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The Impact of Testicular Hyperthermia, Its Physiological Relevance and the Ability of Antioxidants to Overcome the Condition

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Submitted:

13 September 2023

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13 September 2023

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Abstract
Testicular heat stress is a well described phenomenon that occurs in mammals that possess a scrotum. Different models to induce testicular hyperthermia, such as surgical cryptorchidism, hot water bath, scrotal insulation or increased environmental temperature have all shown that spermatocytes and spermatids are unambiguously affected by high temperature, resulting in poor sperm production weeks later. Furthermore, a body of evidence suggest the involvement of oxidative stress is either a major or contributory pathway, which gives rise to the potential to overcome this condition. Whilst experimental models conclusively show the deleterious effect of testicular heat on sperm quality, the physiological relevance of the work is still debated. Herein we summarise a cohort of studies that report the effect of “season” on sperm quality. The data show season can affect sperm production, motility and morphology depending on where the work was performed. In countries where temperatures drop below zero, there is evidence showing summer conditions tend to improve semen quality. However, in sub-tropical countries, some studies show a decrease in summer, whilst others show no change. Herein we offer a reasonable explanation for this apparent controversy and present a range of antioxidant supplements that may offer some protection against testicular hyperthermia.
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Subject: Biology and Life Sciences  -   Agricultural Science and Agronomy

Different models of testicular hyperthermia but similar outcomes.

The impact of testicular heat-stress has its origins back in 1893, when Joseph Griffiths noticed nobody had tried to “experimentally determine” the observation of John Hunters that testicles fail to reach their full size and produce sperm when retained in the abdomen (cited in 1). To understand the origin of that condition, Griffiths offered two postulates. First, the lack of testis growth was the fault of a “young-testis”, being imperfectly formed at the beginning then failing to descend and mature. Second, the main problem is not within testis but rather comes from the environment to which it is exposed. By performing unilateral surgical cryptorchidism in Fox Terriers, Griffiths noted the testis “dwindle to a considerable extent” and were incapable of producing spermatozoa after 6 months[1]. Unbeknownst at that time, this work heralded the beginning of the field of studies in testicular hyperthermia.
Since then, a diverse range of experimental models have been used, all of which confirm that spermatogenesis is a heat-sensitive process. Such models seek to do one of two things; either prevent the testis from descending to its normal position or overwhelm the ability of the scrotum to regulate testicular temperature. With regards to the latter, strategies include surgical cryptorchid models, mostly performed in laboratory animals (e.g., mice[2,3], rats[4],[5],[6]rabbits[2],[7] and non-human primates2,[8]), or wrapping the scrotum up in woollen cloths or other textile material to hold testis close to the abdomen and prevent their descent or insulation, more commonly used for domestic animals (e.g., rams[9,10,11,12] 8,9 bulls[13,14,15,16,17,18,19,20,21], boars[22], and dogs[23]). In all cases, a decline in sperm concentration, motility and normal morphology was shown. For bulls, one of the most well studied model species, a decline in semen quality begins 5-15 days post-intervention, peaking around 4 weeks later[13,14,15,16,17,18,19,20,21], suggesting that early precursor cells exposed at the time of heat were sensitive to hyperthermia.
The use of a hot-water bath[24,25,26,27,28,29,30,31,32,33,34,35] and elevated environmental temperatures[36,37,38,39,40,41,42] are examples of models to “overwhelm” the ability of the scrotum to thermoregulate. These models allows the investigation of a range of temperatures and their impact on sperm production. In the case of rabbit[37] and ram[36], increasing the ambient air temperature up to 43.3oC for one hour, showed a significant decline in sperm parameters, particularly motility[37]. When left for longer (32oC for up to one week), a significant decline in all sperm parameters (i.e., motility, morphology and counts) can be seen five weeks later[37]. Notably, semen quality begins to improve eight weeks post intervention, suggesting spermatogonia are not affected by short-term heat duration.

