By Robert W. Rebar, MD
Professor and Chair, Department of Obstetrics and Gynecology, Western Michigan University Homer Stryker MD School of Medicine, Kalamazoo
Dr. Rebar reports no financial relationships relevant to this field of study.
Synopsis: This special feature is intended to provide readers with information needed about the potential impact of the environment and lifestyle on male reproductive function so that they can better take histories and counsel couples presenting with questions about infertility.
The fact that various chemical substances found in the environment can impact reproductive function in men has been known for decades. In 1975, it was proposed that fertility was impaired in male workers exposed to excessive quantities of lead.1 A few years later, reduced sperm counts were reported in employees working at a plant manufacturing the pesticide 1,2-dibromo-3-chloropropane.2 In 1993, Colburn and colleagues suggested that endocrine-disrupting chemicals (EDCs), which mimic the effects of endogenous hormones or induce changes in the activity or levels of endogenous steroidogenic hormones, might impact the progeny of those exposed as well as the individuals themselves.3 In the subsequent years, it has become apparent that EDCs are extremely common, being found in small amounts in foods as pesticides and fumigants, in insecticides and solvents, and as plasticizers in a number of household items. The majority of EDCs act either as an estrogenic substance or as an antiandrogen.
In fact, it is estimated that about 50,000 chemicals are used in consumer products and industrial processes in the United States; however, the actual number is uncertain because chemicals are not registered or proven safe before use.4 Because the U.S. Environmental Protection Agency must demonstrate that a substance is dangerous after consumer release, only about 300 chemicals have been tested and fewer than 10 have had their usage restricted. Yet it is estimated that 10-30% of chemicals merit additional restrictions because of their risks to health. These numbers emphasize the difficulties in studying the impact of any one chemical on reproductive function.
Coincident with these reports was a series of alarming suggestions that sperm counts were decreasing over time in Western countries.5,6 Whether there is indeed a worldwide decline in sperm quality remains controversial, but it is certainly plausible given the increasing prevalence of EDCs and remains a reason for concern.
Pesticides, Bisphenol A, and Phtalates
As one example, eating produce containing higher quantities of pesticide residue (based on annual USDA reports) appears to be associated with lower sperm counts.7 Researchers assessed pesticide residues in the diets of 155 men aged 26-51 years who were seen at a Boston fertility clinic and then analyzed these findings in relation to semen quality. Participants consumed a mean of 0.9 daily servings of high-pesticide fruits and vegetables and 2.3 servings of low-to-moderate pesticide produce. Although total produce intake was not associated with semen quality, men in the highest quartile of high-pesticide fruit and vegetable consumption had on average 49% fewer sperm, 32% fewer morphologically normal sperm, and 29% lower ejaculate volumes than men in the lowest quartile. (High-residue produce includes such items as strawberries, peaches, plums, blueberries, apples, pears, spinach, celery, and potatoes; lowest residue produce includes peas, lima beans, grapefruit, prunes, onion, beans or lentils, avocado, and corn.)
Diesters of phthalic acid, commonly called phthalates, have been one continuing source of concern because they are used in so many products, including personal care products (such as makeup, shampoos, and soaps), plastics, paints, and even some pesticides. Phthalates have been shown to disrupt reproductive tract development in male rodents by acting as an antiandrogen.8 Because a number of studies suggested that prenatal exposure to various phthalates led to significant reductions in the anogenital distance (AGD) in rodents (and the AGD is uniformly less in females than in males in most species), Swan and colleagues9 measured the AGD and recorded other genital measurements in male infants with varying phthalate exposure and reported that the AGD was also reduced in humans and that phthalates can affect human male reproductive tract development. Very recent studies have indicated that paternal phthalate and bisphenol A (BPA) exposure is associated with excess female births, and maternal phthalate and BPA exposure is associated with excess male births.10
Epigenetic Changes, Spermatogenesis, and Male Infertility
Several genes in the testes are regulated through epigenetic programming wherein changes occur in DNA methylation, histone modification, or chromatin remodeling. Alarmingly, it is now clear, for example, that exposure to the antiandrogenic endocrine disruptor vinclozolin (a fungicide that is used on fruits, vegetables, ornamental plants, and turf grass) during embryonic gonadal sex determination in the rodent can alter this epigenetic programming and affect not only the developing offspring, but also subsequent generations.11,12 Exposure to vinclozolin leads to transgenerational adult onset disease in the rodent, including spermatogenic defects, prostate disease, kidney disease, and cancer.13 Might there be similar effects in human males exposed to some EDCs?
