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Association between ambient temperature and semen quality: A longitudinal study of 10 802 men in China
Environment International 135 (2020) 105364
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Association between ambient temperature and semen quality: A longitudinal study of 10 802 men in China
T
Yun Zhoua,1, Tianqing Mengb,1, Li Wuc, Yonggang Duand, Guo Lie, Chunxiang Shif, Hai Zhangg, ⁎ ⁎ Zhe Pengg, Chuangang Fang, Jixuan Mah, Chengliang Xiongb, Wei Baoi, , Yuewei Liuj, a
School of Public Health, Guangzhou Medical University, Guangzhou, Guangdong 511436, China Center for Reproductive Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China c Reproductive Medical Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China d Shenzhen Key Laboratory of Fertility Regulation, Centre of Assisted Reproduction and Embryology, The University of Hong Kong – Shenzhen Hospital, Shenzhen, Guangdong 518053, China e Department of Neurology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China f National Meteorological Information Center, Beijing 100081, China g Institute of Health Surveillance, Analysis and Protection, Hubei Provincial Center for Disease Control and Prevention, Wuhan, Hubei 430079, China h Department of Occupational and Environmental Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China i Department of Epidemiology, College of Public Health, University of Iowa, Iowa City, IA 52242, USA j Department of Epidemiology, School of Public Health, Sun Yat-sen University, Guangzhou, Guangdong 510080, China b
ARTICLE INFO
ABSTRACT
Handling editor: Mark Nieuwenhuijsen
Semen quality is a vital determinant for male fertility. The process of spermatogenesis is highly sensitive to fluctuations in temperature. However, the impact of ambient temperature on semen quality remains unclear. We aimed to quantitatively assess the association between ambient temperature and semen quality. Using data from Hubei provincial human sperm bank in Wuhan, China, we conducted a longitudinal study including 10 802 volunteers who lived in Wuhan and passed the initial physical examination for sperm donation between Mar 27, 2013 and April 9, 2018. Semen quality parameters including sperm concentration, total sperm number, total motility, progressive motility, total motile sperm count and progressively motile sperm count were determined in the sperm bank. We used linear mixed models to identify estimate changes of outcomes in relation to ambient temperature (i.e., air temperature and apparent temperature) exposure measured as the mean daily temperature during the 0–90 days before semen collection. Among 10 802 subjects who underwent 41 689 semen examinations, we observed inverted U-shaped exposure-response associations between air temperature exposure and all semen quality parameters, with an identical threshold exposure of 13 °C. For air temperature exposure < 13 °C, each 5 °C lower temperature was significantly associated with 1.94 × 106/ml, 7.12 × 106, 0.77%, 0.81%, 6.48 × 106, and 5.87 × 106 decrease in sperm concentration, total sperm count, total motility, progressive motility, total motile sperm count and progressively motile sperm count, respectively. When air temperature exposure was ≥13 °C, each 5 °C higher temperature was significantly associated with 0.70 × 106/ ml, 4.09 × 106, 1.01%, 1.06%, 4.31 × 106, and 4.20 × 106 decrease in sperm concentration, total sperm count, total motility, progressive motility, total motile sperm count and progressively motile sperm count, respectively. Age, BMI and smoking did not significantly modify these associations. Similar results were observed for apparent temperature. This study provides a comprehensive picture of nonlinear association between ambient temperature and semen quality, as well as an optimal temperature for the benefit of semen quality. Both lower and higher ambient temperature exposures compared with the optimal temperature were significantly associated with decreased semen quality. The findings highlight the needs and importance to reduce extreme ambient temperature exposures in maintaining optimal semen quality for men. Further investigation is warranted to determine the causality of the association and the underlying mechanisms.
Keywords: Ambient temperature Semen quality Exposure-response relationship
Corresponding authors at: Department of Epidemiology, School of Public Health, Sun Yat-sen University, 74 Zhongshan Second Road, Guangzhou, Guangdong 510080, China (Y. Liu); Department of Epidemiology, College of Public Health, University of Iowa, 145 North Riverside Drive, Iowa City, Iowa 52242, USA (W. Bao). E-mail addresses: [email protected] (W. Bao), [email protected] (Y. Liu). 1 These authors contributed equally to this work. ⁎
https://doi.org/10.1016/j.envint.2019.105364 Received 6 May 2019; Received in revised form 20 October 2019; Accepted 25 November 2019 0160-4120/ © 2019 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/BY-NC-ND/4.0/).
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1. Introduction
and laboratory tests for various conditions including genetic disorders and sexually transmitted diseases were qualified as sperm donors. The qualified sperm donors were then asked to donate sperm multiple times and determined for semen quality during each donation. All data used in this study was de-identified and coded. This study was approved by the ethical committee of the Hubei Provincial Center for Disease Control and Prevention.
As a global public health issue, infertility affects approximately 15% of all reproductive age couples worldwide (Salas-Huetos et al., 2017). It has been estimated that male factors, mainly poor semen quality, are responsible for 20% to 70% of the infertility cases (Agarwal et al., 2015). Extensive evidence suggests that semen quality is continuously declining globally (Carlsen et al., 1992; Swan et al., 2000). A recent systematic review and meta-regression analysis reported that sperm count measured by both sperm concentration and total sperm number decreased by 50–60% among men from North America, Europe and Australia from 1973 to 2011 (Levine et al., 2017). In a large sperm bank in China, sperm concentration, progressively motile sperm count, and percentage of normal sperm morphology were estimated to decrease by 31%, 38%, and 66% respectively between 2001 and 2015, while the percentage of qualified sperm donors decreased from 55.8% to 17.8% (Huang et al., 2017). Although previous studies have linked endocrine disrupting chemicals, diet, stress, smoking and obesity with decreased semen quality (Bloom et al., 2015; Chiu et al., 2016; Hammiche et al., 2012; Nordkap et al., 2016; Sharma et al., 2016), the causes of decreased semen quality remain to be elucidated. The process of spermatogenesis is sensitive to fluctuations in temperature. An optimal temperature of 2 °C to 4 °C below the core body temperature is required for normal spermatogenesis (Ivell, 2007). Scrotum has a mandatory function to maintain the temperature of the testes by physiological structures including scrotum skin, arterial and spermatic veins, as well as the dartos fascia in the scrotum and the cremaster muscle (Ivell, 2007; Kleisner et al., 2010; Song and Seo, 2009). However, several animal studies have observed adverse effects of high environmental temperature and humidity on semen production and semen quality, indicating that the ability of temperature regulation in scrotum is limited (Fuerst-Waltl et al., 2006; Suriyasomboon et al., 2005). Ambient temperature exposure has been associated with various reproductive health outcomes including low birth weight, stillbirth and preterm birth (Ha et al., 2017; He et al., 2016; Ngo and Horton, 2016). However, little is known about the impact of ambient temperature exposure, especially extremely heat or cold, on semen quality. A limited number of epidemiological studies have investigated the season fluctuation of semen quality (Mao et al., 2017; Santi et al., 2018; Santi et al., 2016), compared semen quality of workers exposed to heat stress with non-occupational individuals (Bonde, 1992; Hamerezaee et al., 2018; Momen et al., 2010), and suggested that high environmental temperature might be related with decreased semen quality. However, most of these studies did not conduct quantitative exposure-response analysis and the results remain inconsistent. Furthermore, to our knowledge, no studies have examined the association between low ambient temperature exposure and semen quality to date. Therefore, we conducted a large longitudinal study of 10 802 Chinese men in Wuhan, China who underwent 41 689 semen examinations between 2013 and 2018. This study aimed to quantitatively assess the exposure-response association between ambient temperature exposure and semen quality. We hypothesized that both high and low temperature exposure would be associated with decreased semen quality.
