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EDITORIAL: High Prevalence of Male infertility in Africa: Are Mycotoxins to Blame?

Ukpai Agwu Eze, Friday E Okonofua

Abstract

There is an increase in reports indicating a continuous decline in human fertility in both developed and developing countries1. The infertility prevalence varies between developing and developed countries. For instance, in the United States of America it is estimated to be 6%2 whereas it is 10-15% in United Kingdom3. In Africa, infertility prevalence rates are higher and range from 20-35%4-7. The “infertility belt”, geographical regions with high infertility prevalence, is well-known to Africa, stretching from West Africa, through Central to East Africa7.
Several reports have shown deterioration of male sperm quality worldwide. Carlsen et al.8 carried out a meta-analysis of 61 studies published between 1938 and 1991 involving semen quality of 14,947 men with no history of infertility and showed that the sperm concentration of fertile males have dropped from a mean concentration of 133 million/mL in 1940 to 66 million/mL in 1990, indicating an average yearly decrease of 1%,. Sperm morphology/motility abnormalities were also significantly increased. In addition, this report showed that sperm count declined to a mean of 71.2 million/ml in Ibadan, Nigeria, 54.6 million/ml in Lagos, Nigeria, 65.0 million/ml in Salem, Libya, 66.9 million/ml in Dar Es salaam, Tanzania and 57.4 million/ml in Copenhagen, Denmark. Swan and colleagues re-evaluated Carson’s publication and confirmed that sperm concentrations in fertile males have gradually declined overtime globally9. Also, in 2000, Swan and colleagues10 conducted another analysis based on 101 papers published between 1934-1996, involving only English-language studies and concluded that the decline in sperm quality of fertile men were as previously reported. This continuous decline in human fertility worldwide has been attributed to many factors including activities of endocrine-disrupting chemicals (EDCs) such as mycotoxins and pesticides11-14. Recent reports indicate that EDCs may affect the development and functioning of the reproductive system in both sexes, particularly in fetuses, causing developmental and reproductive disorders, including infertility.
Mycotoxins are pharmacologically active secondary metabolites produced by fungal species, particularly Aspergillus, Fusarium and Penicillium species, which elicit some complicated toxicological effects in man and animals. More than 400 of these secondary metabolites have been identified. However, the mycotoxins of major public health concern are aflatoxins (e.g. AFB1), ochratoxin A (OTA), deoxynivalenol (DON), zearalenone (ZEN) and fumonisins (e.g. FB1) because of their prevalence in agricultural produce and their adverse health effects in animals and humans15. Mycotoxin contamination of food is a global health problem as it is estimated that more than 25% of world agricultural produce are contaminated by mycotoxins16. Due to the more conducive climatic and environmental conditions for fungal growth in developing countries, mycotoxins contamination and exposure is more common than in developed countries17. In addition, the occurrence of mycotoxins is regulated by legal limits in developed countries; however, there is little or no regulation/legislation in place for monitoring mycotoxin contamination of agricultural products and foodstuffs in most developing countries which results to higher exposure in these regions.
Studies show that mycotoxins are common contaminants of staple foods in Nigeria, including garri, beans, yam flour, cassava flour, melon, rice, plantain, red pepper, onion, maize, groundnuts, guinea corn, sorghum, and millets18. Human exposure can be either through the consumption of contaminated agricultural products, or the consumption of contaminated animal products containing residual amounts of the mycotoxin ingested by the food producing animals19. Chronic exposure of a large proportion of African population to mycotoxins is a serious problem and in utero exposure is a common phenomenon20. Apart from contaminating agricultural products, human exposures to mycotoxins have also been reported using exposure biomarkers. High levels of single or multiple mycotoxin biomarkers have been reported in several population studies which show that humans are often simultaneously exposed to mixtures of mycotoxins21. Multi-mycotoxins exposures have also been reported in South Africa22, Cameroun23 and Nigeria24. Multiple exposures to mycotoxins pose a significant threat to human health since combinationsof mycotoxins could be agonistic, additive or antagonistic in nature.
The well-known adverse health effects of mycotoxins in humans include liver cancer25, Balkan Endemic Nephropathy25, child growth impairment26, modification of immune function27, esophageal cancer28, neural tube defects29 and death in acute exposure30. In particular, there is growing evidence suggesting that mycotoxins may negatively influence human fertility.
Studies using animal and cellular models indicate that zearalenone (ZEN) and metabolites [α-zearalenol (α-ZOL), β- zearalenol (β-ZOL)], deoxynivalenol (DON), ochratoxin A (OTA) and aflatoxin B1 (AFB1) can adversely affect fertility, through damage to sex organs, gametes and disruption of steroidogenesis. For instance, studies using animal and cellular models have described that exposure to the aforementioned mycotoxins can promote adverse effects on spermatozoa, Sertoli and Leydig cell function, oocyte maturation, and uterine and ovarian development and function, both in vivo, ex-vivo and in vitro31-35. They may also induce oxidative stress resulting in sperm DNA damage36 and sperm DNA damage reduces fertilization rates and lowers embryo quality37. Furthermore, mycotoxins may act as endocrine disrupters, altering the steroid hormone homeostasis and interfering with receptor signaling38-44. It is well known that proper steroid hormones homeostasis and oocyte/sperm quality are the major determinants of reproductive function in both humans and animals and therefore, their impairment leads to subfertility/ infertility.
Interestingly, the impact of mycotoxins on reproductive function have also been reported in humans. In Benin City-Nigeria, Ibe and colleagues11 reported higher concentrations of aflatoxin B1 (AFB1) in the semen of infertile men compared to the semen of fertile controls and proposed that exposure to AFB1 could be a potential contributory factor to male infertility in Nigeria. In this study, 50% of infertile men with AFB1 in their semen had a greater percentage of abnormalities in sperm count, motility and morphology compared to the fertile men (10-15%). In male rats fed with AFB1 contaminated feeds (8.5 μg AFB1/g of feed) for 14 days, the observed effects on the sperm parameters were similar to those found in the sperm of infertile men exposed to AFB1. In another study, Uriah et al.12 conducted a case-control study involving 30 infertile and 25 fertile males. Detectable levels of AFB1 were found in the semen and blood of 37% of the infertile males with abnormal sperm profile and AFB1 levels in infertile males were significantly higher than the fertile males. The levels of AFB1 ranged from 700 to 1392 ng/ml, exceeding the World Health Organisation recommended level. Although these data indicate a possible link between AFB1 and male infertility, the use of valid aflatoxin exposure biomarkers (blood aflatoxin-albumin adduct; AF-alb or urinary aflatoxin M1) and properly designed epidemiological study would certainly provide stronger evidence for establishing a causal association. Mycotoxins as endocrine disrupters may also be involved in female reproductive disorders since other EDCs have been implicated in endometriosis, premature ovarian failure (POF) and polycystic ovary syndrome (PCOS)45. In a study in Puerto-Rico, zearalenone (ZEN) was associated with precocious puberty in girls13 correlating with significantly high estrogen levels (25 pg/mL).
From the above data, it is plausible that mycotoxins might produce some adverse reproductive health effects in exposed individuals, and might be implicated in the declining fertility rate, especially in Africa. This constitutes a serious public health threat that should not be overlooked. Therefore, this growing body of evidence should increase public awareness of the serious implications of mycotoxin exposures in human fertility and should warrant a greater study of reproductive impacts of these mycotoxins through in vitro and in vivo bioassays and human epidemiological studies.

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