Testicular hyperthermia-induced oxidative stress in mice

To understand how different temperatures affect spermatogenesis, the best available models come from using hot-water baths on anesthetised mice. From this work, it is very clear that the impact on spermatogenesis is directly related to the temperature and time exposure to heat. For example, scrotal heating with water bath at 41°C, 42°C or 43°C for 30 minutes reduces sperm counts by 54%, 76% and 88% respectively[28]. Furthermore, mice that receive higher degrees of testicular hypothermia take longer to recover [28]. Notably, in this same model system, 25 min of testicular exposure to heat in mice lead to increased levels of the lipid peroxidation marker malondialdehyde, suggesting the involvement of oxidative stress[43]. What is intriguing is that whilst in some cases, testicular hypothermia leads to cell death, in other cases, some cells are able to survive and progress through the spermatogenic pathway leading to sperm production (albeit reduced amounts). How this occurs is unknown, but may involve regulation of heme oxygenase 1 (HO-1), which increases within 6 h post heat together with the antioxidant enzymes glutathione S-transferase (GPX; increases 24 h post heat) [43]. Both HO-1 and GPX are known to scavenge free radicals, thereby reducing the level of MDA and by implication, increase cell survivability. Tying into this idea, is the transcription factor, erythroid 2-realted factor 2 (Nrf2). Under normal conditions, newly synthesized Nrf2 associates with Kelch-like ECH-associated protein and is then degraded through the ubiquitin proteosome pathway[44]. However, the presence of excess free radicals, nitric oxide, zinc and alkenals, cysteine residues within Keap1 are modified[44]. The consequence of which leads to translocation of Nrf2 into the nucleus and up-regulation of specific antioxidant genes through binding to the antioxidant response element sequence [44]. Thus, whilst testicular hypothermia leads to aldehyde production, this in turn activates the Nrf2-antioxidant system to help overcome heat-induced oxidative stress. Furthermore, as outline below, addition of zinc (which activates the Nrf2 system) before testicular hyperthermia is a remarkable defence against cell death, implication involvement of this pathway.

Is ”heat-stress” physiologically relevant?

The use of testicular-hyperthermia animal models makes it easier to study the impact of heat on sperm quality. However, the question remains as to whether this is a physiologically relevant event, especially in agriculture species and humans? Furthermore, if changes in sperm production are ‘seasonal’ this gives rise to the idea that agriculture and potential clinics can use antioxidant therapy to overcome the effect.
The first report of seasonal effects on breeding efficiency in dairy cattle occurred in 1938[45]. Dairy records taken from the University of Nebraska showed more natural “services” were required for conception from May to October (i.e., summer) compared to winter months. This appeared to be consistent throughout the years 1896 to 1934[45], suggesting summer was detrimental to fertility. In 1941, an examination of 11 years of the breeding records from the Louisiana State University showed seasonal differences in the rate of conception[46]. Again, summer months required more services per conception, whilst the best record for rate of conception was during winter[46]. These data pointed to three possible interpretations; either the cow, the bull or both are somehow affected by heat stress. The notion that physiological temperatures could affect bull fertility was then advanced in 1942, when Purdue University reported that, on average, semen volume and motility were lowest in July, August and September (i.e., summer) whilst the average concentration was maximum during April, May and June[47]. Finally, Anderson also showed bull sperm volume and motility declined during summer in Kenya[48] Experimentally, the idea that summer could be causing a drop in semen quality was verified by the purposeful heating of dairy bulls inside chambers at physiologically relevant (32.2oC) temperatures[49]. Such bulls showed clear evidence that a warm environment can lead to a decrease in sperm morphology and motility[49]. In addition, it is clear that reactive oxygen species generation are involved[50].
Despite these early works, the notion that “season” can impact bull fertility does not come without controversy. In deference to the idea that summer is detrimental to semen quality, reports from Cornell University show winter was the poorest season for breeding dairy cattle in Canada and New York State [48,51], which was later confirmed [52,53,54,55]. Furthermore, others have reported season has no-significant effect on bull semen quality [52,56,57,58]. To allow for a broader view, we have taken a closer examination of studies that evalulated the effect of season on bull semen parameters (Table 1).
In Table 1, where available, the motility, morphology and cell counts from each study, together with the reported climatic conditions at the time of semen collection are included. If no climatic data were given, this information was then obtained online (weather-and-climate.com) using seasonal averages. Although this table does not list all the works performed in this area, it is very indicative of the results in this field. From this review it is evident there are two variables that need to be considered, both of which appear to explain much of the “contradictory” results around season and semen quality.
Firstly, most of the work was performed at very different locations, with extremely different climatic conditions. For example, in both Kenya and Thailand in which ambient temperature is consistent throughout the year, little variation in semen quality was observed [56,63]. However, in northern parts of USA [57] and Sweden [80], where winter temperatures drop below zero and summer is quite mild, sperm motility is higher during the latter season.
The most controversial work comes from countries considered sub-tropical, for example Brazil and Australia. Herein, summer temperatures greatly exceed the core body temperature of the bull (~38oC), whilst winter temperatures can drop will below (10-15oC). Based on the experimental work (purposeful heating in a chamber, water bath etc), it would be expected that such temperatures would impact bulls, if season played a role. Indeed, there is clear evidence of semen quality deteriorating in summer in these countries[72]. However, these findings are not consistent, with one major report from Australia, which looked at 11,387 bulls finding no evidence of seasonal variation[81]. In this report, bulls were sourced from all over the country (as opposed to one area). As Australia is so large, the changes in temperature from the north to south are vast, making it difficult to analyse effectively. However, these same authors did note that bulls found in the hottest part of the country (north region) were less likely to pass a semen test. In support of this, we have reported definitive evidence of seasonal variation within bulls taken from central QLD, Australia[82] where temperatures in summer are exceedingly hot.

