregnancy can only be terminated prior to embryo implantation, but other species will interrupt even a late-term pregnancy.^[5]

The Bruce effect is also observed in deer-mice,^[6] meadow voles,^[7] collared lemmings,^[8] and it has also been proposed, but not confirmed, in other non-rodent species such as lions^[9] and geladas.^[10]

Discovery

In an experiment published in 1959, zoologist Hilda Bruce of the National Institute for Medical Research in London housed pregnant mice with male mice that were not the father of the carried embryo. As a result, the rate of miscarriages increased, followed by mating with the new male. No increased rate of miscarriages occurred when pregnant mice were paired with castrated or juvenile male mice.^[4]^[11]^[12] The effect remained when the male mice were kept out of sight or hearing of the females. This suggested that females were distinguishing the males by smell. To test this hypothesis, Bruce and her colleague Alan Parkes recruited perfumers to smell pieces of cloth from the mouse cages. The perfumers could distinguish the smells of different mouse strains.^[11]

Mechanisms of action

Detection of pheromones

The vomeronasal system serves as a "vascular pump" that, stimulated by the presence of a novel male, actively draws in substances.^[13] Male mouse urine contains MHC class I peptides that bind to receptors in the female's vomeronasal organ,^[3]^[14] a mucus-filled structure in the nasal septum.^[15] These chemical signals, which are specific to each male, are learned by the female during mating,^[16] or shortly after.^[3] The hormone vasopressin is crucial in coupling a chemosensory cue with an appropriate physiological response. When the vasopressin 1b receptor gene is knocked out in females, the presence of an unfamiliar male does not trigger pregnancy disruption.^[17]

Recognizing familiar males

Exposure to a male's urinal pheromones will activate a neuroendocrine pathway leading to pregnancy failure. However, if the pheromones correspond with those memorized by the female (usually the male mating partner), a release of noradrenaline will lower the receptivity of the accessory olfactory bulb to these pheromones.^[16] The pregnancy disruption will, thus, be averted. This role for noradrenaline has recently been called into question.^[15] The hormone oxytocin is also important in this social memory process. Females treated with an oxytocin antagonist are unable to recognize the urinary scent of their mate, and will terminate pregnancy when exposed to any male, known or unknown.^[18]

Neuroendocrine pathway

The activation of vomeronasal neuron receptors by male pheromones triggers a complex neuroendocrine pathway. The pheromonal information travels via nerves to the accessory olfactory bulb, and then to the corticomedial amygdala, accessory olfactory tract, and stria terminalis.^[15] These areas stimulate the hypothalamus to increase the release of dopamine,^[15]^[19] which thus prevents the secretion of prolactin from the anterior pituitary.^[3] In the absence of prolactin, an essential hormone for maintaining the corpus luteum, luteolysis takes place.^[3] As the corpus luteum can no longer release progesterone, the uterus remains unprimed for embryo implantation, and the pregnancy fails.^[19]

Role of estrogens

Androgens and estrogens, particularly estradiol (E2), are also crucial chemosignals regulating the Bruce effect.^[13] However, they are believed to act via a separate pathway to that discussed above. Small steroid molecules such as E2 can enter the bloodstream directly via nasal ingestion^[13] and travel to the uterus, which has a high density of suitable receptors. Normally, E2 is essential in preparing both the blastocyst and uterus for implantation. However, excessive E2 will prevent implantation from taking place.^[20]^[21] Castrated males are incapable of terminating female pregnancies,^[22] except when castrated males are given testosterone.^[13] estradiol, a metabolic product of testosterone, is known to disrupt pregnancy in females,^[13] and is present in male urine.

Timing

The incidence of the Bruce effect depends on the timing of pheromone exposure. Post-mating, females experience twice-daily surges of prolactin.^[3] Pregnancy is only terminated if exposure to novel male scent coincides with two prolactin surges, one of these occurring in a daylight period.^[19]

Evolutionary benefits

In order to have evolved and persisted in the population, the Bruce effect must afford individuals a fitness advantage.^[3] The possible advantages of pregnancy block are widely debated.

Males

When given the opportunity, male mice tend to direct their urine in the female's direction.^[23] This allows males to improve their fitness success by "sabotaging" the pregnancy of a male competitor,^[3] and more quickly returning the female to estrus.^[24] The Bruce effect can also aid in maintaining social status, with dominant males leaving more urinal scent markings,^[25] and so blocking the pregnancies initiated by subordinate males.

