Premature reproductive aging in female rats after developmental exposure to mixtures of endocrine disrupters

Long-lasting and delayed reproductive effects of developmental exposure to mixtures of environmental chemicals were investigated in female rats. Wistar rats were dosed during gestation and lactation to mixtures of endocrine disrupters, and effects in offspring were studied. The mixtures consisted of 13 estrogenic and anti-androgenic chemicals, including phthalates, pesticides, UV-filters, bisphenol A, butylparaben and paracetamol, and the mixture ratio was chosen to reflect high-end human intakes.

Groups received combined exposures of 0,100, 150, 200 or 450 times high-end human intake levels. Additionally, groups received mixtures including only the anti-androgens or estrogens at 200 or 450 times human intake. Female offspring exposed to the high dose mixture of all 13 chemicals showed earlier reproductive aging measured as early onset of irregular estrous cycle as compared to controls.

As a similar trend was observed in the groups receiving anti-androgens or estrogens only, the effects of the total mixture were attributable to both groups of chemicals. No effects on estrous cycle were observed before 12 months of age. Perinatal programming of the hypothalamic–pituitary–gonadal axis or effects on ovary development may account for the observed effect.

This study demonstrated that developmental exposure of rats to mixtures of endocrine disrupters can induce long-lasting adverse effects manifested as early reproductive senescence even though no effects on estrous cyclicity were observed in younger animals. Moreover, endpoints related to early reproductive senescence should be the focus of future investigations as this is an adverse effect easily overlooked because most study designs do not address effects in old animals.