Emerging evidence shows there are “degrees” of heat-sensitivity within species.

In a previous study, six bulls were subject to scrotal insulation “by enclosing the scrotum with a sack constructed of insulated material held in place by Velcro fasteners and medical tape” (cited from [83]). The bulls were then subject to the exact same environmental conditions throughout the study. However, after 9-30 days, two animals showed large increases in abnormal spermatozoa (~65 and 69%), three animals had between 47-51% abnormal sperm and one animal had fewer than 24% abnormal forms[14,83]. As such, there was large differences in bull thermotolerance, suggesting individual bulls can display degrees of thermosensitivity. Supporting this observation, 48 hours scrotal insulation of 4 bulls caused one animal to drop to a staggering 0.5% morphologically normal spermatozoa, whilst bull 2 and 3 dropped to 22% and 29% respectively. However, the 4th bull, despite undergoing the same experimental insult, showed no change in his semen profile, and maintained 82% normal forms for 3 weeks[84]. Finally, in our work, we took 20 bulls and purposefully heated them in a shed. We found large changes in semen quality following intervention. Some bulls dropped to below 50% normal forms, whilst others maintained their baseline 80% average throughout 12 weeks of testing [82]. Thus, it is clear that there is a spectrum of thermo-sensitivity within individual animals.
The idea of thermo-sensitivity is not restricted to bulls, as evidence points to this being a phenomenon in other animal model systems, and we propose all mammals with a scrotum. For example, within boars used for artificial insemination (AI) it has been previously noted that some breeder-lines appeared to have a high “heat-tolerance” [85].
The mechanism of thermo-sensitivity may be due to oxidative stress. Notably, reports show during summer there is an increase in reactive oxygen species within the mitochondria of cells, leading to lipid peroxidation and an imbalance between pro- and anti-oxidants [50,86]. As such, the level at which each bull expresses their antioxidant capacity may explain why some bulls are more thermotolerant than others. In addition, it would be interesting to integrate the NRf2 pathway to see if differences in the levels of oxidative stress are occurring between bulls to explain this discriminating phenomenon.

Evidence of genetic heritability of “testicular heat-sensitivity”

Although scarce, there is some data suggesting testicular heat-sensitivity could be inherited. As outlined above, within boars used for AI, there is significant variation in sperm production among the genetic lines[85], with some of them showing higher “heat-tolerance” compared to others. For example, while in one lineage high environmental temperatures led to a 5-7% reduction in sperm output, a decrease of 15-20% was observed in two other lineages, despite using the same amount of heat stress[85]. Additionally, in Drosophila, the idea of heat-sensitive and heat-tolerant males has also been reported[87]. Heat-sensitive Drosophila males, produce no, or a low number of maggots, after a heat event. Remarkably, the “trait” is heritable. Heat-sensitive males produce “heat-sensitive” male offspring[87]. Conversely, heat-tolerant males produce heat-tolerant offspring[87] even when the same female is used. As such, thermo-sensitivity in Drosophila is thought to be passed on from sire to son through the Y-chromosome [87].