Females

Females can control their likelihood of terminating pregnancy by pursuing or avoiding novel male contact during their most susceptible periods.^[26] In this way, females can exert a post-copulatory mate choice, reserving their reproductive resources for the highest-quality male. Certainly, females are more likely to seek proximity to dominant males.^[26] In many rodent species, males kill unrelated young; pregnancy block may avoid the wasted investment of gestating offspring likely to be killed at birth.^[5]^[27] The Bruce effect is most common in polygynous rodent species, for which the risk of infanticide is highest.^[28]

References

^ ^a ^b Heske, E. J.; Nelson, RJ (1984). "Pregnancy interruption in Microtus ochrogaster: Laboratory artifact or field phenomenon?". Biology of Reproduction. 31 (1): 97–103. doi:10.1095/biolreprod31.1.97. PMID 6380603.
^ Hofmann, J. E.; Getz, L. L.; Gavish, L. (1987). "Effect of Multiple Short-Term Exposures of Pregnant Microtus ochrogaster to Strange Males". Journal of Mammalogy. 68 (1): 166–169. doi:10.2307/1381067. JSTOR 1381067.
^ ^a ^b ^c ^d ^e ^f ^g ^h Becker, Stuart D.; Hurst, Jane L. (2008). "Pregnancy Block from a Female Perspective". Chemical Signals in Vertebrates 11. Vol. 11. pp. 141–50. doi:10.1007/978-0-387-73945-8_13. ISBN 978-0-387-73944-1. {{cite book}}: |journal= ignored (help)
^ ^a ^b Bruce, Hilda M. (1959). "An Exteroceptive Block to Pregnancy in the Mouse". Nature. 184 (4680): 105. Bibcode:1959Natur.184..105B. doi:10.1038/184105a0. PMID 13805128. S2CID 4200823.
^ ^a ^b Labov, J. B. (1981). "Pregnancy Blocking in Rodents: Adaptive Advantages for Females". The American Naturalist. 118 (3): 361–371. doi:10.1086/283828. JSTOR 2460637. S2CID 85020158.
^ Eleftheriou, Basil E.; Bronson, F. H.; Zarrow, M. X. (1962). "Interaction of Olfactory and Other Environmental Stimuli on Implantation in the Deer Mouse". Science. 137 (3532): 764. Bibcode:1962Sci...137..764E. doi:10.1126/science.137.3532.764. PMID 13889805. S2CID 42871324.
^ Clulow, F. V.; Langford, P. E. (1971). "Pregnancy-Block in the Meadow Vole, Microtus Pennsylvanicus". Reproduction. 24 (2): 275–7. doi:10.1530/jrf.0.0240275. PMID 5551417.
^ MALLORY, F. F. (1980). "Infanticide and Pregnancy Failure: Reproductive Strategies in the Female Collared Lemming (Dicrostonyx groenlandicus)". Biology of Reproduction. 22 (2): 192–6. doi:10.1095/biolreprod22.2.192. PMID 7378528.
^ Packer, C.; Pusey, A. E. (1983). "Adaptations of Female Lions to Infanticide by Incoming Males". The American Naturalist. 121 (5): 716–728. doi:10.1086/284097. JSTOR 2460874. S2CID 84927815.
^ Eila K. Roberts; Amy Lu; Thore J. Bergman; Jacinta C. Beehner (2012). "A Bruce Effect in Wild Geladas". Science. 335 (6073): 1222–1225. Bibcode:2012Sci...335.1222R. doi:10.1126/science.1213600. PMID 22362878. S2CID 34095168.
^ ^a ^b MRC National Institute for Medical Research (2014). A Century of Science and Health. MRC National Institute for Medical Research. p. 208.
^ Carlson, Neil R. (2013). Physiology of behavior (11th ed.). Boston: Pearson. p. 335. ISBN 978-0205239399.
^ ^a ^b ^c ^d ^e Guzzo, A. C; Berger, R. G; Decatanzaro, D. (2009). "Excretion and binding of tritium-labelled oestradiol in mice (Mus musculus): Implications for the Bruce effect". Reproduction. 139 (1): 255–63. doi:10.1530/REP-09-0382. PMID 19793839.
^ Zufall, Frank; Leinders-Zufall, Trese (2007). "Mammalian pheromone sensing". Current Opinion in Neurobiology. 17 (4): 483–9. doi:10.1016/j.conb.2007.07.012. PMID 17709238. S2CID 36527505.
