Estrogenic endocrine disrupting chemicals (EEDCs) are present ubiquitously in sediments and aquatic ecosystems worldwide. The detrimental impact of EEDCs on the reproduction of wildlife is widely recognized. Increasing evidence shows the immunosuppressive effects of EEDCs in vertebrates. Yet, no studies have considered concomitantly EEDC-induced impacts on reproductive impairment and immune suppression in vivo, which are deemed essential for risk assessment and environmental monitoring. In this study, EE2 was used as a representative EEDC, for parallel evaluation of EEDC-induced immune suppression (immune marker gene expression, leukocyte numbers, host resistance assay, and immune competence index) and reproductive impairment (estrogen responsive gene expression, fecundity, fertilization success, hatching success, and reproductive competence index) in an established fish model (marine medaka Oryzias melastigma), considering sex-specific induction and adaptation and recovery responses under different EE2 exposure scenarios. The findings in marine medaka reveal distinct sex differences in the EE2-mediated biological responses. For female fish, low concentration of exogenous EE2 (33 ng/L) could induce hormesis (immune enhancement), enable adaptation (restored reproduction) and even boost fish resistance to bacterial challenge after abatement of EE2. However, a prolonged exposure to high levels of EE2 (113 ng/L) not only impaired F0 immune function, but also perturbed females recovering from reproductive impairment, resulting in a persistent impact on the F1 generation output. Thus, for female fish, the exposure concentration of EE2 is more critical than the dose of EE2 in determining the impacts of EE2 on immune function and reproduction. Conversely, male fish are far more sensitive than females to the presence of low levels of exogenous EE2 in water and the EE2-mediated biological impacts are clearly dose-dependent. It is also evident in male fish that direct contact of EE2 is essential to sustain impairments of immune competence and reproductive output as well as deregulation of immune function genes in vivo. The immunomodulatory pathways altered by EE2 were deciphered for male and female fish, separately. Downregulation of hepatic tlr3 and c3 (in female) and tlr3, tlr5 and c3 (in male) may be indicative of impaired fish immune competence. Taken together, impaired immune competence in the EE2-exposed fish poses an immediate thread on the survival of F0 population. Impaired reproduction in the EE2-exposed fish can directly affect F1 output. Parallel evaluation of immune competence and reproduction are important considerations when assessing the risk of sublethal levels of EE2/EEDCs in aquatic environments.

全世界范围内的沉积物和水生生态系统中普遍存在雌激素内分泌干扰物（EEDCs）。EEDC对野生动植物繁殖的有害影响已广为人知。越来越多的证据表明，EEDC在脊椎动物中具有免疫抑制作用。然而，尚无研究考虑EEDC诱导的对体内生殖功能障碍和免疫抑制的影响，对于风险评估和环境监控而言，这是必不可少的。在这项研究中，EE2被用作代表性的EEDC，用于并行评估EEDC诱导的免疫抑制（免疫标记基因表达，白细胞数目，宿主抗性测定和免疫能力指数）和生殖功能障碍（雌激素反应性基因表达，繁殖力，成熟的鱼类模型（海洋高产Oryzias melastigma）中的受精成功率，孵化成功率和生殖能力指数）），考虑在不同的EE2暴露情景下针对性别的诱导，适应和恢复反应。海洋的发现揭示了在EE2介导的生物学反应中明显的性别差异。对于雌鱼，低浓度的外源EE2（33 ng / L）可能会引起兴奋作用（增强免疫力），实现适应性（恢复繁殖），甚至增强鱼类对EE2消除后对细菌攻击的抵抗力。但是，长时间暴露于高水平的EE2（113 ng / L）不仅会损害F0免疫功能，还会干扰从生殖功能障碍中恢复的雌性，从而对F1代产量产生持续影响。因此，对于雌鱼，在确定EE2对免疫功能和繁殖的影响时，EE2的暴露浓度比EE2的剂量更为关键。反过来，雄鱼对水中低水平的外源EE2的敏感性要比雌鱼高得多，并且EE2介导的生物学影响显然是剂量依赖性的。在雄鱼中也很明显，EE2的直接接触对于维持免疫能力和生殖输出的损害以及免疫功能基因的失控是必不可少的体内。分别对雄性和雌性鱼类解密了由EE2改变的免疫调节途径。肝tlr3和c3（雌性）和tlr3，tlr5和c3（雄性）的下调可能表明鱼类免疫能力受损。综上所述，暴露于EE2的鱼的免疫能力受损，直接影响了F0种群的生存。暴露于EE2的鱼的生殖能力受损会直接影响F1的产量。在评估水生环境中EE2 / EEDC亚致死水平的风险时，对免疫能力和繁殖的并行评估是重要的考虑因素。