Mammary carcinoma in aged gerbil mothers after endocrine disruption in pregnancy and lactation

Abstract

Compounds that trigger breast cancer onset and establishment are of great interest in biological research. Endocrine disruptors are relevant because they initiate carcinogenesis by changing endocrine pathways. Bisphenol A (BPA), as a ubiquitous xenoestrogen, is largely associated with dysfunctions in the female reproductive system and associated organs. This study proposes an investigation of the mammary gland (MG) in aged Mongolian gerbil (Meriones unguiculatus) mothers after their exposure to BPA in two windows of morphophysiological plasticity: pregnancy and lactation. A low dose (50 μg/kg), and a high dose (5000 μg/kg) were considered and results showed few differences between them. As expected, we observed contrasts among control and BPA-exposed MG. The control groups presented a regressive phase with high apoptotic activity and elastic stroma. However, BPA damaged mammary tissue and provoked multifocal carcinoma development supported by an apparent epithelial-mesenchymal transition (EMT) and reactive stroma establishment. BPA remodeled stromal fibers deposition and enhanced the recruitment of tumor-associated cells, contributing to a tumoral microenvironment. Overexpression of TGF-β1 was induced by BPA in the epithelial compartment of exposed MG and increased expression of metalloproteinases (MMP-2, MMP-3, MMP-9) was present in carcinoma cells. In conclusion, exposure of mothers to BPA during the gestational/lactational window of susceptibility leads to carcinogenic impacts with aging.

Developmental Programming in Animal Models: Critical Evidence of Current Environmental Negative Changes

“…However, by the moment, they did not report as substantial changes associated with developmental programming or DOHaD [187]. Other studies performed in Mongolian gerbil (Meriones unguiculatus), in which mothers were exposed to bisphenol during pregnancy and lactation, showed that bisphenol causes adverse effects on mammary gland tissue, inducing the development of carcinoma through the increase in TGFβ and metalloproteinases MMP2, MMP3, and MMP9 expression, making it obvious the deleterious effects of bisphenol exposure [188]. In addition, Yousef MM.…”

Chemical Effects on Breast Development, Function, and Cancer Risk: Existing Knowledge and New Opportunities

“…Rodent Bisphenols (BPA [139,227,[232][233][234] (also sensitizes to DMBA [233,[237][238][239]), BPS [117,229], BPAF [117]), PCBs [242] (also sensitize to DMBA and MNU [242]), TCDD sensitizes to DMBA [240], phthalate mixture sensitizes to MNU [129] BPA sensitizes to DMBA [238] Pharmaceutical hormones [138],…”

“…Rodent studies also provide evidence that chemicals that alter MG development can also induce mammary tumors and/ or sensitize the MG to other chemical carcinogens. One example is BPA, which, as noted above, alters MG development in rodents with exposure during WoS [118,119,[227][228][229][230][231], and exposures during multiple WoS induce mammary hyperplasia and spontaneous mammary adenocarcinomas in rodents [139,227,[232][233][234][235]. BPA analogs such as BPS and BPAF have been reported to have similar developmental and tumorigenic outcomes [117,229].…”

“…As an example, epidemiological studies have not linked BPA exposure with breast cancer, but the case–control studies that have been conducted have not been able to reliably estimate early life exposures [ 247 – 250 ]. However, as discussed above, chemicals such as BPA and its analogs both alter MG development and induce hyperplasia and tumors in rodents that manifest during adulthood [ 117 – 119 , 139 , 227 – 234 ], demonstrating a plausible and direct connection between altered MG development and cancer.…”

“…The MG undergoes dynamic developmental processes for longer than any other tissue, with distinct biological alterations during gestational, perinatal, pubertal, pregnancy/lactation, and menopausal periods [ 3 , 18 , 19 , 312 ]. Chemical exposures, particularly hormonally active ones, can exert adverse effects during any of these WoS, and early developmental alterations can predispose the tissue to adverse outcomes later in life (e.g., reduced ability to breastfeed and cancer, as described above) [ 3 , 18 , 19 , 234 , 313 ]. The chemical effects on the MG during WoS discussed in the previous sections are summarized in Table 1 .…”