Testicular heat stress and its relation to male-factor infertility.

Although the impact of testicular hyperthermia is often studied in the context of livestock animals, there is little doubt that it also plays a significant role in humans. Male infertility is a medical condition affecting one in 20 men in the western world[88,89] and accounts solely, or in a contributory way, for ~50% of couples attending assisted conception facilities/clinics(AC)[90]. Whilst some infertile men have associated conditions, such as (i) varicocele[91,92,93] (27% of cases) or (ii) cryptorchidism[94,95,96,97] (6% of cases), others do not, therefore falling into the category of “idiopathic infertility” – or infertility of unknown aetiology (35% of clinical load). In all cases, these men produce an abnormal semen profile. Their ejaculate contains low sperm counts, low sperm motility, low sperm morphology[98] or (as is often the case) a combination of these phenotypes. In addition, infertile men produce 2-3 times higher levels of DNA damaged spermatozoa compared to their fertile counterparts[99,100]; a phenomenon that is often associated with oxidative stress. This contributes to the problem, as men with high levels of sperm DNA damage (i.e., more than 40% of sperm population) are essentially infertile[99,100,101].
In clinical trials, many dating back to the 1980s, scrotal cooling has been shown to improve semen quality and natural pregnancy rates. For example, trials performed in 25 infertile men showed that in 18 (70%), semen parameters improved with scrotal cooling[102]. Furthermore, six (24%) went on to naturally conceive during the 14-week scrotal cooling regime, despite the fact they had been “trying” to conceive for 3-8 years previously[103,104,105]. To put this into perspective, if a couple has not conceived within 2 years of trying, their chance of conception thereafter is less than 2%[106]. A second trial involving 64 men, showed improvements in semen parameters in 66% of cases and a natural pregnancy rate of 27%[107] within 16 weeks of scrotal cooling. This was statistically significant as the background pregnancy rate (in this case, men with poor semen quality that pulled out of the trial after two weeks) was 5%[107]. However, if men diagnosed with azoospermia (produce no sperm in their ejaculate) or severe oligozoospermia (<1 million sperm/mL in ejaculate) are removed from the analysis, this increases the pregnancy success rate to 50% [107] against a background rate of 10%. Three further studies have looked at pregnancy rates following scrotal cooling with remarkable outcomes (24%[107], 27%[108] and 14% on a background rate of less than 5% in men with history of reduced fertility of at least 3 years). Moreover, these studies were done over 14, 16 and 8 weeks, respectively. Considering sperm parameters take 4-8 weeks to improve with scrotal cooling, this leaves only an one- to two-month window to achieve a pregnancy, which is a remarkable success rate. As such, it is clear that in around 40-80% of infertile/subfertile men, scrotal heat stress is a physiological phenomenon that can be overcome.

Overcoming the impact of testicular hyperthermia.

