Ziracin-Induced Congenital Urogenital Malformations in Female Rats

Abstract

Spontaneous hypospadias is seldom observed in rats in contrast to its occurrence in 1 out of 250 human births. Ziracin, an antibacterial of the everninomycin class under development for serious enterococcal, staphylococcal, and streptococcal infections, caused anomalies of the external genitalia in F1 female rats and decreased reproductive performance. To characterize the urogenital malformations and determine the period of sensitivity to the effects of Ziracin during development, pregnant rats (F0) were administered 60 mg/kg IV of Ziracin from GD6 to LD21, GD6 to 13, GD14 to the last day of gestation or LD0 to 21. Controls received saline or placebo from GD6 to LD21. Ziracin-induced changes occurred in F1 rats exposed from GD6 to LD21 and GD14 to the last day of gestation, indicating that the period of sensitivity to Ziracin was from GD 14 to the last day of gestation. The urogenital abnormalities consisted of cranial displacement of the urethral opening within the vagina from its normal location at the tip of the genital tubercle. When the urethrovaginal junction occurred at the distal third of the vagina, it created an urogenital cloaca. As a result, ascending infections were seen in the urinary and genital tract. No differences in survivability, body weight, and date of vaginal opening were observed in F1 females. The estrous cycles were slightly prolonged. The mating and fertility indices were decreased as a result of the urogenital anomalies. The mammary glands of pregnant F1 females were underdeveloped, thus F2 pups from affected F1 females had a decreased survival rate. Although the cause of these effects is not known, the findings are consistent with a potential hormonal mechanism.

Evaluating chemical effects on mammary gland development: A critical need in disease prevention

“…While these high doses are rarely seen in humans, it is possible that ecological systems may be exposed to levels that alter animals' development, impair lactation, and reduce offspring survival [43]. Other animal studies demonstrate that gestational exposure to dioxin [45,103], BPA [46,[104][105][106][107], genistein [108], and Ziracin [109] not only alter mammary epithelial development, but impair lactation. It is possible that exposure to EDs contributes to difficulty breastfeeding in women, but this outcome has not been investigated.…”

Environmental Exposures and Mammary Gland Development: State of the Science, Public Health Implications, and Research Recommendations

“…Changes include delayed MG development, ductal hyperplasia, alveolar hypoplasia, reduced apoptosis in TEBs, altered gene or protein expression, increased or decreased numbers of terminal ducts or lobules, and accelerated alveolar differentiation [see Supplemental Material, Table 1 (doi:10.1289/ehp.1002864)], as well as increased MG tumors after carcinogen challenge (Brown et al 1998; Durando et al 2007; Jenkins et al 2007). In addition, late-gestational treatment with Ziracin, a candidate antibacterial drug, induced hypoplasia (ducts without any acinar development) in rats (Poulet et al 2005). …”

“…For example, in utero exposure to dioxin, Ziracin, PFOA, or BPA led to permanent changes in the adult MG (Fenton et al 2002; Poulet et al 2005; Vandenberg et al 2007; White et al 2009). In contrast, effects of genistein and ethinyl estradiol in male MG appeared to reverse after treatment withdrawal (Latendresse et al 2009).…”

“…In human studies, strong early findings of associations between serum DDE and shortened lactation in two populations have been only partly replicated, and few other agents have been studied (Cupul-Uicab et al 2008; Gladen and Rogan 1995; Rogan et al 1987). In rodents, impaired lactation has been observed in conjunction with altered MG development in one or more generations after gestational exposure to dioxin (Vorderstrasse et al 2004), PFOA (White et al 2007, 2009), atrazine (Rayner et al 2005), BPA (California Office of Environmental Health Hazard Assessment 2009; Matsumoto et al 2004), genistein [National Toxicology Program (NTP) 2008], and the candidate pharmaceutical Ziracin (Poulet et al 2005). For example, atrazine fed to rats during gestation induced MG developmental changes in offspring, characterized by stunted development, and when these rats were bred, their offspring (second-generation) had significantly reduced weight gain, suggesting insufficient milk production (Rayner et al 2005).…”

Ocorrência e diversidade estrutural de metabólitos fúngicos com atividade antibiótica

“…O oligossacarídeo Sch 58761 (87), análogo clorado da Ziracin (em desenvolvimento pela Shering-Poulgh) 37 demonstrou atividade in vitro e in vivo contra cepas de Staphylococcus aureus resistentes à meticilina e contra espécies de Enterococcus resistentes à vancomicina. Sch 58761, cuja estrutura foi elucidada por criterioso estudo de fragmentação da molécula por FAB-MS e estudos espectroscópicos de NOESY e HMBC, também apresentou atividade contra diversas cepas tradicionais de organismos Gram-positivos.…”