TOXICOLOGICAL HIGHLIGHT Cracking the Nut

Phthalate esters impart flexibility to hard plastics, are used as inert ingredients in cosmetics and personal hygiene products, and are ubiquitous environmental contaminants. Finding the underlying molecular mechanism of phthalate-induced testicu-lar injury has been a vision quest of male reproductive toxicol-ogists for many decades. Since 1945, when Shaffer et al. (1945) first described ‘‘tubular atrophy and degeneration... resembling senile changes’ ’ (p. 131) in the testis following exposure to di-(2-ethylhexyl) phthalate, phthalates have become the most studied and most thoroughly characterized class of testicular toxicants. What is especially exciting about the phthalates for mechanistic toxicologists is the rapid onset of testis-specific abnormalities; ‘‘rapid’ ’ and ‘‘specific’ ’ should mean simple and straightfor-ward, right? Wrong! A number of mechanistic hypothesis have been proposed t