2.2. Exposure assessment Hourly gridded meteorological data with a 0.0625° × 0.0625° resolution in Wuhan were obtained from the China Meteorological Administration Land Data Assimilation System (CLDAS version 2.0), which was released and maintained by the China Meteorological Administration. For each day between December 27, 2012 and April 9, 2018, we extracted hourly average 2 m air temperature, 2 m specific humidity, and surface air pressure values for all grids within Wuhan, and then averaged them by day to calculate city-level daily mean air temperature (°C), specific humidity (kg/kg), and air pressure (mb). Daily apparent temperature was calculated using air temperature and relative humidity (%) with weathermetrics, an R package developed by Anderson et al., (Anderson et al., 2013), where the relative humidity was estimated using the following formulas (Bolton, 1980): 17.67 ×
Saturation vapor pressure = 6.112 × e Actual vapor pressure =
Relative humidity =
air temperature air temperature + 243.5
specific humidity × air pressure 0.378 × specific humdity + 0.622
actual vapor pressure × 100 saturation vapor pressure
(1) (2) (3)
Because the entire process of human spermatogenesis takes approximately 90 days, we estimated exposures to both air temperature and apparent temperature for each subject on each date of semen collection by calculating mean daily temperature during the 0–90 days before semen collection (i.e. lag 0–90 day exposure) (Johnson et al., 1997). 2.3. Study outcome Semen quality was determined in the sperm bank as described previously (Ma et al., 2019). We defined semen quality as the study outcome. In brief, each subject was advised to practice abstinence for 2 to 7 days before semen analysis. Semen samples were collected by masturbating into a sterile plastic container, and then liquefied in an incubator at 37 °C for 30 min. Each semen sample was weighed to determine the semen volume and was extracted for 10 μl to a Makler chamber to assess sperm concentration, total motility, and progressive motility. In this study, the outcome variables included sperm concentration, total motility, and progressive motility measured in the semen analyses, as well as total sperm number, total motile sperm count and progressively motile sperm count which were calculated as semen volume multiplying sperm concentration, total sperm number multiplying total motility, and total sperm number multiplying progressive motility, respectively.
2. Methods
2.4. Covariates
2.1. Study design and subjects
Trained investigators collected demographic and lifestyle information on age, height, weight, education, smoking, and abstinence period at semen collection for all subjects. Data on height, weight, and smoking were collected for all qualified sperm donors and 13.3% of those who did not donate sperm. Body mass index (BMI) was calculated as weight (kg) divided by square of height (m). Current smokers were defined as those who had smoked at least 1 cigarette per day in the past 6 months. Participants without smoking information were classified as
This is a longitudinal study of 10 802 men from Wuhan, China who intended to donate sperm at the Hubei provincial human sperm bank and passed the initial physical examination for color vision deficiency (which can be passed on to the offspring via sperm), hypertension and abnormal heart rate during Mar 27, 2013 and April 9, 2018. All these subjects were tested for semen quality at least once, and only those who passed at least one semen quality test and further physical examination 2
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“Unknown”. In addition, we considered particulate matter ≤ 2.5 μm in aerodynamic diameter (PM2.5) as a covariate to account for potential confounding by air pollution (Wu et al., 2017). We collected daily 24hour average PM2.5 concentrations measured at 20 fixed air quality monitoring stations in Wuhan between December 27, 2012 and April 9, 2018 from the Wuhan Environmental Protection Bureau, and averaged them by day to obtain daily mean PM2.5 concentration in Wuhan. Similar to the exposure assessment for temperature, exposure to PM2.5 was calculated as the mean of daily concentrations on the same day of semen collection and 90 days prior. To account for potential acute effect of temperature on semen quality, we also included daily temperature on the same day of semen collection in all models. In all analyses on air temperature, we treated relative humidity exposure as a covariate, which was estimated using the same approach as that for the air temperature.
Table 1 Baseline characteristics of study subjects. Characteristic
Age, y 20–25, n (%) 25–29, n (%) ≥30, n (%) BMI*, kg/m2 < 18.5, n (%) 18.5–24.9, n (%) 25.0–29.9, n (%) ≥30.0, n (%) Unknown, n (%) Education, n (%) High school and lower Junior college Undergraduate and higher Unknown Current smoking*, n (%) No Yes Unknown
2.5. Statistical analysis We used linear mixed models with a subject-specific random intercept to quantitatively assess the exposure-response associations between ambient temperature (both air temperature and apparent temperature) exposure and semen quality parameters. This method allowed us to account for correlations among repeated measures of semen quality at different visits contributed by a single subject. By assuming that both low and high temperature exposures may adversely affect semen quality, we first modeled temperature exposure as a natural cubic spline function with 4 degrees of freedom to allow for a nonlinear relationship with semen quality, and plotted estimated changes with 95% confidence intervals (CIs) for each semen quality parameter. Likelihood ratio test was used to examine the nonlinear trend. We also detected threshold temperature that occurred at the minimal absolute estimated changes. Specific estimated changes relative to the threshold temperature exposure were calculated for locally extreme cold, moderate cold, moderate heat and extreme heat, which were defined as the 1th, 5th, 95th, and 99th percentile of daily mean lag 0–90 day temperature during the study period, respectively. All models were adjusted for potential confounders including age, BMI, education, smoking, abstinence period, year, season, and daily temperature on the day of semen collection, as well as lag 0–90 day PM2.5 concentration, and lag 0–90 day relative humidity (for air temperature model only). In addition, we conducted subgroup analyses according to the identified threshold temperature exposure for each semen quality parameter. For temperature exposure lower than the threshold, we estimated changes in each semen quality parameter associated with each 5 °C decrease of temperature exposure; for temperature exposure higher than the threshold, estimated changes were assessed for each 5 °C increase of temperature exposure. We conducted stratified analyses by age, BMI and smoking, and used likelihood ratio tests to examine their potential effect modification on the association between temperature exposure and semen quality. Sensitivity analyses were performed to assess the robustness of our results. First, we analyzed the data without adjustment for temperature exposure on the same day of semen collection. Second, we restricted data on qualified sperm donors only. Finally, we examined potential confounding effects by smoking and BMI by fitting models with or without adjustment for them among qualified sperm donors. All data analyses were performed using R version 3.5.1. All statistical tests were 2-sided, and a P value < 0.05 was considered statistically significant.
No. of semen collection Abstinence period before semen examination, days 2–3, n (%) 4–5, n (%) 6–7, n (%) Year at semen examination, n (%) 2013 2014 2015 2016 2017 2018 Season at semen examination, n (%) Warm (Mar-Aug) Cool (Sep-Dec, Jan, Feb)
All subjects (n = 10 802)
Subjects qualified as sperm donors (n = 3966)
Subjects not qualified as sperm donors (n = 6836)
3829 (35.4) 3595 (33.3) 3378 (31.3)
1312 (33.1) 1356 (34.2) 1298 (32.7)
2517 (36.8) 2239 (32.8) 2080 (30.4)
286 (2.6) 3734 (34.6) 808 (7.5) 49 (0.5) 5925 (54.9)
222 (5.6) 3046 (76.8) 660 (16.6) 38 (1.0) 0 (0.0)
64 (0.9) 688 (10.1) 148 (2.2) 11 (0.2) 5925 (86.7)
3510 (32.5) 3693 (34.2) 3592 (33.3)
1122 (28.3) 1385 (34.9) 1458 (36.8)
2388 (34.9) 2308 (33.8) 2134 (31.2)
7 (0.1)
1 (0.0)
6 (0.1)
3246 (30.0) 1628 (15.1) 5928 (54.9)
2694 (67.9) 1269 (32.0) 3 (0.1)
552 (8.1) 359 (5.3) 5925 (86.7)
41 689
29 849
11 840
5449 (13.1) 15 026 (36.0) 21 214 (50.9)
3095 (10.4) 11 290 (37.8)
2354 (19.9) 3736 (31.6)
15 464 (51.8)
5750 (48.6)
6923 (16.6) 8837 (21.2) 9600 (23.0) 9325 (22.4) 6015 (14.4) 989 (2.4)
3647 (12.2) 6077 (20.4) 7825 (26.2) 7187 (24.1) 4446 (14.9) 667 (2.2)
3276 (27.7) 2760 (23.3) 1775 (15.0) 2138 (18.1) 1569 (13.3) 322 (2.7)
22 824 (54.7) 18 865 (45.3)
16 111 (54.0)
6713 (56.7)
13 738 (46.0)
5127 (43.3)
BMI = body mass index; SD = standardized deviation; IQR = interquartile range. * Only available for qualified sperm donors and 13.3% of subjects not qualified as sperm donors.
