Age- and Species-Dependent Infiltration of Macrophages into the Testis of Rats and Mice Exposed to Mono-(2-Ethylhexyl) Phthalate (MEHP)1

Abstract

The mechanism by which noninfectious testicular inflammation results in infertility is poorly understood. Here the infiltration of CD11b+ immunoreactive testicular interstitial cells (neutrophil, macrophages, dendritic cells) in immature (Postnatal Day [PND] 21, 28, and 35) and adult (PND 56) Fischer rats is described at 12, 24, and 48 h after an oral dose of 1 g/kg mono-(2-ethylhexyl) phthalate (MEHP), a well-described Sertoli cell toxicant. Increases of CD11b+ cells are evident 12 h after MEHP exposure in PND 21 and 28 rats. In PND 28 rats, CD11b+ cells remained significantly elevated at 48 h, while in PND 21 rats, it returned to control levels by 24 h. The peak number of CD11b+ cells in PND 35 rat testis is delayed until 24 h, but remains significantly elevated at 48 h. In PND 56 rats, no increase in CD11b+ cells occurs after MEHP exposure. In PND 21, 28, and 35 rats, a significant increase in monocyte chemoattractant protein-1 (MCP-1) by peritubular myoid cells occurs 12 h after MEHP. Interestingly, MEHP treatment of C57BL/6J mice did not incite an infiltration of CD11b+ cells at either PND 21 or 28. The peak level of germ cell apoptosis observed 24 h after MEHP exposure in young rats is not seen in mice at any age or in PND 56 rats. Taken together, these findings implicate MCP-1 released by peritubular myoid cells in provoking the migration of CD11b+ cells into the immature rat testis early after MEHP exposure and point to a role for CD11b+ cells in triggering germ cell apoptosis in an age- and species-dependent manner.

Phthalate esters affect maturation and function of primate testis tissue ectopically grafted in mice

“…It was reported recently that phthalate exposure is associated with increased inflammation and oxidative stress and phthalates activate macrophages in different tissues (Murphy et al, 2014; Campioli et al, 2014; Ferguson et al, 2014). Therefore, using immune-deficient recipient mice may have underestimated the effects of phthalates.…”

The presence of macrophages and inflammatory responses in an in vitro testicular co-culture model of male reproductive development enhance relevance to in vivo conditions

“…Barbhuiya 2013, Murphy et al 2014). Researchers have proposed that macrophages partially mediate the toxic action of phthalate esters in the testes in vivo (Murphy et al 2014). …”

“…Observed effects include increases in macrophages and macrophage produced cytokines after exposure to phthalate esters and benzo(a)pyrene, as well as effects on macrophage function after exposure to lead (Zheng et al 2010, Shamim Ahmed S.K. Barbhuiya 2013, Murphy et al 2014). Researchers have proposed that macrophages partially mediate the toxic action of phthalate esters in the testes in vivo (Murphy et al 2014).…”

Regulation of microtubule (MT)-based cytoskeleton in the seminiferous epithelium during spermatogenesis

“…The seminiferous epithelium is comprised of only two cell types, Sertoli cells and germ cells, unless infiltrated by macrophages in the basal and/or adluminal compartment of the seminiferous tubules during pathological conditions such as inflammation induced by orchitis [5,6] or following exposure to environmental toxicants (e.g., MEHP) [7]. Due to the unique association between Sertoli cells and germ cells at specific stages of their development in the seminiferous epithelium during spermatogenesis, the epithelium can be divided into stages I–XII, I–XIV, and I–VI in the mouse, rat and human testis respectively, known as the epithelial cycle of spermatogenesis [2, 8, 9].…”