During the past 50 years, the rapid expansion of the chemicals industry in both the developed and developing worlds has resulted in the release of various xenobiotics into the environment. These compounds have worked their way into our lives in a variety of forms, including pesticides, herbicides, cosmetics, preservatives, cleaning materials, municipal and private waste, pharmaceuticals and industrial by-products. During the past few decades, worries about environmental threats to male germ line, are causing disquiet considering growing evidence that the quality of human semen is deteriorating worldwide.

　　In males, the hypothalamic hormone gonadotropin-releasing hormone stimulates the release of follicle-stimulating hormone (FSH) and luteinizing hormone (LH), which in turn induces steroid hormone production of testis. Considering widespread distribution of the aromatase gene, it is argued that the estrogenic effect in men might stem from both central and local actions and that the balance in action between androgens and estrogens might be of central importance at multiple target sites. Within the testis, all three types of cells (germ cell, Sertoli cell, and Leydig cell) express estrogen receptors and aromatase. These cells are potential targets of both exogenous and endogenous estrogens. Estrogens have been shown to play a role in the regulation of germ cell survival, apoptosis, and fluid re-absorption from the efferent ducts. Inappropriately low or high exposure to estrogens during different developmental stages can lead to disorders of spermatogenesis and infertility. Biologic evidences also support that both endogenous and exogenous estrogens may exert their effect on different levels (hypothalamus, pituitary, testis and post-testis) in different developmental stages (fetal, pre-pubertal and post-pubertal).

　　Sperm production is the consequence of complex gene-environment interaction. Environmental toxins have been implicated in male infertility. For example, genetic variants of dioxin receptor genes (e.g. AHR, AHRR and ARNT) and metabolism/ detoxification genes (e.g. CYP1A1, GSTM1, GSTT1) have been reported to be associated with male infertility. Endogenous estrogens are metabolized by CYP1A1 (cytochrome p450, family 1, subfamily A, polypeptide 1), CYP1B1, CYP3A4 and COMT (catechol-O- methyltransferase) into hydroxy and methoxy estrogens, respectively. Xenobiotic substances could be also metabolized by the same group of enzymes and enter the pathway of estrogen functioning.
Many case-control studies already showed associations of single or multiple estrogen-related genes with male infertility. Recently we found common polymorphisms of estrogen-related genes confer susceptibility to impaired sperm production (sperm counts less than 2×106/mL) at the pre-receptor, receptor and both receptor levels (Su et al., 2010). We went go further to provide evidence that estrogen-related pathway is involved in regulating sperm counts and motility (Lee et al., unpublished data).

　　Several epigenetic mechanisms, including DNA methylation, histone modifications, and microRNA expression, can change genome function under exogenous influence. In-vitro, animal, and human investigations have identified several classes of environmental chemicals that modify epigenetic marks, including metals (cadmium, arsenic, nickel, chromium, and methylmercury), peroxisome proliferators (trichloroethylene, dichloroacetic acid, and TCA), air pollutants (particulate matter, black carbon, and benzene), and endocrine-disrupting/reproductive toxicants (diethylstilbestrol, bisphenol A, persistent organic pollutants, and dioxin). During the past 5 years, it has become aware that not only are genetics factors are implicated in sperm production, environmental chemicals also exert transgenerational epigenetic effect on sperm production. Researchers reported that several chemicals (e.g. vinclozolin, methoxyclor, bisphenol), cause fertility defects in male rodents that are passed down to nearly every male in subsequent generations. These finding seem to support the controversial idea that endocrine disrupters could be causing population-wide reproductive problems, such as lowered sperm counts in men.