semen samples, and 6836 (63.3%) subjects who did not donate sperm provided 11 840 (28.4%) semen samples. The mean age of all subjects was 28.3 years, and 68.7% were under 30 years. About 87% of the semen samples were collected and tested after an abstinence for at least 4 days. 3.2. Semen quality The mean daily number of semen collection was 24, ranging from 1 to 66. Table 2 gives distribution of each semen quality parameter based on 41 689 semen examinations. The qualified sperm donors completed a median of 7 donations, with median sperm concentration, total sperm number, total motility, progressive motility, total motile sperm count, and progressively motile sperm count of 62.0 × 106/ml, 168.0 × 106, 66.0%, 61.0%, 107.1 × 106, and 99.3 × 106, respectively, and 94.3% of the semen samples met the WHO lower reference limits (sperm concentration: 15 × 106/ml; total sperm number: 39 × 106; total motility: 40%; progressive motility: 32%) (World Health Organization, 2010). For those who did not donate sperm, about 94% of them
3. Results 3.1. Study subjects and characteristics As shown in Table 1, a total of 10 802 subjects who underwent 41 689 semen examinations were enrolled in this study. Of them, 3966 (36.7%) subjects qualified as sperm donors provided 29 849 (71.6%) 3
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Table 2 Distributions of semen quality parameters based on 41 689 semen examinations. Semen Quality Parameter Semen examinations by subjects qualified as sperm donors (n = 29 849) Sperm concentration, ×106/ml Total sperm number, ×106 Total motility, % Progressive motility, % Total motile sperm count, ×106 Progressively motile sperm count, ×106 Semen examinations by subjects not qualified as sperm donors (n = 11 840) Sperm concentration, ×106/ml Total sperm number, ×106 Total motility, % Progressive motility, % Total motile sperm count, ×106 Progressively motile sperm count, ×106
Mean
SD
Minimum
P25
Median
P75
Maximum
59.5 188.3 63.1 58.6 119.9 111.4
15.0 89.7 9.7 9.6 61.7 57.8
0.1 0.3 5.0 3.0 0.04 0.04
60.0 130.0 62.0 60.0 81.6 75.6
62.0 168.0 66.0 61.0 107.1 99.3
67.0 240.0 68.0 64.0 152.1 143.2
240.0 928.0 98.0 94.0 621.8 566.1
35.7 108.8 55.7 50.0 59.4 53.6
20.0 84.3 14.5 14.6 47.3 43.8
0.01 0.01 1.0 1.0 0.01 0.01
20.0 45.0 46.0 40.0 23.9 21.0
34.0* 90.2* 56.0* 50.0* 48.4* 43.2*
48.0 151.7 66.0 62.0 84.0 76.6
280.0 750.4 99.0 91.0 462.1 433.2
SD = standardized deviation; P25 = the 25th percentile; P75 = the 75th percentile. * P < 0.05 compared with semen examinations by qualified sperm donors.
provided 1 to 3 semen samples, and all median semen quality parameters were significantly lower than those of qualified sperm donors (all P < 0.05).
3.4. Exposure-response analysis As shown in Fig. 2, we observed inverted U-shaped exposure-response relationships between air temperature exposure and all semen quality parameters, with generally the same threshold of 13 °C, and the relationship was close to linearity when the exposure was lower or higher than the threshold. Extreme and moderate cold were significantly associated with all semen quality parameters, except for moderate cold and total motility, and the associations were overall weaker than that of corresponding associations for extreme and moderate heat, especially sperm motility (Fig. 2, Fig A.1 and Table A.1 in the supplementary materials). The subgroup analyses demonstrated that each 5 °C decrease of air temperature exposure was significantly associated with 1.94 × 106/ml, 7.12 × 106, 0.77%, 0.81%, 6.48 × 106, and 5.87 × 106 decrease in sperm concentration, total sperm number, total motility, progressive motility, total motile sperm count and progressively motile sperm count, respectively (all P < 0.05), when the air temperature was lower than 13 °C; while each
3.3. Ambient temperature exposure Fig. 1 shows the distributions of daily temperature and daily mean lag 0–90 day temperature in Wuhan during the study period. The daily air temperature in the study area (mean: 17.2 °C; range: −3.0 °C to 34.6 °C) was higher in summers and lower in winters. The apparent temperature showed similar trend, but were overall higher than that of the air temperature in summer, and lower in winter. The 1th, 5th, 95th, and 99th percentile of daily mean lag 0–90 day temperature were 5.6 °C, 6.5 °C, 28.3 °C, 29.3 °C for air temperature, and were 4.7 °C, 5.5 °C, 33.1 °C, 34.2 °C for apparent temperature. The mean exposures to air temperature and apparent temperature in this study were 18.9 °C (range: 5.4 °C to 29.6 °C) and 19.8 °C (range: 4.5 °C to 34.6 °C), respectively.
Fig. 1. Distributions of ambient temperature and number of semen collection in Wuhan, China between 2013 and 2018. The blue lines present daily air temperatures and apparent temperatures. The red lines present daily mean lag 0–90 day air temperatures and apparent temperatures. 4
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Fig. 2. Inverted U-shaped exposure-response association between air temperature exposure and semen quality. The air temperature exposure was defined as the mean of daily air temperature during 0–90 days before semen collection. Extreme cold, moderate cold, moderate heat, and extreme heat were defined by the 1st (5.6 °C), 5th (6.5 °C), 95th (28.3 °C), and 99th (29.3 °C) percentile of daily mean lag 0–90 day air temperature in Wuhan, China between 2013 and 2018. Estimated changes (95% CIs) were assessed by including air temperature exposure as a natural cubic spline function in the linear mixed model, adjusting for age, BMI, education, smoking, abstinence period, year, season, and daily air temperature on the date of semen collection, as well as lag 0–90 day PM2.5 concentration and lag 0–90 day relative humidity. The vertical dashed lines present threshold exposure values. CI = confidence interval; BMI = body mass index; PM2.5 = particulate matter ≤ 2.5 μm in aerodynamic diameter.
Table 3 Estimated changes for semen quality associated with each 5 °C change of air temperature exposure by threshold. Semen quality parameter
Air temperature exposure* < 13 °C, per 5 °C decrease†
Sperm concentration, ×106/ml Total sperm number, ×106 Total motility, % Progressive motility, % Total motile sperm count, ×106 Progressively motile sperm count, ×106
≥13 °C, per 5 °C increase†
Estimated change (95% CIs)
p value
Estimated change (95% CIs)
p value
−1.94 −7.12 −0.77 −0.81 −6.48 −5.87
< 0.001 0.007 0.03 0.02 < 0.001 < 0.001
−0.70 −4.09 −1.01 −1.06 −4.31 −4.20
0.002 < 0.001 < 0.001 < 0.001 < 0.001 < 0.001
(−2.91, −0.97) (−12.31, −1.93) (−1.46, −0.07) (−1.50, −0.11) (−9.92, −3.04) (−9.11, −2.64)
(−1.14, (−6.31, (−1.32, (−1.37, (−5.77, (−5.57,
−0.26) −1.87) −0.70) −0.75) −2.84) −2.82)
CI = confidence interval; BMI = body mass index; PM2.5 = particulate matter ≤ 2.5 μm in aerodynamic diameter. * The air temperature exposure was defined as the mean of daily air temperature during 0–90 days before semen collection. † Estimated changes (95% CIs) were estimated using linear mixed models, adjusting for age, BMI, education, smoking, abstinence period, year, season, and daily air temperature on the date of semen collection, as well as lag 0–90 day mean PM2.5 concentration and lag 0–90 day relative humidity.
3.5. Sensitivity analyses
5 °C increase of air temperature exposure was significantly associated with 0.70 × 106/ml, 4.09 × 106, 1.01%, 1.06%, 4.31 × 106, and 4.20 × 106 decrease in sperm concentration, total sperm number, total motility, progressive motility, total motile sperm count and progressively motile sperm count, respectively (all P < 0.05), when the air temperature was equal to or higher than 13 °C (Table 3). Similar results were observed for apparent temperature exposure (Fig A.2 and Table A.2 in the supplementary materials).
Fig A.3 (in the supplementary materials) shows that age, BMI and smoking did not appear to significantly modify the association between air temperature exposure and semen quality (all P > 0.05), though some associations became insignificant possibly due to small sample size. Models without adjustment for temperature on the same day of semen collection gave similar results (Fig A.4 in the supplementary materials). As shown in Table A.3 (in the supplementary materials), analyses restricted to qualified sperm donors yielded overall stronger 5
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associations between air temperature exposure and semen quality parameters. Compared with models adjusting for smoking and BMI, the results remained very similar without adjustment for smoking and BMI, indicating that smoking and BMI did not significantly confound the associations.
4.2. Meaning of the study Infertility has become an important issue not only in human health but also in politics and economy, leading to the growing use of assisted reproduction techniques worldwide. However, the fertility clinics do not remarkably increasing fertility rate, which remains well below the replacement rate in many countries (Skakkebaek, 2017). Deterioration of semen quality is a main cause of male infertility. The declining semen quality coincides with the global climate change especially the occurrence of extreme temperature. Although accumulating evidence indicates that high or low ambient temperature could increase the risks of noncommunicable diseases (Chen et al., 2018; Valdes et al., 2019; Zhao et al., 2018) as well as adverse reproductive outcomes in pregnant women or infants (Ha et al., 2018; He et al., 2016), the effect on semen quality remains unclear. Consistent with previous animal studies and most of the limited epidemiological studies, this study provides a comprehensive picture of nonlinear association between ambient temperature and semen quality to help better understand the impact of ambient temperature on male reproductive health. The findings support the hypotheses that high temperature exposure adversely affects human semen quality, and provide new insight into the impact of temperature on semen quality that low ambient temperature exposure may also affect semen quality. This study highlights the needs and importance to reduce extreme ambient temperature exposure in maintaining optimal semen quality for men.
