Introduction

A broad class of endocrine disrupting chemicals, the polychlorinated biphenyls (PCBs),were first manufactured in 1929 and widely used in electric transformers, capacitors, and hydraulic fluids [2]. In 1933, Cook and Dodds described the first synthetic estrogen and a test for estrogenicity [3]. Three years later Dodds (the discoverer of diethylstilbestrol, DES) synthesized a class of chemicals with bi-phenolic structures with full estrogenic activity in rats [4]. Notably this class included bisphenol-A (BPA), a chemical subsequently used in the manufacture of Bakelite and other plastics, and currently the subject of intensive study. DES was widely distributed soon after its discovery under a variety of trade names and for a range of indications [5]. Approval for use in pregnancy was obtained in 1947, despite considerable concern about its carcinogenic potential. Soon afterwards it was noted that not only pharmaceuticals, but also environmental chemicals, possessed hormonal activity. In 1950 Burlington published the first observation in support of the estrogenicity of the widely used pesticide 2,2-bis(p-chlorophenyl)-

1,1,1-trichloroethane (DDT) [6]. Other reports of the estrogenicity of organo-chlorine pesticides appeared during the 1950s and 1960s when the use of these pesticides was at its height in the United States. For example, female-female pairings and significantly decreased male to female sex ratio in gull populations were observed [7,8]. In the ensuing years, reproductive damage to wildlife, attributed to DDT, other pesticides and industrial chemicals with estrogenic, antiandro-genic, and antithyroid activity, was reported with growing frequency. DDT use was restricted in the United States in 1972 [9], and PCBs were banned shortly thereafter, following the enactment of the Toxic Substances Control Act in 1976.

In 1975, the first Conference on Estrogens in the Environment was held to address concerns that environmental chemicals with estrogenic properties could alter sexual development in the exposed offspring. The immediate focus of concern was a large cluster of premature breast development in Puerto Rico, which has continued until the present. This phenomenon remains largely unexplained, though hormone contaminated food products and waste products from the manufacture of oral contraceptives were suspected [10]. The suspicion that an estrogenic compound was a likely explanation had been heightened by the discovery in 1971 that prenatal exposure to DES resulted in a rare vaginal cancer in a small proportion of the exposed offspring and also caused numerous other abnormalities in the reproductive system in a much greater proportion. DES was thus identified as a human transplacental carcinogen [11] and as a teratogen targeting the developing genital tract [12]. By the mid-1970s it was well established that exposure to DES during prenatal development was capable of profoundly altering reproductive development in both males and females. In the quarter century that followed, these initial DES findings were replicated and model systems developed to explicate mechanisms of action. These findings profoundly influenced the ensuing science. One consequence was the development of the field of teratology, a discipline devoted to the study of adverse effects of such prenatal exposures.

At the same time as DES was becoming recognized as a transplacental carcinogen, transplacental effects were reported in children exposed to potent endocrine disruptors, not through pharmaceuticals, but in environmental settings, e.g., in Yusho [13] and Yu-Cheng [14]. In addition, sterility or subfertility was documented following high exposures in occupational settings, e.g., dibro-mochloropropane [15], ethylene dibromide [16], and kepone [17]. These episodes alerted the scientific community to the range of organic chemicals capable of profoundly altering human reproductive development. Further, several widely used environmental chemicals had been shown to alter endocrine function in the laboratory, and there was growing evidence that these chemicals were disrupting development in wildlife. However, it was not until the first Wingspread Conference in 1991 that the potential of these chemicals to impact profoundly human health at background levels present in the environment began to be appreciated [18]. By then concern about the potential health effects of environmental estrogens had broadened to encompass a variety of chemicals that had the potential to alter endocrine function, agents that soon became known as Endocrine Disrupting Chemicals (EDCs). It has more recently been recognized that endocrine disruption refers not just to disruption of hormonal messengers transported in blood, but to disruption of any component of signaling systems that are involved in intercellular communication.

Concern about the health consequences of environmental EDCs has largely focused on male reproductive health, in contrast to the research on DES that was conducted primarily in prenatally exposed females. This may be a consequence, in part, of the difficulty in examining the reproductive tract of young females, an examination that requires invasive techniques such as those used to screen DES-exposed females at puberty or later. Since only the grossest of genital tract defects in females can be ascertained in infancy, no population-based surveillance data on these hidden reproductive endpoints are available. In contrast, a large literature describes the etiology and epidemiology of male genital tract anomalies, outcomes that can be ascertained at birth or by the end of the first year of life. Furthermore, population studies of biomarkers of female reproductive health (such as serum hormone levels) have not been conducted until recently. In contrast, the literature on semen quality dates from 1929 when the hemocytometer (designed originally to count white cells) was first used to count sperm [19].

As early as the 1970s, authors expressed concern that environmental factors may be contributing to a decline in male reproductive function. For example, Nelson and Bunge found sperm concentrations in 1970-1973 to be markedly lower than those reported in 1951 [20] and concluded: "The overall decrease in the sperm concentration and the semen volumes would tend to incriminate an environmental factor to which the entire population has been exposed" [21]. This study, and other analyses of historical data on semen quality [22,23], which found declines in sperm density and suggested environmental causes, went relatively unnoticed. However, a 1992 analysis by Carlsen and colleagues, the most extensive such analysis published up until that time [24], was widely discussed, criticized, and reanalyzed, reflecting the considerable controversy concerning the safety of environmental chemicals in which the sperm decline issue had become imbedded. The link between a decline in sperm count and environmental factors was made more plausible by experimental evidence that developmental exposure to doses of estrogenic EDCs within the range of human exposure can permanently alter testicular function and decrease sperm production in laboratory animals [25,26].

Sharpe and Skakkebaek noted in 1993 that decreasing sperm concentrations in Western countries were often paralleled by increases in the incidence of testicular cancer and male genital tract abnormalities. These authors suggested that since these reproductive endpoints share a common hormonal influence, they may result from a common cause and suggested prenatal disruption of Sertoli cell formation, a hormonally sensitive process [27]. Several authors [27-29] have hypothesized that these related trends might be the result of prenatal "over exposure" to endogenous estrogen, or possibly environmental estrogens. However, as these authors are careful to note, this is, as yet, a hypothesis to be tested in humans. Some authors have argued that it is unlikely that estrogenic compounds could have produced these trends. Other authors have questioned the validity of the trend analyses underlying this hypothesis [30, 31]. Here we review these trend analyses, beginning with semen quality and sperm density in particular, the measure of male reproductive function that has generated the greatest controversy to date.

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