Estrogenic Chemicals Impair Immune Function and Reproduction in Fish: Unraveling Gender Specific Effects and the Underlying Mechanisms

Estrogenic chemicals impair immune function and reproduction in fish: Unraveling gender specific effects and the underlying mechanisms.AbstractEndocrine disruptive chemicals (EDCs) can be found ubiquitously in aquatic environment, and many of which can impair fish reproduction by mimicking the normal functions of estrogen (estrogenic EDCs). As shown by our and other groups, estrogenic EDCs can also disturb innate immune function of fish and weaken their resistance to pathogens. In fish, the complement system serves as the central pillar of the innate immune system and the first line of host defense against pathogens, while C3 is the central protein of all four complement activation pathways. Remarkably, C3 appears sensitive to estrogens: recent studies on several fish species have shown that long-term exposure to 17β-estradiol (E2, a potent estrogenic EDCs) can suppress C3 mRNA expression, reduce complement activity or lower pathogen resistance of juvenile and male fish. Since the actions of estrogenic EDCs are mainly mediated through binding to the estrogen receptors, in particular ERα, and interfering with estrogen signaling, responses of female fish with higher levels of endogenous estrogen and ERα to estrogenic EDCs are expected to be different from their male counterparts. However, gender-dependent immunosuppressive effect of estrogenic EDCs has never been demonstrated in fish.Interestingly, our earlier work on Japanese medaka found clear gender differences in liver mRNA expressions of (i) C3 (M > F), receptors ERα (F > M) and ERRγ (expressed in males but undetectable in females) and (ii) plasma E2 (F > M). We have also identified a putative estrogen responsive element (ERRE) for estrogen-related receptors (ERRs) in the promoters of medaka C3 genes (olC3-1, olC3-2). The above results therefore lend support to the hypothesis that there are gender differences in immuno-responses to estrogenic EDCs in fish. Using medaka as a model, we attempt to decipher the following fundamental, but yet unsolved issues: (i) the immunotoxic potency of estrogenic EDCs, alongside with their impact on fish reproduction; (ii) the link between C3 suppression (gene/protein) to impairments of complement function, and the consequences for fish immune competence; (iii) how gender may confound C3 expressions and fish sensitivity to estrogen EDCs; (iv) the mechanism underlying gender-specific regulation of C3 transcription in medaka. This milestone study will unravel the mechanisms underlying gender-specific immune responses to estrogenic EDCs. The results represent a breakthrough for risk assessment of estrogenic EDCs in fish and may potentially enable us to develop immune biomarkers (e.g. C3 gene/protein) for early diagnosis of immunotoxicants in aquatic environments.