4. Discussion In this large longitudinal study, we found an inverted U-shaped exposure-response association between ambient temperature and semen quality, and identified the threshold exposures for air temperature (13 °C) and apparent temperature (12 °C). Both low (< threshold exposure) and high (≥threshold exposure) temperature exposures were significantly and linearly associated with decreased sperm count and motility. Compared with low temperature, high temperature exposure had a similar association with sperm count, but a much stronger association with sperm motility. These associations were considerably robust, and were not significantly modified by age, BMI or smoking. 4.1. Comparison with other studies and implications of findings To our knowledge, this is the first study to quantitatively assess the exposure-response association between ambient temperature exposure and semen quality with a large sample size. In 2006, Sokol et al., investigated the acute effect of temperature on semen quality with a small sample size of 48 sperm donors from Los Angeles, US, and reported that air temperature on the day of semen collection was not significantly associated with either sperm concentration or total motile sperm count. However, this study did not account for temperature exposure during the spermatogenesis (i.e. 90 days before the date of semen collection), and only examined potential linear associations (Sokol et al., 2006). Other studies reported significant lower semen quality in summer when the temperature was relatively high (Mao et al., 2017; Santi et al., 2018; Santi et al., 2016) or decreased semen quality among workers exposed to heat stress (Bonde, 1992; Hamerezaee et al., 2018) though the results were inconsistent (Momen et al., 2010). These results, although still limited, were generally consistent with our results that high ambient temperature was significantly associated with decreased semen quality. The mechanisms on how heat exposure affects semen quality are not fully understood. Consistent results demonstrate that environmental heat exposure can rise scrotal skin temperature (Sheynkin et al., 2005), which is crucial for deleterious semen quality (Hjollund et al., 2000; Jung et al., 2001). High scrotal skin temperature may destroy the protection of enzymatic and non-enzymatic antioxidants, activate testicular heat stress and induce an excessive generation of reactive oxygen species (ROS) (Hamilton et al., 2016; Li et al., 2014), leading to germ cell death in testes and suppression of spermatogenesis (Wang et al., 2007). We also found that low temperature exposure was significantly associated with decreased semen quality, though the association between extreme/moderate cold exposure was weaker than that of extreme/ moderate heat exposure especially for sperm motility. The exposureresponse association between low temperature and semen quality has not been reported previously. Recently, Santi et al., found that minimum temperature exposures at the same day of semen collection, as well as during the 30 and 60 days prior to the date of semen collection were negatively associated with semen quality, indicating better semen quality for lower temperature (Santi et al., 2018). Note that the correlation coefficients were very small (Spearman’s correlation coefficients: −0.05), and this study did not consider potential nonlinear relationship between temperature and semen quality. Cold shock can induce expression of heat shock proteins (Liu et al., 1994) and increase spermatogonial apoptosis (Blanco-Rodriguez and Martinez-Garcia, 1997; Perotti et al., 1990), which may result in reduced number of viable spermatozoa, decreased motility, increasing acrosomal defects and even cell death.
4.3. Strengths and limitations of this study Our study has several strengths. First, the sample size of our longitudinal study was considerably large, which enabled us to conduct exposure-response analyses with sufficient statistical power. The repeated measures of semen quality helped us account for within-subject variability and provide robust results. Second, previous semen quality studies typically investigated qualified sperm donors, college students, or patients from infertility clinics, which were “healthier” or “unhealthier” than the general male population. In this study, we enrolled both qualified sperm donors and those who did not pass the screening of sperm donation, which were closer to the general male population. Third, we considered apparent temperature, which was widely used to assess the effect of temperature on heat-related disorders (Basu et al., 2018; Davis et al., 2016). There are also several limitations. First, we used the mean daily temperatures in Wuhan to estimate ambient temperature exposure for each subject on a given day, which might induce misclassification due to spatial variation of ambient temperature, though the results were biased towards the null. Our meteorological data with high spatial resolution had the potential to provide more precise individual-level exposure assessment; however, we did not have detailed home address information during the study period. Nonetheless, because all participants were living in the same city, variations in ambient temperature due to spatial distribution were expected to be relatively small. Second, the generalizability of our study is limited because all the subjects were from a single city in China. Like in the association between ambient temperature and mortality (Gasparrini et al., 2015), the threshold temperature exposure may vary across regions or populations due to different distributions of ambient temperature exposures. Cautions should be taken to apply our results to other regions or populations. Note that Wuhan is located in central China with distinct seasons and a wide range of ambient temperature throughout the year, making it an ideal place to examine the health effects of ambient temperature. 5. Conclusions In this large longitudinal study, we found an inverted U-shaped exposure-response association between ambient temperature and semen quality. Both low and high ambient temperature exposures were 6
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significantly associated with decreased semen quality. The findings highlight the needs and importance to reduce extreme ambient temperature exposures in maintaining optimal semen quality for men. Further investigation is warranted to determine the causality of the association and the underlying mechanisms.
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Seasonal variation of semen parameters correlates with environmental temperature and air pollution: a big data analysis over 6 years. Environ. Pollut. 235, 806–813. Santi, D., Vezzani, S., Granata, A.R., Roli, L., De Santis, M.C., Ongaro, C., Donati, F., Baraldi, E., Trenti, T., Setti, M., Simoni, M., 2016. Sperm quality and environment: a retrospective, cohort study in a Northern province of Italy. Environ. Res. 150, 144–153. Sharma, R., Harlev, A., Agarwal, A., Esteves, S.C., 2016. Cigarette smoking and semen quality: a new meta-analysis examining the effect of the 2010 World Health Organization Laboratory methods for the examination of human semen. Eur. Urol. 70, 635–645. Sheynkin, Y., Jung, M., Yoo, P., Schulsinger, D., Komaroff, E., 2005. Increase in scrotal temperature in laptop computer users. Hum. Reprod. 20, 452–455. Skakkebaek, N.E., 2017. Sperm counts, testicular cancers, and the environment. BMJ 359, j4517. 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Funding This study was supported by grants from the Fundamental Research Funds for the Central Universities from Sun Yat-sen University (grant number: 19ykpy89), the Hubei Provincial Committee of the Communist Youth League of China, and the Center for Global and Regional Environmental Research at the University of Iowa. Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. Appendix A. Supplementary material Supplementary data to this article can be found online at https:// doi.org/10.1016/j.envint.2019.105364. References Agarwal, A., Mulgund, A., Hamada, A., Chyatte, M.R., 2015. A unique view on male infertility around the globe. Reprod. Biol. Endocrinol. 13, 37. Anderson, G.B., Bell, M.L., Peng, R.D., 2013. Methods to calculate the heat index as an exposure metric in environmental health research. Environ. Health Perspect. 121, 1111–1119. Basu, R., Gavin, L., Pearson, D., Ebisu, K., Malig, B., 2018. Examining the association between apparent temperature and mental health-related emergency room visits in California. Am. J. Epidemiol. 187, 726–735. Blanco-Rodriguez, J., Martinez-Garcia, C., 1997. Mild hypothermia induces apoptosis in rat testis at specific stages of the seminiferous epithelium. J. Androl. 18, 535–539. Bloom, M.S., Whitcomb, B.W., Chen, Z., Ye, A., Kannan, K., Buck Louis, G.M., 2015. Associations between urinary phthalate concentrations and semen quality parameters in a general population. Hum. Reprod. 30, 2645–2657. Bolton, D., 1980. The computation of equivalent potential temperature. Am. Meteorol. Soc. 108, 1046–1053. Bonde, J.P., 1992. Semen quality in welders exposed to radiant heat. Br. J. Ind. Med. 49, 5–10. Carlsen, E., Giwercman, A., Keiding, N., Skakkebaek, N.E., 1992. Evidence for decreasing quality of semen during past 50 years. BMJ 305, 609–613. Chen, R., Yin, P., Wang, L., Liu, C., Niu, Y., Wang, W., Jiang, Y., Liu, Y., Liu, J., Qi, J., You, J., Kan, H., Zhou, M., 2018. Association between ambient temperature and mortality risk and burden: time series study in 272 main Chinese cities. BMJ 363, k4306. Chiu, Y.H., Gaskins, A.J., Williams, P.L., Mendiola, J., Jorgensen, N., Levine, H., Hauser, R., Swan, S.H., Chavarro, J.E., 2016. Intake of fruits and vegetables with low-tomoderate pesticide residues is positively associated with semen-quality parameters among young healthy men. J. Nutr. 146, 1084–1092. Davis, R.E., Hondula, D.M., Patel, A.P., 2016. Temperature observation time and type influence estimates of heat-related mortality in seven U.S Cities. Environ. Health Perspect. 124, 795–804. Fuerst-Waltl, B., Schwarzenbacher, H., Perner, C., Solkner, J., 2006. Effects of age and environmental factors on semen production and semen quality of Austrian Simmental bulls. Anim. Reprod. Sci. 95, 27–37. Gasparrini, A., Guo, Y., Hashizume, M., Lavigne, E., Zanobetti, A., Schwartz, J., Tobias, A., Tong, S., Rocklov, J., Forsberg, B., Leone, M., De Sario, M., Bell, M.L., Guo, Y.L., Wu, C.F., Kan, H., Yi, S.M., de Sousa Zanotti Stagliorio Coelho, M., Saldiva, P.H., Honda, Y., Kim, H., Armstrong, B., 2015. Mortality risk attributable to high and low ambient temperature: a multicountry observational study. Lancet 386, 369–375. Ha, S., Liu, D., Zhu, Y., Sherman, S., Mendola, P., 2018. Acute associations between outdoor temperature and premature rupture of membranes. Epidemiology 29, 175–182. Ha, S., Liu, D., Zhu, Y., Soo Kim, S., Sherman, S., Grantz, K.L., Mendola, P., 2017. Ambient temperature and stillbirth: a multi-center retrospective cohort study. Environ. Health Perspect. 125, 067011. Hamerezaee, M., Dehghan, S.F., Golbabaei, F., Fathi, A., Barzegar, L., Heidarnejad, N., 2018. Assessment of semen quality among workers exposed to heat stress: a crosssectional study in a steel industry. Saf. Health Work 9, 232–235. Hamilton, T.R., Mendes, C.M., de Castro, L.S., de Assis, P.M., Siqueira, A.F., Delgado Jde, C., Goissis, M.D., Muino-Blanco, T., Cebrian-Perez, J.A., Nichi, M., Visintin, J.A., Assumpcao, M.E., 2016. Evaluation of lasting effects of heat stress on sperm profile and oxidative status of ram semen and epididymal sperm. Oxid. Med. Cell Longev.
