Sperm thermotaxis is a form of sperm guidance, in which

sperm cell Sperm (: sperm or sperms) is the male reproductive cell, or gamete, in anisogamous forms of sexual reproduction (forms in which there is a larger, female reproductive cell and a smaller, male one). Animals produce motile sperm with a tail k ...

s (spermatozoa) actively change their swimming direction according to a temperature gradient, swimming up the gradient. Thus far this process has been discovered in

mammals A mammal () is a vertebrate animal of the class Mammalia (). Mammals are characterised by the presence of milk-producing mammary glands for feeding their young, a broad neocortex region of the brain, fur or hair, and three middle e ...

only.

Background

The discovery of mammalian

sperm chemotaxis Sperm chemotaxis is a form of sperm guidance, in which sperm cells (spermatozoa) follow a concentration gradient of a chemoattractant secreted from the oocyte and thereby reach the oocyte. Background Since the discovery of sperm attraction to the ...

and the realization that it can guide spermatozoa for short distances only, estimated at the order of millimeters,Pérez-Cerezales, S., Boryshpolets, S. and Eisenbach, M. (2015) ''Behavioral mechanisms of mammalian sperm guidance''. Asian J. Androl. 17, 628-632. triggered a search for potential long-range guidance mechanisms. The findings that, at least in rabbits and pigs, a temperature difference exists within the

oviduct The oviduct in vertebrates is the passageway from an ovary. In human females, this is more usually known as the fallopian tube. The eggs travel along the oviduct. These eggs will either be fertilized by spermatozoa to become a zygote, or will dege ...

, and that this temperature difference is established at

ovulation Ovulation is an important part of the menstrual cycle in female vertebrates where the egg cells are released from the ovaries as part of the ovarian cycle. In female humans ovulation typically occurs near the midpoint in the menstrual cycle and ...

in rabbits due to a temperature drop in the oviduct near the junction with the

uterus The uterus (from Latin ''uterus'', : uteri or uteruses) or womb () is the hollow organ, organ in the reproductive system of most female mammals, including humans, that accommodates the embryonic development, embryonic and prenatal development, f ...

, creating a temperature gradient between the sperm storage site and the fertilization site in the oviduct (Figure 1), led to investigation whether mammalian spermatozoa can respond to a temperature

gradient In vector calculus, the gradient of a scalar-valued differentiable function f of several variables is the vector field (or vector-valued function) \nabla f whose value at a point p gives the direction and the rate of fastest increase. The g ...

by thermotaxis.Bahat, A., Tur-Kaspa, I., Gakamsky, A., Giojalas, L. C., Breitbart, H. and Eisenbach, M. (2003) ''Thermotaxis of mammalian sperm cells: A potential navigation mechanism in the female genital tract.'' Nature Med. 9, 149-150.

Establishing sperm thermotaxis as an active process

Mammalian sperm thermotaxis was, hitherto, demonstrated in three species: humans, rabbits, and mice.Pérez-Cerezales, S., Boryshpolets, S., Afanzar, O., Brandis, A., Nevo, R., Kiss, V. and Eisenbach, M. (2015) ''Involvement of opsins in mammalian sperm thermotaxis.'' Sci. Rep. 5, 16146. This was done by two methods. One involved a Zigmond chamber, modified to make the temperature in each well separately controllable and measurable. A linear temperature gradient was established between the wells and the swimming of spermatozoa in this gradient was analyzed. A small fraction of the spermatozoa (at the order of ~10%), shown to be the capacitated cells, biased their swimming direction according to the gradient, moving towards the warmer temperature. The other method involved twoBahat, A. and Eisenbach, M. (2010) ''Human sperm thermotaxis is mediated by phospholipase C and inositol trisphosphate receptor Ca²⁺ channel''. Biol. Reprod. 82, 606-616.Bahat, A., Caplan, S.R. and Eisenbach, M. (2012) ''Thermotaxis of human sperm cells in extraordinarily shallow temperature gradients over a wide range''. PLoS ONE 7, e41915.- or three-compartment separation tube placed within a thermoseparation device that maintains a linear temperature gradient. Sperm accumulation at the warmer end of the separation tube was much higher than the accumulation at the same temperature but in the absence of a temperature gradient. This gradient-dependent sperm accumulation was observed over a wide temperature range (29-41 °C). Since temperature affects almost every process, much attention has been devoted to the question of whether the measurements, mentioned just above, truly demonstrate thermotaxis or whether they reflect another temperature-dependent process. The most pronounced effect of temperature in liquid is convection, which raised the concern that the apparent thermotactic response could have been a reflection of a passive drift in the liquid current or a rheotactic responseMiki K. and Clapham, D. E. (2013) ''Rheotaxis guides mammalian sperm''. Curr. Biol. 23, 443-452. to the current (rather than to the temperature gradient per se). Another concern was that the temperature could have changed the local pH of the

buffer solution A buffer solution is a solution where the pH does not change significantly on dilution or if an acid or base is added at constant temperature. Its pH changes very little when a small amount of strong acid or base is added to it. Buffer solution ...

in which the spermatozoa are suspended. This could generate a pH gradient along the temperature gradient, and the spermatozoa might have responded to the formed pH gradient by chemotaxis. However, careful experimental examinations of all these possibilities with proper controls demonstrated that the measured responses to temperature are true thermotactic responses and that they are not a reflection of any other temperature-sensitive process, including rheotaxis and chemotaxis.