Dietary supplementation to overcome heat-stress has typically used an antioxidant approach as a major course of amelioration. However, the contribution of oxidative stress to male fertility has recently come under heavy scrutiny mainly due to the limitations and drawbacks of various “probes” used to measure ROS. For example, many reports have used tetrazolium salts (often used to report ROS in sperm) or lucigenin to suggested sperm produce copious amounts of free radicals. However, these assays are actually measuring cytochrome-based enzymes including cytochrome P450-reductase [101] and cytochrome b5-reductase (Cb5R) [102]. Thus, it is likely that such reports simply measure sperm with excess cytoplasm or increased poor morphology. Along similar lines, the use of Luminol-HRP should be avoided, as the assay has indiscriminate recognition of reduced compounds (for example, NADH) and several free radicals making it impossible to determine what is being measured [118]. In contrast, when better discriminatory problems such as 2-methyl-6-(p-methoxyphenyl)-3,7-dihydroimidazo [1,2-a] pyrazine-3-one (MCLA) [109] and the electron spin method [100] are used, there is again no evidence that sperm generate large amounts of free radicals.
A better approach to demonstrate whether oxidative stress is a player in testicular hyperthermia is to investigate if supplementation can limit the effect of heat stress. We focused on studies that reported germ cell parameters, sperm quality and pregnancy rates, following heat stress with and without supplementation, rather than those who attempt to biochemically measure ROS through many of the assays aforementioned which are clearly obfuscated in terms of their interpretation. Although many compounds show a significant improvement in sperm counts, the biological relevance of these observations needs to be considered. In most cases, the average decrease following treatment was modest (<10%) [110,111] [112], [113], [114], [115] [116] despite being statistically significant. However, there have been some exceptional outcomes.
Mice given phytochemicals showed a significantly lower amount of abnormal seminiferous tubules 48 hours after a 15-min exposure to testicular hyperthermia at 41oC. [117] Furthermore, sperm density and motility of treated mice were not significantly different from control mice 7 days later. Phytochemicals appears to work by increasing the expression of Heat shock proteins (HSP) HSPa1a, Hspa1l and Hspa2, together with the transcription factor Heat-shock factor 1. HSP have shown to play an anti-apoptotic role, which may explain phytochemically treated mice able to withstand hyperthermic shock [117]. A second model involved the use of rats, in which males surgically made unilateral cryptorchid received xanthine-oxidase inhibitors. After 7 days, the treated group showed significantly higher testicular weights and decrease in apoptotic cells. Furthermore, treated testis showed presence of near-normal testis histology, whereas cryptorchid had lost the majority of round and spermatocytes [118]. These data suggested that a major mechanism by which high temperature leads to apoptosis or poor sperm formation may be through Xanthine-Xanthine oxidase and, in particular, superoxide anion production. Finally, one of the most remarkable protective effects against heat-shock has been seen through administration of zinc. Firstly, mice were given zinc supplements for one month prior to heat stress, which significantly increased the level of testicular zinc. Then, following heat stress (40oC, 2 h daily) for eight days, it was apparent the preservation of most of the germ cells present in the tubules.[119] In proof of concept, zinc supplementation in a similar model also led to an improvement in the number of foetuses born[120]. However, one of the main concerns with this study, is control mice given zinc (without heat stress) showed a reduction in the number of foetuses compared to non-supplemented control mice (40 pups vs 120 pups)[120]. As such, zinc supplementation whilst protects against heat stress must be used with caution as it can decrease the overall birth rates.

Concluding remarks.

Several sources of environmental stress have been suggested to affect semen quality, yet none of them hold up the rigour of scrotal hyperthermia. Although we still do not understand the biochemical mechanisms nor the reason why male-precursor germ cells need to remain at or below 34˚C, it is clear that this must be the case. Once temperatures exceed 34oC, spermatocytes tend to undergo apoptosis, whilst spermatids continue to develop into misshapen spermatozoa. Yet the environment may not be the end of the story. The emerging role of genetics, oxidative stress and expression levels of different proteins/enzyme will likely explain the concept of “thermo-sensitivity”. The biggest “hint” in terms of causation, is the case of Drosophila, where heat-sensitive males produce other heat-sensitive males. Further work to understand the mechanism of testicular heat stress, and answer the age-old question of why the scrotum exists? will certainly be useful not just from a medical point of view, but also in the agriculture industry to identify males that are heat-resistant.

Author Contributions

MB wrote the original draft and undertook the analysis, BRR, RAO and RKN wrote sections and reviewed and edited the original draft. AISB and AG reviewed the final draft for editing.