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Y. Zhou, et al. Sha, J.H., Zhou, Z.M., Hull, L., Leung, A., Swerdloff, R.S., 2007. transient scrotal hyperthermia and levonorgestrel enhance testosterone-induced spermatogenesis suppression in men through increased germ cell apoptosis. J. Clin. Endocrinol. Metab. 92, 3292–3304. World Health Organization, 2010. WHO laboratory manual for the examination and processing of human semen (Accessed Oct 20, 2019). http://whqlibdoc.who.int/ publications/2010/9789241547789_eng.pdf. Wu, L., Jin, L., Shi, T., Zhang, B., Zhou, Y., Zhou, T., Bao, W., Xiang, H., Zuo, Y., Li, G.,
Wang, C., Duan, Y., Peng, Z., Huang, X., Zhang, H., Xu, T., Li, Y., Pan, X., Xia, Y., Gong, X., Chen, W., Liu, Y., 2017. Association between ambient particulate matter exposure and semen quality in Wuhan, China. Environ. Int. 98, 219–228. Zhao, Q., Zhao, Y., Li, S., Zhang, Y., Wang, Q., Zhang, H., Qiao, H., Li, W., Huxley, R., Williams, G., Zhang, Y., Guo, Y., 2018. Impact of ambient temperature on clinical visits for cardio-respiratory diseases in rural villages in northwest China. Sci. Total., Environ. 612, 379–385.
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Association between ambient temperature and semen quality: A longitudinal study of 10 802 men in China
T
Yun Zhoua,1, Tianqing Mengb,1, Li Wuc, Yonggang Duand, Guo Lie, Chunxiang Shif, Hai Zhangg, ⁎ ⁎ Zhe Pengg, Chuangang Fang, Jixuan Mah, Chengliang Xiongb, Wei Baoi, , Yuewei Liuj, a
School of Public Health, Guangzhou Medical University, Guangzhou, Guangdong 511436, China Center for Reproductive Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China c Reproductive Medical Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China d Shenzhen Key Laboratory of Fertility Regulation, Centre of Assisted Reproduction and Embryology, The University of Hong Kong – Shenzhen Hospital, Shenzhen, Guangdong 518053, China e Department of Neurology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China f National Meteorological Information Center, Beijing 100081, China g Institute of Health Surveillance, Analysis and Protection, Hubei Provincial Center for Disease Control and Prevention, Wuhan, Hubei 430079, China h Department of Occupational and Environmental Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China i Department of Epidemiology, College of Public Health, University of Iowa, Iowa City, IA 52242, USA j Department of Epidemiology, School of Public Health, Sun Yat-sen University, Guangzhou, Guangdong 510080, China b
ARTICLE INFO
ABSTRACT
Handling editor: Mark Nieuwenhuijsen
Semen quality is a vital determinant for male fertility. The process of spermatogenesis is highly sensitive to fluctuations in temperature. However, the impact of ambient temperature on semen quality remains unclear. We aimed to quantitatively assess the association between ambient temperature and semen quality. Using data from Hubei provincial human sperm bank in Wuhan, China, we conducted a longitudinal study including 10 802 volunteers who lived in Wuhan and passed the initial physical examination for sperm donation between Mar 27, 2013 and April 9, 2018. Semen quality parameters including sperm concentration, total sperm number, total motility, progressive motility, total motile sperm count and progressively motile sperm count were determined in the sperm bank. We used linear mixed models to identify estimate changes of outcomes in relation to ambient temperature (i.e., air temperature and apparent temperature) exposure measured as the mean daily temperature during the 0–90 days before semen collection. Among 10 802 subjects who underwent 41 689 semen examinations, we observed inverted U-shaped exposure-response associations between air temperature exposure and all semen quality parameters, with an identical threshold exposure of 13 °C. For air temperature exposure < 13 °C, each 5 °C lower temperature was significantly associated with 1.94 × 106/ml, 7.12 × 106, 0.77%, 0.81%, 6.48 × 106, and 5.87 × 106 decrease in sperm concentration, total sperm count, total motility, progressive motility, total motile sperm count and progressively motile sperm count, respectively. When air temperature exposure was ≥13 °C, each 5 °C higher temperature was significantly associated with 0.70 × 106/ ml, 4.09 × 106, 1.01%, 1.06%, 4.31 × 106, and 4.20 × 106 decrease in sperm concentration, total sperm count, total motility, progressive motility, total motile sperm count and progressively motile sperm count, respectively. Age, BMI and smoking did not significantly modify these associations. Similar results were observed for apparent temperature. This study provides a comprehensive picture of nonlinear association between ambient temperature and semen quality, as well as an optimal temperature for the benefit of semen quality. Both lower and higher ambient temperature exposures compared with the optimal temperature were significantly associated with decreased semen quality. The findings highlight the needs and importance to reduce extreme ambient temperature exposures in maintaining optimal semen quality for men. Further investigation is warranted to determine the causality of the association and the underlying mechanisms.
Keywords: Ambient temperature Semen quality Exposure-response relationship
Corresponding authors at: Department of Epidemiology, School of Public Health, Sun Yat-sen University, 74 Zhongshan Second Road, Guangzhou, Guangdong 510080, China (Y. Liu); Department of Epidemiology, College of Public Health, University of Iowa, 145 North Riverside Drive, Iowa City, Iowa 52242, USA (W. Bao). E-mail addresses: [email protected] (W. Bao), [email protected] (Y. Liu). 1 These authors contributed equally to this work. ⁎
https://doi.org/10.1016/j.envint.2019.105364 Received 6 May 2019; Received in revised form 20 October 2019; Accepted 25 November 2019 0160-4120/ © 2019 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/BY-NC-ND/4.0/).
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1. Introduction
and laboratory tests for various conditions including genetic disorders and sexually transmitted diseases were qualified as sperm donors. The qualified sperm donors were then asked to donate sperm multiple times and determined for semen quality during each donation. All data used in this study was de-identified and coded. This study was approved by the ethical committee of the Hubei Provincial Center for Disease Control and Prevention.
