Prenatal exposure to a mixture of different phthalates increases the risk of mammary carcinogenesis in F1 female offspring

DE FREITAS, THIAGO; ZAPATERINI, JOYCE R.; MOREIRA, CRISTIANE M.; DE AQUINO, ARIANA M.; ALONSO-COSTA, LUIZ G.; BIDINOTTO, LUCAS T.; KASS, LAURA; FLAWS, JODI A.; SCARANO, WELLERSON R.; BARBISAN, LUIS F.

FOOD AND CHEMICAL TOXICOLOGY

PERGAMON-ELSEVIER SCIENCE LTD

Año: 2021 vol. 156

0278-6915

Phthalates are a group of phthalic acid diesterstypically used as plasticizers to soften and increase the flexibility of thepolyvinyl chloride-based plastic (PVC) products and recognized as endocrinedisrupters for male and female reproductive systems. Thus, the aim of thisstudy was to evaluate the noxious effects of maternal exposure to a mixture ofsix different phthalates (Pht mix, 35 % diethyl phthalate, 21 % di-(2-ethylhexyl) phthalate, 15 % dibutylphthalate, 15 % diisononyl phthalate, 8% diisobutyl phthalate, and 5%benzylbutyl phthalate) at different doses on mammary glanddevelopment and carcinogenesis susceptibility in female offspring (F1).Pregnant female Sprague-Dawley rats (n=8 dams/group) were daily exposed to anenvironmentally relevant Pht mix by gavage (20µg/kg; 200µg/kg or 200mg/kg). Pregnantrats received the respective doses of the Pht mix or vehicle during gestationalday 10 (GD 10) to postnatal day 21 (PND 21). After weaning (PND 22), femaleoffspring were euthanized for mammary gland analyses (1 female/litter, n=8 eachgroup) and other females received a single dose of N-methyl-N-nitrosourea (MNU,50 mg/kg) (2 female/litter, n=16 each group) or vehicle and tumor incidence andmultiplicity were recorded until PND 180. No significant alteration wasobserved in mammary gland development. However, maternal Pth mix exposureincreased the number of Ki-67 and progesterone receptor-positive epithelialcells (p = 0.03 and p = 0.017, respectively) in the mammary gland from Pth mix 200µg/kgand 200mg/kg groups. Also, both tumor incidence and mean numberwere higher only in Pth mix 200mg/kg when compared to the vehicle-treated group(p=0.033 and p=0.006, respectively), and percentage of tumor-freeanimals was lower in Pth mix 200µg/kg and 200mg/kg groups (p=0.010) throughoutthe experimental period. The findings indicate that Pht mixture exposure duringcritical developmental windows increased susceptibility to MNU-induced mammarycarcinogenesis in adult F1 female offspring.