Behavioral mechanism of mammalian sperm thermotaxis

The behavioral mechanism of sperm thermotaxis has been so far only investigated in human spermatozoa.Boryshpolets, S., Pérez-Cerezales, S. and Eisenbach, M. (2015) ''Behavioral mechanism of human sperm in thermotaxis — a role for hyperactivation.'' Hum. Reprod. 30, 884-892. Like the behavioral mechanisms of bacterial chemotaxis and human

,Armon, L. and Eisenbach, M. (2011) ''Behavioral mechanism during human sperm chemotaxis: Involvement of hyperactivation.'' PLoS ONE 6, e28359. the behavioral mechanism of human sperm thermotaxis appears to be stochastic rather than deterministic. Capacitated human spermatozoa swim in rather straight lines interrupted by turns and brief episodes of

hyperactivation Hyperactivation is a type of sperm motility. Hyperactivated sperm motility is characterised by a high amplitude, asymmetrical beating pattern of the sperm tail (flagellum). This type of motility may aid in sperm penetration of the zona pellucida ...

. Each such episode results in swimming in a new direction. When the spermatozoa sense a decrease in temperature, the frequency of turns and hyperactivation events increases due to increased flagellar-wave amplitude that results in enhanced side-to-side head displacement. With time, this response undergoes partial adaptation. The opposite happens in response to an increase in temperature. This suggests that when capacitated spermatozoa swim up a temperature gradient, turns are repressed and the spermatozoa continue swimming in the gradient direction. When they happen to swim down the gradient, they turn again and again until their swimming direction is again up the gradient.

Temperature sensing

The response of spermatozoa to temporal temperature changes even when the temperature is kept constant spatially suggests that, as in the case of human sperm chemotaxis,Gakamsky, A., Armon, L. and Eisenbach, M. (2009) ''Behavioral response of human spermatozoa to a concentration jump of chemoattractants or intracellular cyclic nucleotides.'' Hum. Reprod. 24, 1152-1163. sperm thermotaxis involves temporal gradient sensing. In other words, spermatozoa apparently compare the temperature (or a temperature-dependent function) between consecutive time points. This, however, does not exclude the occurrence of spatial temperature sensing in addition to temporal sensing. Human

spermatozoa A spermatozoon (; also spelled spermatozoön; : spermatozoa; ) is a motile sperm cell (biology), cell produced by male animals relying on internal fertilization. A spermatozoon is a moving form of the ploidy, haploid cell (biology), cell that is ...

can respond thermotactically within a wide temperature range (at least 29–41 °C). Within this range they preferentially accumulate in warmer temperatures rather than at a single specific, preferred temperature. Amazingly, they can sense and thermotactically respond to temperature gradients as low as <0.014 °C/mm. This means that when human spermatozoa swim a distance that equals their body length (~46 μm) they respond to a temperature difference of <0.0006 °C!

Molecular mechanism

The molecular mechanism underlying thermotaxis, in general, and thermosensing with such extreme sensitivity, in particular, is obscure. It is known that, unlike other recognized thermosensors in mammals, the thermosensors for sperm thermotaxis do not seem to be temperature-sensitive

ion channel Ion channels are pore-forming membrane proteins that allow ions to pass through the channel pore. Their functions include establishing a resting membrane potential, shaping action potentials and other electrical signals by Gating (electrophysiol ...

s. They are rather

opsin Animal opsins are G-protein-coupled receptors and a group of proteins made light-sensitive via a chromophore, typically retinal. When bound to retinal, opsins become retinylidene proteins, but are usually still called opsins regardless. Most pro ...

s, known to be

G-protein-coupled receptor G protein-coupled receptors (GPCRs), also known as seven-(pass)-transmembrane domain receptors, 7TM receptors, heptahelical receptors, serpentine receptors, and G protein-linked receptors (GPLR), form a large protein family, group of evoluti ...

s that act as photosensors in

vision Vision, Visions, or The Vision may refer to: Perception Optical perception * Visual perception, the sense of sight * Visual system, the physical mechanism of eyesight * Computer vision, a field dealing with how computers can be made to gain und ...

. The opsins are present in spermatozoa at specific sites, which depend on the species and the opsin type. They are involved in sperm thermotaxis via two signaling pathways—a

phospholipase C Phospholipase C (PLC) is a class of membrane-associated enzymes that cleave phospholipids just before the phosphate group (see figure). It is most commonly taken to be synonymous with the human forms of this enzyme, which play an important role i ...

signaling pathway and a cyclic-nucleotide pathway. The former was shown by pharmacological means in human spermatozoa to involve the enzyme phospholipase C, an

inositol trisphosphate receptor Inositol trisphosphate receptor (InsP3R) is a membrane glycoprotein complex acting as a Ca2+ channel activated by inositol trisphosphate (InsP3). InsP3R is very diverse among organisms, and is necessary for the control of cellular and physi ...

calcium channel A calcium channel is an ion channel which shows selective permeability to calcium ions. It is sometimes synonymous with voltage-gated calcium channel, which are a type of calcium channel regulated by changes in membrane potential. Some calcium chan ...

located on internal

calcium Calcium is a chemical element; it has symbol Ca and atomic number 20. As an alkaline earth metal, calcium is a reactive metal that forms a dark oxide-nitride layer when exposed to air. Its physical and chemical properties are most similar to it ...

stores, the

TRPC3 Short transient receptor potential channel 3 (TrpC3) also known as transient receptor protein 3 (TRP-3) is a protein that in humans is encoded by the TRPC3 gene. The TRPC3/6/7 subfamily are implicated in the regulation of vascular tone, cell grow ...

, and intracellular calcium. The latter was hitherto shown to involve

phosphodiesterase A phosphodiesterase (PDE) is an enzyme that breaks a phosphodiester bond. Usually, ''phosphodiesterase'' refers to cyclic nucleotide phosphodiesterases, which have great clinical significance and are described below. However, there are many oth ...

. Blocking both pathways fully inhibits sperm thermotaxis.

References

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External links

Semenax Clinical Study Results
Semen Cell biology