As a global public health issue, infertility affects approximately 15% of all reproductive age couples worldwide (Salas-Huetos et al., 2017). It has been estimated that male factors, mainly poor semen quality, are responsible for 20% to 70% of the infertility cases (Agarwal et al., 2015). Extensive evidence suggests that semen quality is continuously declining globally (Carlsen et al., 1992; Swan et al., 2000). A recent systematic review and meta-regression analysis reported that sperm count measured by both sperm concentration and total sperm number decreased by 50–60% among men from North America, Europe and Australia from 1973 to 2011 (Levine et al., 2017). In a large sperm bank in China, sperm concentration, progressively motile sperm count, and percentage of normal sperm morphology were estimated to decrease by 31%, 38%, and 66% respectively between 2001 and 2015, while the percentage of qualified sperm donors decreased from 55.8% to 17.8% (Huang et al., 2017). Although previous studies have linked endocrine disrupting chemicals, diet, stress, smoking and obesity with decreased semen quality (Bloom et al., 2015; Chiu et al., 2016; Hammiche et al., 2012; Nordkap et al., 2016; Sharma et al., 2016), the causes of decreased semen quality remain to be elucidated. The process of spermatogenesis is sensitive to fluctuations in temperature. An optimal temperature of 2 °C to 4 °C below the core body temperature is required for normal spermatogenesis (Ivell, 2007). Scrotum has a mandatory function to maintain the temperature of the testes by physiological structures including scrotum skin, arterial and spermatic veins, as well as the dartos fascia in the scrotum and the cremaster muscle (Ivell, 2007; Kleisner et al., 2010; Song and Seo, 2009). However, several animal studies have observed adverse effects of high environmental temperature and humidity on semen production and semen quality, indicating that the ability of temperature regulation in scrotum is limited (Fuerst-Waltl et al., 2006; Suriyasomboon et al., 2005). Ambient temperature exposure has been associated with various reproductive health outcomes including low birth weight, stillbirth and preterm birth (Ha et al., 2017; He et al., 2016; Ngo and Horton, 2016). However, little is known about the impact of ambient temperature exposure, especially extremely heat or cold, on semen quality. A limited number of epidemiological studies have investigated the season fluctuation of semen quality (Mao et al., 2017; Santi et al., 2018; Santi et al., 2016), compared semen quality of workers exposed to heat stress with non-occupational individuals (Bonde, 1992; Hamerezaee et al., 2018; Momen et al., 2010), and suggested that high environmental temperature might be related with decreased semen quality. However, most of these studies did not conduct quantitative exposure-response analysis and the results remain inconsistent. Furthermore, to our knowledge, no studies have examined the association between low ambient temperature exposure and semen quality to date. Therefore, we conducted a large longitudinal study of 10 802 Chinese men in Wuhan, China who underwent 41 689 semen examinations between 2013 and 2018. This study aimed to quantitatively assess the exposure-response association between ambient temperature exposure and semen quality. We hypothesized that both high and low temperature exposure would be associated with decreased semen quality.
2.2. Exposure assessment Hourly gridded meteorological data with a 0.0625° × 0.0625° resolution in Wuhan were obtained from the China Meteorological Administration Land Data Assimilation System (CLDAS version 2.0), which was released and maintained by the China Meteorological Administration. For each day between December 27, 2012 and April 9, 2018, we extracted hourly average 2 m air temperature, 2 m specific humidity, and surface air pressure values for all grids within Wuhan, and then averaged them by day to calculate city-level daily mean air temperature (°C), specific humidity (kg/kg), and air pressure (mb). Daily apparent temperature was calculated using air temperature and relative humidity (%) with weathermetrics, an R package developed by Anderson et al., (Anderson et al., 2013), where the relative humidity was estimated using the following formulas (Bolton, 1980): 17.67 ×
Saturation vapor pressure = 6.112 × e Actual vapor pressure =
Relative humidity =
air temperature air temperature + 243.5
specific humidity × air pressure 0.378 × specific humdity + 0.622
actual vapor pressure × 100 saturation vapor pressure
(1) (2) (3)
Because the entire process of human spermatogenesis takes approximately 90 days, we estimated exposures to both air temperature and apparent temperature for each subject on each date of semen collection by calculating mean daily temperature during the 0–90 days before semen collection (i.e. lag 0–90 day exposure) (Johnson et al., 1997). 2.3. Study outcome Semen quality was determined in the sperm bank as described previously (Ma et al., 2019). We defined semen quality as the study outcome. In brief, each subject was advised to practice abstinence for 2 to 7 days before semen analysis. Semen samples were collected by masturbating into a sterile plastic container, and then liquefied in an incubator at 37 °C for 30 min. Each semen sample was weighed to determine the semen volume and was extracted for 10 μl to a Makler chamber to assess sperm concentration, total motility, and progressive motility. In this study, the outcome variables included sperm concentration, total motility, and progressive motility measured in the semen analyses, as well as total sperm number, total motile sperm count and progressively motile sperm count which were calculated as semen volume multiplying sperm concentration, total sperm number multiplying total motility, and total sperm number multiplying progressive motility, respectively.
2. Methods
2.4. Covariates
2.1. Study design and subjects
Trained investigators collected demographic and lifestyle information on age, height, weight, education, smoking, and abstinence period at semen collection for all subjects. Data on height, weight, and smoking were collected for all qualified sperm donors and 13.3% of those who did not donate sperm. Body mass index (BMI) was calculated as weight (kg) divided by square of height (m). Current smokers were defined as those who had smoked at least 1 cigarette per day in the past 6 months. Participants without smoking information were classified as
This is a longitudinal study of 10 802 men from Wuhan, China who intended to donate sperm at the Hubei provincial human sperm bank and passed the initial physical examination for color vision deficiency (which can be passed on to the offspring via sperm), hypertension and abnormal heart rate during Mar 27, 2013 and April 9, 2018. All these subjects were tested for semen quality at least once, and only those who passed at least one semen quality test and further physical examination 2
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“Unknown”. In addition, we considered particulate matter ≤ 2.5 μm in aerodynamic diameter (PM2.5) as a covariate to account for potential confounding by air pollution (Wu et al., 2017). We collected daily 24hour average PM2.5 concentrations measured at 20 fixed air quality monitoring stations in Wuhan between December 27, 2012 and April 9, 2018 from the Wuhan Environmental Protection Bureau, and averaged them by day to obtain daily mean PM2.5 concentration in Wuhan. Similar to the exposure assessment for temperature, exposure to PM2.5 was calculated as the mean of daily concentrations on the same day of semen collection and 90 days prior. To account for potential acute effect of temperature on semen quality, we also included daily temperature on the same day of semen collection in all models. In all analyses on air temperature, we treated relative humidity exposure as a covariate, which was estimated using the same approach as that for the air temperature.
Table 1 Baseline characteristics of study subjects. Characteristic
Age, y 20–25, n (%) 25–29, n (%) ≥30, n (%) BMI*, kg/m2 < 18.5, n (%) 18.5–24.9, n (%) 25.0–29.9, n (%) ≥30.0, n (%) Unknown, n (%) Education, n (%) High school and lower Junior college Undergraduate and higher Unknown Current smoking*, n (%) No Yes Unknown
2.5. Statistical analysis We used linear mixed models with a subject-specific random intercept to quantitatively assess the exposure-response associations between ambient temperature (both air temperature and apparent temperature) exposure and semen quality parameters. This method allowed us to account for correlations among repeated measures of semen quality at different visits contributed by a single subject. By assuming that both low and high temperature exposures may adversely affect semen quality, we first modeled temperature exposure as a natural cubic spline function with 4 degrees of freedom to allow for a nonlinear relationship with semen quality, and plotted estimated changes with 95% confidence intervals (CIs) for each semen quality parameter. Likelihood ratio test was used to examine the nonlinear trend. We also detected threshold temperature that occurred at the minimal absolute estimated changes. Specific estimated changes relative to the threshold temperature exposure were calculated for locally extreme cold, moderate cold, moderate heat and extreme heat, which were defined as the 1th, 5th, 95th, and 99th percentile of daily mean lag 0–90 day temperature during the study period, respectively. All models were adjusted for potential confounders including age, BMI, education, smoking, abstinence period, year, season, and daily temperature on the day of semen collection, as well as lag 0–90 day PM2.5 concentration, and lag 0–90 day relative humidity (for air temperature model only). In addition, we conducted subgroup analyses according to the identified threshold temperature exposure for each semen quality parameter. For temperature exposure lower than the threshold, we estimated changes in each semen quality parameter associated with each 5 °C decrease of temperature exposure; for temperature exposure higher than the threshold, estimated changes were assessed for each 5 °C increase of temperature exposure. We conducted stratified analyses by age, BMI and smoking, and used likelihood ratio tests to examine their potential effect modification on the association between temperature exposure and semen quality. Sensitivity analyses were performed to assess the robustness of our results. First, we analyzed the data without adjustment for temperature exposure on the same day of semen collection. Second, we restricted data on qualified sperm donors only. Finally, we examined potential confounding effects by smoking and BMI by fitting models with or without adjustment for them among qualified sperm donors. All data analyses were performed using R version 3.5.1. All statistical tests were 2-sided, and a P value < 0.05 was considered statistically significant.
