Chronic simultaneous exposure of common carp (Cyprinus carpio) from embryonic to juvenile stage to drospirenone and gestodene at low ng/L level caused intersex.

Synthetic progestins are emerging contaminants of the aquatic environment with endocrine disrupting potential. The main aim of the present study was to investigate the effects of the synthetic progestins gestodene, and drospirenone on sex differentiation in common carp (Cyprinus carpio) by histological analysis. To gain insights into the mechanisms behind the observations from the in vivo experiment on sex differentiation, we analyzed expression of genes involved in hypothalamus-pituitary-gonad (HPG) and hypothalamus-pituitary-thyroid (HPT) axes, histology of hepatopancreas, and in vitro bioassays. Carp were continuously exposed to concentrations of 2 ng/L of single progestins (gestodene or drospirenone) or to their mixture at concentration 2 ng/L of each. The exposure started 24 h after fertilization of eggs and concluded 160 days post-hatching. Our results showed that exposure of common carp to a binary mixture of drospirenone and gestodene caused increased incidence of intersex (32%) when compared to clean water and solvent control groups (both 3%). Intersex most probably was induced by a combination of multiple modes of action of the studied substances, namely anti-gonadotropic activity, interference with androgen receptor, and potentially also with HPT axis or estrogen receptor.

Hormonal effects on the mammary gland of postmenopausal nonhuman primates.

Macaques are Old World anthropoid primates with a high degree of genetic identity to human beings and striking similarities in breast development, reproductive endocrinology, and menstrual cycle characteristics. These animals share critical pathways of hormone metabolism with humans, to a degree that is distinct from rodent models. Macaques also express estrogen receptors alpha and beta, progesterone receptors, and androgen receptors in the normal breast in patterns similar to those described for women. Spontaneously occurring hormone-dependent breast cancers occur in macaques at a similar prevalence to lower-risk populations of women, and these neoplasms exhibit similar growth patterns and key molecular changes seen in human lesions. These similarities lend support to a biomarker approach for modeling breast cancer risk. Estrogen+progestogen treatment of postmenopausal animals produces a proliferative response in the normal breast epithelium which reflects the breast cancer promoting effects of continuous combined hormone replacement therapy. Studies of novel agents such as tibolone, selective estrogen receptor modulators, and alternative progestogens in macaques have also helped to identify hormonal therapies with a more acceptable balance of benefit to risk. Future studies of novel selective estrogens, androgens, and dietary estrogens in the macaque model will further contribute to our understanding of breast cancer risk and prevention.