Cigarette Smoking, Alcohol Consumption, and Marijuana Use
Effects on human male reproduction do not appear limited to less commonly known chemicals. There are data suggesting that both cigarette smoking and alcohol consumption can affect male reproductive function, at least for those undergoing in vitro fertilization (IVF). Couples (one or both) who ever smoked had an adjusted relative risk (RR) of 2.41 of not achieving a pregnancy by IVF and of 3.76 of not achieving a live birth; couples smoking for more than 5 years had a RR of 4.26 of not achieving a pregnancy.14 In this study, the number of oocytes retrieved decreased by 40% for couples and 46% for men smoking the week of IVF. It is not clear if the male partner’s smoking affected retrieval of oocytes because of exposure of the female partner to tobacco passively or if another mechanism might be involved. A more recent study showed that cigarette smoking resulted in reductions in total testosterone, total sperm count, and progressive motility of sperm in Saudi Arabian men presenting to an infertility clinic.15 A 2003 study indicated that each additional alcoholic drink (over the recommended 1-2 drinks) each day consumed by the male partner increased the risk of not having a live birth with IVF and gamete intrafallopian transfer.16 More recent data from a self-administered questionnaire completed by 2545 couples undergoing 4729 cycles of IVF indicated that couples in which both partners drank four or more alcoholic drinks per week had a 21% lower live birth rate than those in which both partners drank less.17
Data also indicate that marijuana use by male partners affects reproductive outcomes.18 If men smoked marijuana 11 to 90 times in their lives, there was a 15% decrease in infant birth weight with IVF and gamete intrafallopian transfer (P = 0.03); if they smoked more than 90 times, birthweight was decreased by 23% (P = 0.01). That timing of the marijuana use is important and showed that men who smoked in the 15 years previous to IVF had 16% smaller infants (P = 0.03).
Presumably these data regarding IVF can be extrapolated to men attempting to reproduce naturally and suggest an effect of cigarette smoking, alcohol, and marijuana on male reproductive function.
Physical Activity and Television Watching
Other aspects of lifestyle also may have an impact on sperm count. In a study of 189 young men aged 18-22 years in Rochester, NY, activity levels and time spent watching television were assessed by questionnaire and correlated with sperm counts.19 After multivariable adjustment, sperm concentrations in men in the highest quartile for moderate-to-vigorous physical activity (≥ 15 hours per week) were 73% higher than those in the lowest quartile for activity (< 5 hours weekly). In contrast, sperm concentrations in men in the highest quartile of TV watching (> 20 hours weekly) were 44% lower than those in the lowest quartile (0 hours weekly). Interestingly, only sperm concentrations and not sperm motility nor morphology were affected by either parameter.
IVF and Imprinting Disorders
It now appears that IVF, with or without intracytoplasmic sperm injection, is associated with a slight increase in the risk of imprinting disorders in the progeny, including Angelman syndrome, Beckwith-Wiedemann syndrome, Silver-Russell syndrome, and isolated hemihypertrophy.20 Although the relative risk is increased, the likelihood of having an affected child is actually small indeed. Imprinting disorders are the result of altered DNA methylation, and at this time it is not clear if there is an environmental toxicant in the laboratory affecting the egg, the sperm, and/or the early embryo and/or assisted reproduction itself, particularly the handling of the sperm, that increases epigenetic changes. What these data emphasize is that the environment plays a significant role in epigenetic changes in humans as early as the embryonic stage.