^ ^a ^b ^c ^d Brennan, Peter A. (2009). "Outstanding issues surrounding vomeronasal mechanisms of pregnancy block and individual recognition in mice". Behavioural Brain Research. 200 (2): 287–94. doi:10.1016/j.bbr.2008.10.045. PMID 19071163. S2CID 7946709.
^ ^a ^b Brennan, Peter A.; Zufall, Frank (2006). "Pheromonal communication in vertebrates". Nature. 444 (7117): 308–15. Bibcode:2006Natur.444..308B. doi:10.1038/nature05404. PMID 17108955. S2CID 4431624.
^ Wersinger, S. R.; Temple, J. L.; Caldwell, H. K.; Young, W. S. (2007). "Inactivation of the Oxytocin and the Vasopressin (Avp) 1b Receptor Genes, but Not the Avp 1a Receptor Gene, Differentially Impairs the Bruce Effect in Laboratory Mice (Mus musculus)". Endocrinology. 149 (1): 116–21. doi:10.1210/en.2007-1056. PMC 2194605. PMID 17947352.
^ Neumann, I. D. (2008). "Brain Oxytocin: A Key Regulator of Emotional and Social Behaviors in Both Females and Males". Journal of Neuroendocrinology. 20 (6): 858–65. doi:10.1111/j.1365-2826.2008.01726.x. PMID 18601710.
^ ^a ^b ^c Rosser, A. E.; Remfry, C. J.; Keverne, E. B. (1989). "Restricted exposure of mice to primer pheromones coincident with prolactin surges blocks pregnancy by changing hypothalamic dopamine release". Reproduction. 87 (2): 553–9. doi:10.1530/jrf.0.0870553. PMID 2513390.
^ Valbuena, Diana; Martin, Julio; De Pablo, Jose Luis; Remohí, José; Pellicer, Antonio; Simón, Carlos (2001). "Increasing levels of estradiol are deleterious to embryonic implantation because they directly affect the embryo". Fertility and Sterility. 76 (5): 962–8. doi:10.1016/S0015-0282(01)02018-0. PMID 11704118.
^ Ma, W.-g.; Song, H; Das, SK; Paria, BC; Dey, SK (2003). "Estrogen is a critical determinant that specifies the duration of the window of uterine receptivity for implantation". Proceedings of the National Academy of Sciences. 100 (5): 2963–8. Bibcode:2003PNAS..100.2963M. doi:10.1073/pnas.0530162100. PMC 151449. PMID 12601161.
^ Bruce, H. M. (1965). "Effect of Castration on the Reproductive Pheromones of Male Mice". Reproduction. 10 (1): 141–3. CiteSeerX 10.1.1.485.8060. doi:10.1530/jrf.0.0100141. PMID 14337805.
^ Decatanzaro, Denys; Khan, Ayesha; Berger, Robert G.; Lewis, Elaine (2009). "Exposure to developing females induces polyuria, polydipsia, and altered urinary levels of creatinine, 17β-estradiol, and testosterone in adult male mice (Mus musculus)". Hormones and Behavior. 55 (1): 240–7. doi:10.1016/j.yhbeh.2008.10.013. PMID 19027019. S2CID 39461569.
^ Huck, U. W. (1982). "Pregnancy block in laboratory mice as a function of male social status". Reproduction. 66 (1): 181–4. doi:10.1530/jrf.0.0660181. PMID 7120182.
^ Desjardins, Claude; Maruniak, J. A.; Bronson, F. H. (1973). "Social Rank in House Mice: Differentiation Revealed by Ultraviolet Visualization of Urinary Marking Patterns". Science. 182 (115): 939–41. Bibcode:1973Sci...182..939D. doi:10.1126/science.182.4115.939. PMID 4745598. S2CID 44346136.
^ ^a ^b Becker, S. D; Hurst, J. L (2009). "Female behaviour plays a critical role in controlling murine pregnancy block". Proceedings of the Royal Society B: Biological Sciences. 276 (1662): 1723–9. doi:10.1098/rspb.2008.1780. PMC 2660991. PMID 19324836.
^ Schwagmeyer, P. L. (1979). "The Bruce Effect: An Evaluation of Male/Female Advantages". The American Naturalist. 114 (6): 932–938. doi:10.1086/283541. JSTOR 2460564. S2CID 85097151.
^ Pillay, Neville A.; Kinahan, Anouska A. (2009). "Mating strategy predicts the occurrence of the Bruce effect in the vlei rat Otomys irroratus". Behaviour. 146 (1): 139–51. doi:10.1163/156853908X390968.