Nature Is Complex: Our Orchestra Seats at the Most Wonderful Show on Earth

Any student of Nature’s complexity is constantly rewarded as science slowly uncovers hints about the processes of life and the controls embedded in it. Life scientists, of course, have a front row seat to absolutely the most wonderful show on earth, and if we’re smart, lucky, and tenacious, we get to help discover little pieces of this puzzle. One of the next pieces presented for us in this issue is the article by Bob Markelewicz, Susan Hall, and Kim Boekelheide, ‘‘2,5-Hexanedione and Carbendazim Co-exposure Synergistically Disrupts Rat Spermatogenesis despite Opposing Molecular Effects on Microtubules’’ (pp. 92–100). Toxicologists shoulder a challenge, along with our awe, and that is to use science to serve public health by putting our knowledge to work by recommending things like allowable exposure levels and recommended tolerances. This process is fraught with uncertainties in the best of situations, but the particular situation of regulating mixtures exposures, or understanding the biologic processes involved in responding to mixtures, is at once the most frustrating and most rewarding. Most rewarding, because mixtures really encapsulate the complexities of real world: no one has a single exposure at a time. And the most frustrating because the depth of our ignorance is profound, and it is frequently these knowledge chasms that encompass the very information that the regulator or the scientist most desperately needs. Mixtures science has been making steady progress over the past decade, and several recent reviews (Cassee et al., 1998; Feron and Groten, 2002; Pohl et al., 2003) do an excellent job of capturing the critical issues facing regulators (who must make policy decisions based on imperfect information) and scientists (who must allocate increasingly scarce resources to answer the most pressing or illuminating questions in a complex field). They also review some of the literature in this area (Carpy et al., 2000), which provides an excellent opportunity for reacquainting oneself with this complicated and critical area. The authors of one of these reviews (Feron and Groten, 2002, pp. 836) presciently described the Markelewicz et al. article when they wrote, ‘‘Well-thought-out, tailor-made mechanistic and statistical designs to study the toxicity and the mechanism of toxicity of mixtures have been developed and successfully applied.’’ In this article, the Boekelheide lab turns its long experience with the toxicity and mechanism of 2,5-hexanedione (HD) to prime advantage. Three to four weeks after the start of exposure, HD produces basal vacuoles in the Sertoli cell, with a subsequent loss of germ cells that then happens over the course of one to two weeks. In the 1980’s, Dr. Boekelheide showed that HD stabilized microtubules, and concluded that disrupted microtubule dynamics is responsible for the effects seen in the testis. (reviewed in Boekelheide et al., 1989). This theory has significant appeal: the Sertoli cell is loaded with microtubules; we know that the seminiferous epithelium is astoundingly active, with the Sertoli cells moving the germ cells around, controlling access to the privileged space distal to the blood-tubule barrier and shoving the late spermatids out of the way to make room for the space-hungry and dazzlingly beautiful meiotic divisions that mark the transition from pachytene to spermatid. It seems intuitively obvious that much of this activity would depend on normal cytoskeletal activity, and stabilizing microtubules by HD should logically disrupt this delicately balanced dynamic equilibrium. Enter carbendazim (CBZ), the active metabolite of benomyl, another testicular toxicant. Within 24 h of administration, CBZ causes basal vacuoles and the wholesale sloughing of the adluminal one-half to one-third of the epithelium (germ cells and Sertoli cells), with the result that the efferent ducts become clogged with this debris, while the persistent fluid production by the seminiferous tubules causes those tubules to enlarge in the testis. Carbendazim was found to block microtubule polymerization (Howard and Aist, 1980; Quinlan et al., 1980), which was thought to contribute to the sloughing of the epithelium. It makes some sense: if you rapidly deploymerize the microtubules, and if those microtubules are responsible for the integrity of the Sertoli cell (and if the Sertoli cell controls the structure of the adluminal 7/8ths of the epithelium), then you might, indeed, cause the wholesale detachment of some part of that epithelium. As a Commentary writer, I will employ my poetic license and cherish the image of a late night in the Boekelheide lab, with 1 For correspondence via fax: (860) 715-3577. E-mail: robert_e_chapin@ groton.pfizer.com.