Conflicts of Interest

The authors have no conflict to declare

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Table 1. An overview of studies that have looked at the effect of “season” on sperm quality in bulls.
Table 1. An overview of studies that have looked at the effect of “season” on sperm quality in bulls.
# Bulls Breed # ejaculates Motility (%) Cell counts Morphology (% defective)
 Country Ave, temp
(oC)		 Ave Humidity
(%)		 Ref
Sum. Win. Sum. Win. Sum. Win. Sum. Win. Sum. Win.
6 B. Indicus n/a 55 39 1.29 1.19 39 30 Khon kaen, Thailand 36 30 80 63 [54]
51* Bos Indicus/indicus ND NSD** NSD** 119 119 14 10 Sertãozinho, SP, Brazil
Uberaba, MG, Brazil		 ~26 ~19 84 51 [56]
13 Bos Taurus 1103 4.2*** 3-3.7*** 1023/mm3 1015/mm3 14 14 Missouri, USA 24 -3 60 65 [53]
9 bulls (reduced to 2 over time) Zebu 1049 75 80 600cc3 700cc3 ND ND Kenya 27 20 75 60 [59]
137 Bos Taurus 5644 55 56 13.5-149 14.5-15.59 ND ND Geuth, Canada 26 -3 60 65 [52]
5 Swamp Buffalo 118 73 75 4.28 3.68 10 11 Khon-Khaen, Thailand. 35 33 89 92 [57]
27 16 Bos. Taurus. 11 Bos. Indicus ND NSD NSD ND ND 20 12 Dourados, MS, Brazil 29 22 80 75 [60]
10 Bos Taurus ND 47 55 ND ND 14 15 Uppsala, Sweden 18 -3 65 94 [61]
5 Bos Taurus 86 40 49 ND ND ND ND Hafetz-Haim, Israel 31 16 84 46 [62]
52 Bos Taurus 86 ND ND ND ND 12 11 Sweeden 21 17 74 40 [63]
10 Bos Taurus ND 58 57 1.89 1.79 39 27 Zamiba 28 8 45 59 [58]
218 Bos Indicus ND 68 70 6.68 5.78 ND ND Brooksville, Florida, USA 32 19 79 73 [55]
11 Bos Taurus ND 58 51 ND ND 27 12 Gijon, Span 21 11 75 75 [64]
7 Bos Indicus 142 28% 36.2 4.18 3.98 21 30 Nsukka, Nigernia 27 24 83 44 [65]
2 Buffalo bulls 42 ND ND ND ND 27 18 Pantnagar India, 36 22 28 45 [66]
2 Ongole 86 56 55 8.29 8.59 ND ND Semarang, Indonesia 27 27 81 82 [67]
Simmental 89 70 70 99 9.79 ND ND
271 Bos Taurus ND ND ND ND ND 27 17 Irene, South Africa 28 20 60 37 [68]
19 Bos Taurus ND ND ND ND ND 14 11 Northern USA ? ? 21 to 43 5 to -30 [69]
6 5 ejaculates per season ND 70 70 1.49 1.69 9 7 30 21 8 85 84 [70]
21 Bos Taurus ND 51.5 54.6 ND ND 14 15 Spain/ Sweden 18 2 78 88 [71]
11 Bos Indicus /Taurus 2558
(1095 B. indicus 		57 58 1.66 1.46 27 16 Araçatuba, SP. Brazil 25 19 83 72 [72]
1463 B. taurus) 51 59 1.26 1.26 44 18
933 Bos Taurus 29170 90 84 ND ND 3 7 Netherlands 15 10 95 62 [73]
176 Bos Taurus 8983 82 82 99 ~99 ND ND Ireland 14 6 83 68 [74]
3 Bubalus bubalis ND 65 64 5.29 3.49 ND ND Indonesia 23 23 79 74 [75]
155 Bos sondaicus 155 ND ND 126 146 ND ND Townsville, Australia 33 13 76 64 [76]
288 abattoir/21 breeding bulls Bison ND 69 44 7.18 5.18 39 43 Alberta, Saskatchewan, Monitoba 10 0 [77]
7 Bubalus bubalis 4834 66 68 1.169 1.116 ND ND Salon, India 37 25 62 55 [78]
8 Bos. Taurus and crossbred 558 79 81 3.319 10.19 24 5 Nigeria 37 27 87 76 [79]
ND = not determined. NSD = no significant difference, but no values were reported in the origonal pubication. * three different collections stations used. ** reported as no significant difference, but no values given. ***motility scored from 0-5 (with 5 being the highest).
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