The increased prevalence of neurodevelopmental disorders during the last half-century led us to investigate the potential for intergenerational detrimental neurodevelopmental effects of synthetic female gonadal hormones, typically used in contraceptive pills. We examined 3 separate cohorts of mice over the span of 2 years, a total of 150 female F₀ mice and over 300 male and female rodents from their F₁ progeny. We demonstrate that F₁ male offsprings of female mice previously exposed to the synthetic estrogen 17α-ethinylestradiol (EE2) in combination with the synthetic progestin Norethindrone, exhibit neurodevelopmental and behavioral differences compared to control mice. Because the EE2 + Norethindrone administration resulted in gene expression changes in the exposed F₀ mice ovaries persisting after the end of treatment, it is likely that the synthetic hormone treatment caused changes in the germline cells and that led to altered neurodevelopment in the offsprings. An altered gene expression pattern was discovered in the frontal cortex of male mice from the first offspring (F_1.1) at infancy and an ADHD-like hyperactive locomotor behavior was exhibited in young male mice from the second offspring (F_1.2) of female mice treated with contraceptive pill doses of EE2 + Norethindrone prior to pregnancy. The intergenerational neurodevelopmental effects of EE2 + Norethindrone treatment were sex specific, predominantly affecting males. Our observations in mice support the hypothesis that the use of synthetic contraceptive hormones is a potential environmental factor impacting the prevalence of human neurodevelopmental disorders. Additionally, our results indicate that contraceptive hormone drug safety assessments may need to be extended to F₁ offspring.

在过去的半个世纪中，神经发育障碍的患病率上升，这使我们研究了通常用于避孕药的合成女性性腺激素对代际有害神经发育作用的潜力。我们在2年的时间里检查了3组单独的小鼠，共150只雌性F ₀小鼠和300多只来自其F ₁后代的雄性和雌性啮齿动物。我们证明F ₁与对照小鼠相比，先前暴露于合成雌激素17α-炔雌醇（EE2）与合成孕激素Norethindrone组合的雌性小鼠的雄性后代表现出神经发育和行为差异。由于EE2 +炔诺酮的给药导致暴露的F ₀小鼠卵巢的基因表达变化在治疗结束后持续存在，因此合成激素治疗很可能导致种系细胞发生变化，并导致后代神经发育改变。在婴儿期的第一个后代（F _1.1）的雄性小鼠的额皮质中发现了基因表达模式的改变，第二个后代（F（F ）的年轻雄性小鼠则表现出ADHD样的过度活跃运动行为_1.2）在怀孕前用避孕药剂量的EE2 +炔诺酮治疗的雌性小鼠。EE2 +炔诺酮的代际神经发育作用是性别特异性的，主要影响男性。我们在小鼠中的观察结果支持以下假设：合成避孕药具的使用是影响人类神经发育障碍患病率的潜在环境因素。此外，我们的结果表明，避孕激素药物的安全性评估可能需要扩展到F ₁后代。