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Gestational and Lactational Exposure to an Environmentally-relevant Mixture of Brominated Flame Retardants Down-regulates Junctional Proteins, Thyroid Hormone Receptor α1 Expression and the Proliferation-Apoptosis Balance in Mammary Glands Post Puberty.

Mammary gland development requires hormonal regulation during puberty, pregnancy and lactation. Brominated flame retardants (BFRs) are endocrine disruptors; they are added to consumer products to satisfy flammability standards. Previously, we showed that gestational and lactational exposure to an environmentally-relevant mixture of BFRs disrupts proteins of the adherens junctions in rat dam mammary glands at weaning. Here, we hypothesize that perinatal exposure to the same BFR mixture also disrupts junctional proteins and signaling pathways controlling mammary gland development in pups. Dams were exposed through diet to a BFR mixture based on the substances in house dust; doses of the mixture used were 0, 0.06, 20 or 60 mg/kg/day. Dams were exposed continuously beginning prior to mating until pups' weaning; female offspring were euthanized on postnatal day (PND) 21, 46 and 208. The lowest dose of BFRs significantly down-regulated adherens junction proteins, E-cadherin and β-catenin, and the gap junction protein p-Cx43, as well as thyroid hormone receptor alpha1 protein at PND 46. No effects were observed on estrogen or progesterone receptors. The low dose also resulted in a decrease in cleaved-caspase 3, a downward trend in PARP levels, proteins involved in apoptosis, and an upward trend in PCNA, a marker of proliferation. No effects were observed on ductal elongation or on the numbers of terminal end buds. Together, our results indicate that gestational and lactational exposure to an environmentally-relevant mixture of BFRs disrupts cell-cell interactions, thyroid hormone homeostasis and the proliferation-apoptosis balance at PND 46, a critical stage for mammary gland development.