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Synthetic female gonadal hormones alter neurodevelopmental programming and behavior in F1 offspring
Krassimira A Garbett1, Tianbing Ding2, John Allison3
1Department of Pharmacology, Vanderbilt University, Nashville, TN 37232, United States of America.
Abstract:
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 (F1.1) at infancy and an ADHD-like hyperactive locomotor behavior was exhibited in young male mice from the second offspring (F1.2) 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.
Insights
Synthetic contraceptive hormones may negatively impact offspring neurodevelopment. Exposure to EE2 + Norethindrone in female mice led to neurodevelopmental and behavioral changes in male offspring, suggesting potential intergenerational effects.
Area of Science:
- Endocrinology
- Neuroscience
- Toxicology
Background:
- Rising prevalence of neurodevelopmental disorders necessitates investigation into environmental factors.
- Synthetic female gonadal hormones in contraceptives are widely used.
- Potential for intergenerational effects of these hormones on offspring neurodevelopment is unknown.
Purpose of the Study:
- To investigate the intergenerational neurodevelopmental effects of synthetic female gonadal hormones (17α-ethinylestradiol [EE2] + Norethindrone) used in contraceptive pills.
- To examine if exposure in F0 female mice alters neurodevelopment and behavior in their F1 progeny.
- To explore potential mechanisms involving germline and gene expression changes.
Main Methods:
- Three cohorts of mice (150 F0 females, >300 F1 progeny) were studied over 2 years.
- Female mice were exposed to EE2 + Norethindrone prior to pregnancy.
- Neurodevelopmental and behavioral assessments were conducted on F1 offspring, alongside gene expression analysis in ovaries and frontal cortex.
Main Results:
- F1 male offspring exposed to EE2 + Norethindrone exhibited significant neurodevelopmental and behavioral differences compared to controls.
- Altered gene expression was observed in the ovaries of treated F0 mice and the frontal cortex of infant F1 males.
- ADHD-like hyperactive locomotor behavior was noted in young male mice from the second offspring generation (F1.2).
Conclusions:
- Synthetic contraceptive hormones (EE2 + Norethindrone) can cause sex-specific, intergenerational neurodevelopmental effects, primarily in males.
- Germline and persistent gene expression changes in F0 mice likely mediate these effects in offspring.
- Contraceptive hormone safety assessments should consider F1 offspring, as these hormones may be an environmental factor contributing to neurodevelopmental disorders.
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