No. of semen collection Abstinence period before semen examination, days 2–3, n (%) 4–5, n (%) 6–7, n (%) Year at semen examination, n (%) 2013 2014 2015 2016 2017 2018 Season at semen examination, n (%) Warm (Mar-Aug) Cool (Sep-Dec, Jan, Feb)
All subjects (n = 10 802)
Subjects qualified as sperm donors (n = 3966)
Subjects not qualified as sperm donors (n = 6836)
3829 (35.4) 3595 (33.3) 3378 (31.3)
1312 (33.1) 1356 (34.2) 1298 (32.7)
2517 (36.8) 2239 (32.8) 2080 (30.4)
286 (2.6) 3734 (34.6) 808 (7.5) 49 (0.5) 5925 (54.9)
222 (5.6) 3046 (76.8) 660 (16.6) 38 (1.0) 0 (0.0)
64 (0.9) 688 (10.1) 148 (2.2) 11 (0.2) 5925 (86.7)
3510 (32.5) 3693 (34.2) 3592 (33.3)
1122 (28.3) 1385 (34.9) 1458 (36.8)
2388 (34.9) 2308 (33.8) 2134 (31.2)
7 (0.1)
1 (0.0)
6 (0.1)
3246 (30.0) 1628 (15.1) 5928 (54.9)
2694 (67.9) 1269 (32.0) 3 (0.1)
552 (8.1) 359 (5.3) 5925 (86.7)
41 689
29 849
11 840
5449 (13.1) 15 026 (36.0) 21 214 (50.9)
3095 (10.4) 11 290 (37.8)
2354 (19.9) 3736 (31.6)
15 464 (51.8)
5750 (48.6)
6923 (16.6) 8837 (21.2) 9600 (23.0) 9325 (22.4) 6015 (14.4) 989 (2.4)
3647 (12.2) 6077 (20.4) 7825 (26.2) 7187 (24.1) 4446 (14.9) 667 (2.2)
3276 (27.7) 2760 (23.3) 1775 (15.0) 2138 (18.1) 1569 (13.3) 322 (2.7)
22 824 (54.7) 18 865 (45.3)
16 111 (54.0)
6713 (56.7)
13 738 (46.0)
5127 (43.3)
BMI = body mass index; SD = standardized deviation; IQR = interquartile range. * Only available for qualified sperm donors and 13.3% of subjects not qualified as sperm donors.
semen samples, and 6836 (63.3%) subjects who did not donate sperm provided 11 840 (28.4%) semen samples. The mean age of all subjects was 28.3 years, and 68.7% were under 30 years. About 87% of the semen samples were collected and tested after an abstinence for at least 4 days. 3.2. Semen quality The mean daily number of semen collection was 24, ranging from 1 to 66. Table 2 gives distribution of each semen quality parameter based on 41 689 semen examinations. The qualified sperm donors completed a median of 7 donations, with median sperm concentration, total sperm number, total motility, progressive motility, total motile sperm count, and progressively motile sperm count of 62.0 × 106/ml, 168.0 × 106, 66.0%, 61.0%, 107.1 × 106, and 99.3 × 106, respectively, and 94.3% of the semen samples met the WHO lower reference limits (sperm concentration: 15 × 106/ml; total sperm number: 39 × 106; total motility: 40%; progressive motility: 32%) (World Health Organization, 2010). For those who did not donate sperm, about 94% of them
3. Results 3.1. Study subjects and characteristics As shown in Table 1, a total of 10 802 subjects who underwent 41 689 semen examinations were enrolled in this study. Of them, 3966 (36.7%) subjects qualified as sperm donors provided 29 849 (71.6%) 3
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Table 2 Distributions of semen quality parameters based on 41 689 semen examinations. Semen Quality Parameter Semen examinations by subjects qualified as sperm donors (n = 29 849) Sperm concentration, ×106/ml Total sperm number, ×106 Total motility, % Progressive motility, % Total motile sperm count, ×106 Progressively motile sperm count, ×106 Semen examinations by subjects not qualified as sperm donors (n = 11 840) Sperm concentration, ×106/ml Total sperm number, ×106 Total motility, % Progressive motility, % Total motile sperm count, ×106 Progressively motile sperm count, ×106
Mean
SD
Minimum
P25
Median
P75
Maximum
59.5 188.3 63.1 58.6 119.9 111.4
15.0 89.7 9.7 9.6 61.7 57.8
0.1 0.3 5.0 3.0 0.04 0.04
60.0 130.0 62.0 60.0 81.6 75.6
62.0 168.0 66.0 61.0 107.1 99.3
67.0 240.0 68.0 64.0 152.1 143.2
240.0 928.0 98.0 94.0 621.8 566.1
35.7 108.8 55.7 50.0 59.4 53.6
20.0 84.3 14.5 14.6 47.3 43.8
0.01 0.01 1.0 1.0 0.01 0.01
20.0 45.0 46.0 40.0 23.9 21.0
34.0* 90.2* 56.0* 50.0* 48.4* 43.2*
48.0 151.7 66.0 62.0 84.0 76.6
280.0 750.4 99.0 91.0 462.1 433.2
SD = standardized deviation; P25 = the 25th percentile; P75 = the 75th percentile. * P < 0.05 compared with semen examinations by qualified sperm donors.
provided 1 to 3 semen samples, and all median semen quality parameters were significantly lower than those of qualified sperm donors (all P < 0.05).
3.4. Exposure-response analysis As shown in Fig. 2, we observed inverted U-shaped exposure-response relationships between air temperature exposure and all semen quality parameters, with generally the same threshold of 13 °C, and the relationship was close to linearity when the exposure was lower or higher than the threshold. Extreme and moderate cold were significantly associated with all semen quality parameters, except for moderate cold and total motility, and the associations were overall weaker than that of corresponding associations for extreme and moderate heat, especially sperm motility (Fig. 2, Fig A.1 and Table A.1 in the supplementary materials). The subgroup analyses demonstrated that each 5 °C decrease of air temperature exposure was significantly associated with 1.94 × 106/ml, 7.12 × 106, 0.77%, 0.81%, 6.48 × 106, and 5.87 × 106 decrease in sperm concentration, total sperm number, total motility, progressive motility, total motile sperm count and progressively motile sperm count, respectively (all P < 0.05), when the air temperature was lower than 13 °C; while each
3.3. Ambient temperature exposure Fig. 1 shows the distributions of daily temperature and daily mean lag 0–90 day temperature in Wuhan during the study period. The daily air temperature in the study area (mean: 17.2 °C; range: −3.0 °C to 34.6 °C) was higher in summers and lower in winters. The apparent temperature showed similar trend, but were overall higher than that of the air temperature in summer, and lower in winter. The 1th, 5th, 95th, and 99th percentile of daily mean lag 0–90 day temperature were 5.6 °C, 6.5 °C, 28.3 °C, 29.3 °C for air temperature, and were 4.7 °C, 5.5 °C, 33.1 °C, 34.2 °C for apparent temperature. The mean exposures to air temperature and apparent temperature in this study were 18.9 °C (range: 5.4 °C to 29.6 °C) and 19.8 °C (range: 4.5 °C to 34.6 °C), respectively.
Fig. 1. Distributions of ambient temperature and number of semen collection in Wuhan, China between 2013 and 2018. The blue lines present daily air temperatures and apparent temperatures. The red lines present daily mean lag 0–90 day air temperatures and apparent temperatures. 4
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Fig. 2. Inverted U-shaped exposure-response association between air temperature exposure and semen quality. The air temperature exposure was defined as the mean of daily air temperature during 0–90 days before semen collection. Extreme cold, moderate cold, moderate heat, and extreme heat were defined by the 1st (5.6 °C), 5th (6.5 °C), 95th (28.3 °C), and 99th (29.3 °C) percentile of daily mean lag 0–90 day air temperature in Wuhan, China between 2013 and 2018. Estimated changes (95% CIs) were assessed by including air temperature exposure as a natural cubic spline function in the linear mixed model, adjusting for age, BMI, education, smoking, abstinence period, year, season, and daily air temperature on the date of semen collection, as well as lag 0–90 day PM2.5 concentration and lag 0–90 day relative humidity. The vertical dashed lines present threshold exposure values. CI = confidence interval; BMI = body mass index; PM2.5 = particulate matter ≤ 2.5 μm in aerodynamic diameter.
