The research in our lab brings together two major fields of biology: reproductive endocrinology and chronobiology. Some of the major questions we examine:
- How does the circadian timekeeping system interact with steroid hormones to regulate the timing of female reproductive events?
- How does developmental exposure or lack of exposure to estrogen alter the expression of circadian rhythms?
- How do disruptions of the circadian clock (jet lag, shift work) decreases reproductive function in females? How do these disruptions alter "clock gene" rhythms in the brain and peripheral reproductive tissues?
- How does prenatal exposure to exogenous steroid hormones impact sexual differentiation of the brain of adult animals>
These research aims are of broad significance as they investigate questions important for basic science as well as human health. For example, it deals with fundamental questions in ecology and evolutionary biology such as "how do sex differences in behavior emerge?" It also addresses human health with questions such as "how does jet lag and shift work lead to reduced fertility?" and "How do environmental steroids affect development?"
Circadian Rhythm Research
Rhythms in reproductive processes include multi-day/week estrous and menstrual cycles, daily changes in steroid hormone levels, and the timing of hormone surges critical for ovulation. The coordination of successful hormone secretion, ovulation, and pregnancy are dependent upon the precise function and interaction of endogenous timing systems. There are gender differences in the expression of biological rhythms but relatively little work has investigated the mechanisms underlying these differences. Steroid hormones play a role as there are changes in sleep-wake cycles, endocrine secretion patterns, and body temperature rhythms across the menstrual cycle and during the menopausal transition. Women are more likely then men to experience insomnia and peri-menopausal women have significant disturbances in their sleep onset, quality and efficiency. Hormone replacement therapy alleviates some of these problems.
Further evidence of the reciprocal interaction of circadian rhythms and steroid hormones is seen when rhythms are disrupted. In humans and other species, disruptions of the daily (circadian) mechanism, as occurs in jet lag or shift work, can have a negative impact on fertility leading to reduced conception, increased miscarriage rates, and disrupted menstrual or estrous cycles. However, relatively little is known about how the underlying endogenous circadian system regulates reproductive function, or how disruptions in biological rhythms are correlated with changes in fertility, hormone secretion, and pregnancy outcome.
To investigate the reciprocal interactions between estrogen and circadian rhythms our lab utilizes 3 different strains of transgenic mice. Aromatase knockout (ArKO) animals cannot convert testosterone to estrogen because they lack a critical enzyme. These animals can still respond to estrogen as they possess estrogen receptors. Estrogen receptor knockout (ERKO) mice lack Estrogen Receptor 1 (ESR1 formerly known as ER alpha), however they still possess estrogen receptor 2 (formerly ER beta). Lastly we use NERKI (non traditional estrogen receptor knock-in)mice. These animals have a modified ESR1 which only allows estrogen to act via 2nd messenger pathways.These three strains of mice enable us to determine how changes in the hormonal milieu during development can lead to long term changes in the circadian system of the adult and whether replacement of estrogen or its agonists during specific periods during gestation or adulthood can restore circadian rhythm function to that of wild type animals.
Sexual Differentiation/Prenatal Programming Research
Our lab is also interested in sexual differention, with a particular focus at elucidating how environmental chemicals with estrogenic and anti-estrogenic actions can affect a developing organism. We have been examining the effect of bisphenol-A (BPA), methoxychlor, and excess estrogen on the neuroanatomy of developing mice and sheep.