In our increasingly complex environment, we are exposed to an innumerable number of chemicals and our lifestyles are clearly changing. With the introduction of assisted reproduction, even our methods of reproducing are changing. It is becoming more and more apparent that all of these environmental influences impact reproductive function in men. Although it is true that the same influences discussed also appear to affect reproductive function in females, readers of this publication are more conversant with those changes occurring in women. Because reproduction involves couples, it is important for all obstetrician-gynecologists to be knowledgeable about the effects of various substances and lifestyle habits on male reproductive function as well as of the effects on subsequent progeny. This knowledge should allow clinicians to take more appropriate histories and to provide better counseling to couples with fertility problems. No doubt we will continue to read about new studies in this emerging field and be able to make better use of new information as we acquire it.
From this survey, it is obvious that it is impossible to avoid the many chemicals in common usage today. Still, if the male is involved in handling chemicals toxic to sperm, it certainly makes sense to suggest avoiding them as much as possible, perhaps by even finding alternative employment. With regard to pesticides and plasticizers, it makes sense to attempt to limit exposure, but altering lifestyle and diet dramatically does not seem warranted at this point. Leading an active life and making reasonable food choices seems most prudent. It also makes sense to counsel patients to at least moderate alcohol and tobacco consumption and to avoid the use of illicit drugs.
- Lancranjan I, et al. Reproductive ability of workmen occupationally exposed to lead. Arch Environ Health 1975;30:396-401.
- Whorton D, et al. Infertility in male pesticide workers. Lancet 1977;2:1259-1261.
- Colburn T, et al. Developmental effects of endocrine-disrupting chemicals in wildlife and humans. Environ Health Perspect 1993;101:378-384.
- Fischetti M. The great chemical unknown: A graphical view of limited lab testing. Sci Am 2010;303:92.
- Carlsen E, et al. Evidence for decreasing quality of semen during past 50 years. BMJ 1992;305:609-613.
- Swan SH, et al. Have sperm densities declined? A reanalysis of global trend data. Environ Health Perspect 1997;105:1228-1232.
- Chiu YH, et al. Fruit and vegetable intake and their pesticide residues in relation to semen quality among men from a fertility clinic. Hum Reprod 2015;30:1342-1351.
- Parks LG, et al. The plasticizer diethylhexyl phthalate induces malformations by decreasing fetal testosterone synthesis during sexual differentiation in the male rat. Toxicol Sci 2000;58:339-349.
- Swan SH, et al. Decrease in anogenital distance among male infants with prenatal phthalate exposure. Environ Health Perspect 2005;113:1056-1061.
- Bae J, et al. Couples’ urinary bisphenol A and phthalate metabolite concentrations and the secondary sex ratio. Environ Res 2015;137:450-457.
- Anway MD, et al. Endocrine disruptor vinclozolin induced epigenetic transgenerational adult-onset disease. Endocrinology 2006;147:5515-5523.
- Rajender S, et al. Epigenetics, spermatogenesis and male infertility. Mutat Res 2011;727:62-71.
- Anway MD, Skinner MK. Epigenetic programming of the germ line: effects of endocrine disruptors on the development of transgenerational disease. Reprod Biomed Online 2008;16:23-25.
- Klonoff-Cohen HS, et al. Effect of female and male smoking on success rates of IVF and gamete intra-Fallopian transfer. Hum Reprod 2001;161382-1390.
- Al-Turki HA. Effect of smoking on reproductive hormones and semen parameters of infertile Saudi Arabians. Urol Ann 2015;7:63-66.
- Klonoff-Cohen H, et al. Effects of maternal and paternal alcohol consumption on the success rates of in vitro fertilization and gamete intrafallopian transfer. Fertil Steril 2003;79:330-339.
- Rossi BV, et al. Effect of alcohol consumption on in vitro fertilization. Obstet Gynecol 2011;117:136-142.
- Klonoff-Cohen HS, et al. A prospective study of the effects of female and male marijuana use on in vitro fertilization (IVF) and gamete intrafallopian transfer (GIFT). Am J Obstet Gynecol 2006;194:369-376.
- Gaskins AJ, et al. Physical activity and television watching in relation to semen quality in young men. Br J Sports Med 2015;49:265-270.
- Lazaraviciute G, et al. A systematic review and meta-analysis of DNA methylation levels and imprinting disorders in children conceived by IVF/ICSI compared with children conceived spontaneously. Hum Reprod 2014;20:840-852.