Table 3 Estimated changes for semen quality associated with each 5 °C change of air temperature exposure by threshold. Semen quality parameter
Air temperature exposure* < 13 °C, per 5 °C decrease†
Sperm concentration, ×106/ml Total sperm number, ×106 Total motility, % Progressive motility, % Total motile sperm count, ×106 Progressively motile sperm count, ×106
≥13 °C, per 5 °C increase†
Estimated change (95% CIs)
p value
Estimated change (95% CIs)
p value
−1.94 −7.12 −0.77 −0.81 −6.48 −5.87
< 0.001 0.007 0.03 0.02 < 0.001 < 0.001
−0.70 −4.09 −1.01 −1.06 −4.31 −4.20
0.002 < 0.001 < 0.001 < 0.001 < 0.001 < 0.001
(−2.91, −0.97) (−12.31, −1.93) (−1.46, −0.07) (−1.50, −0.11) (−9.92, −3.04) (−9.11, −2.64)
(−1.14, (−6.31, (−1.32, (−1.37, (−5.77, (−5.57,
−0.26) −1.87) −0.70) −0.75) −2.84) −2.82)
CI = confidence interval; BMI = body mass index; PM2.5 = particulate matter ≤ 2.5 μm in aerodynamic diameter. * The air temperature exposure was defined as the mean of daily air temperature during 0–90 days before semen collection. † Estimated changes (95% CIs) were estimated using linear mixed models, adjusting for age, BMI, education, smoking, abstinence period, year, season, and daily air temperature on the date of semen collection, as well as lag 0–90 day mean PM2.5 concentration and lag 0–90 day relative humidity.
3.5. Sensitivity analyses
5 °C increase of air temperature exposure was significantly associated with 0.70 × 106/ml, 4.09 × 106, 1.01%, 1.06%, 4.31 × 106, and 4.20 × 106 decrease in sperm concentration, total sperm number, total motility, progressive motility, total motile sperm count and progressively motile sperm count, respectively (all P < 0.05), when the air temperature was equal to or higher than 13 °C (Table 3). Similar results were observed for apparent temperature exposure (Fig A.2 and Table A.2 in the supplementary materials).
Fig A.3 (in the supplementary materials) shows that age, BMI and smoking did not appear to significantly modify the association between air temperature exposure and semen quality (all P > 0.05), though some associations became insignificant possibly due to small sample size. Models without adjustment for temperature on the same day of semen collection gave similar results (Fig A.4 in the supplementary materials). As shown in Table A.3 (in the supplementary materials), analyses restricted to qualified sperm donors yielded overall stronger 5
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associations between air temperature exposure and semen quality parameters. Compared with models adjusting for smoking and BMI, the results remained very similar without adjustment for smoking and BMI, indicating that smoking and BMI did not significantly confound the associations.
4.2. Meaning of the study Infertility has become an important issue not only in human health but also in politics and economy, leading to the growing use of assisted reproduction techniques worldwide. However, the fertility clinics do not remarkably increasing fertility rate, which remains well below the replacement rate in many countries (Skakkebaek, 2017). Deterioration of semen quality is a main cause of male infertility. The declining semen quality coincides with the global climate change especially the occurrence of extreme temperature. Although accumulating evidence indicates that high or low ambient temperature could increase the risks of noncommunicable diseases (Chen et al., 2018; Valdes et al., 2019; Zhao et al., 2018) as well as adverse reproductive outcomes in pregnant women or infants (Ha et al., 2018; He et al., 2016), the effect on semen quality remains unclear. Consistent with previous animal studies and most of the limited epidemiological studies, this study provides a comprehensive picture of nonlinear association between ambient temperature and semen quality to help better understand the impact of ambient temperature on male reproductive health. The findings support the hypotheses that high temperature exposure adversely affects human semen quality, and provide new insight into the impact of temperature on semen quality that low ambient temperature exposure may also affect semen quality. This study highlights the needs and importance to reduce extreme ambient temperature exposure in maintaining optimal semen quality for men.
4. Discussion In this large longitudinal study, we found an inverted U-shaped exposure-response association between ambient temperature and semen quality, and identified the threshold exposures for air temperature (13 °C) and apparent temperature (12 °C). Both low (< threshold exposure) and high (≥threshold exposure) temperature exposures were significantly and linearly associated with decreased sperm count and motility. Compared with low temperature, high temperature exposure had a similar association with sperm count, but a much stronger association with sperm motility. These associations were considerably robust, and were not significantly modified by age, BMI or smoking. 4.1. Comparison with other studies and implications of findings To our knowledge, this is the first study to quantitatively assess the exposure-response association between ambient temperature exposure and semen quality with a large sample size. In 2006, Sokol et al., investigated the acute effect of temperature on semen quality with a small sample size of 48 sperm donors from Los Angeles, US, and reported that air temperature on the day of semen collection was not significantly associated with either sperm concentration or total motile sperm count. However, this study did not account for temperature exposure during the spermatogenesis (i.e. 90 days before the date of semen collection), and only examined potential linear associations (Sokol et al., 2006). Other studies reported significant lower semen quality in summer when the temperature was relatively high (Mao et al., 2017; Santi et al., 2018; Santi et al., 2016) or decreased semen quality among workers exposed to heat stress (Bonde, 1992; Hamerezaee et al., 2018) though the results were inconsistent (Momen et al., 2010). These results, although still limited, were generally consistent with our results that high ambient temperature was significantly associated with decreased semen quality. The mechanisms on how heat exposure affects semen quality are not fully understood. Consistent results demonstrate that environmental heat exposure can rise scrotal skin temperature (Sheynkin et al., 2005), which is crucial for deleterious semen quality (Hjollund et al., 2000; Jung et al., 2001). High scrotal skin temperature may destroy the protection of enzymatic and non-enzymatic antioxidants, activate testicular heat stress and induce an excessive generation of reactive oxygen species (ROS) (Hamilton et al., 2016; Li et al., 2014), leading to germ cell death in testes and suppression of spermatogenesis (Wang et al., 2007). We also found that low temperature exposure was significantly associated with decreased semen quality, though the association between extreme/moderate cold exposure was weaker than that of extreme/ moderate heat exposure especially for sperm motility. The exposureresponse association between low temperature and semen quality has not been reported previously. Recently, Santi et al., found that minimum temperature exposures at the same day of semen collection, as well as during the 30 and 60 days prior to the date of semen collection were negatively associated with semen quality, indicating better semen quality for lower temperature (Santi et al., 2018). Note that the correlation coefficients were very small (Spearman’s correlation coefficients: −0.05), and this study did not consider potential nonlinear relationship between temperature and semen quality. Cold shock can induce expression of heat shock proteins (Liu et al., 1994) and increase spermatogonial apoptosis (Blanco-Rodriguez and Martinez-Garcia, 1997; Perotti et al., 1990), which may result in reduced number of viable spermatozoa, decreased motility, increasing acrosomal defects and even cell death.
4.3. Strengths and limitations of this study Our study has several strengths. First, the sample size of our longitudinal study was considerably large, which enabled us to conduct exposure-response analyses with sufficient statistical power. The repeated measures of semen quality helped us account for within-subject variability and provide robust results. Second, previous semen quality studies typically investigated qualified sperm donors, college students, or patients from infertility clinics, which were “healthier” or “unhealthier” than the general male population. In this study, we enrolled both qualified sperm donors and those who did not pass the screening of sperm donation, which were closer to the general male population. Third, we considered apparent temperature, which was widely used to assess the effect of temperature on heat-related disorders (Basu et al., 2018; Davis et al., 2016). There are also several limitations. First, we used the mean daily temperatures in Wuhan to estimate ambient temperature exposure for each subject on a given day, which might induce misclassification due to spatial variation of ambient temperature, though the results were biased towards the null. Our meteorological data with high spatial resolution had the potential to provide more precise individual-level exposure assessment; however, we did not have detailed home address information during the study period. Nonetheless, because all participants were living in the same city, variations in ambient temperature due to spatial distribution were expected to be relatively small. Second, the generalizability of our study is limited because all the subjects were from a single city in China. Like in the association between ambient temperature and mortality (Gasparrini et al., 2015), the threshold temperature exposure may vary across regions or populations due to different distributions of ambient temperature exposures. Cautions should be taken to apply our results to other regions or populations. Note that Wuhan is located in central China with distinct seasons and a wide range of ambient temperature throughout the year, making it an ideal place to examine the health effects of ambient temperature. 5. Conclusions In this large longitudinal study, we found an inverted U-shaped exposure-response association between ambient temperature and semen quality. Both low and high ambient temperature exposures were 6
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significantly associated with decreased semen quality. The findings highlight the needs and importance to reduce extreme ambient temperature exposures in maintaining optimal semen quality for men. Further investigation is warranted to determine the causality of the association and the underlying mechanisms.
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