Abstract
The hypothesis that developmental estrogenic exposure induces a constellation of male reproductive tract abnormalities is supported by experimental and human evidence. Experimental data also suggest that some induced effects persist in descendants of exposed males. These multi- and transgenerational effects are assumed to result from epigenetic changes to the germline, but few studies have directly analyzed germ cells. Typically, studies of transgenerational effects have involved exposing one generation and monitoring effects in subsequent unexposed generations. This approach, however, has limited human relevance, since both the number and volume of estrogenic contaminants has increased steadily over time, intensifying rather than reducing or eliminating exposure. Using an outbred CD-1 mouse model, and a sensitive and quantitative marker of germline development, meiotic recombination, we tested the effect of successive generations of exposure on the testis. We targeted the germline during a narrow, perinatal window using oral exposure to the synthetic estrogen, ethinyl estradiol. A complex three generation exposure protocol allowed us to compare the effects of individual, paternal, and grandpaternal (ancestral) exposure. Our data indicate that multiple generations of exposure not only exacerbate germ cell exposure effects, but also increase the incidence and severity of reproductive tract abnormalities. Taken together, our data suggest that male sensitivity to environmental estrogens is increased by successive generations of exposure.
Highlights
Data from human populations around the world provide evidence of a marked decline in male fertility during the past several decades
Developmental exposure to manmade chemicals that interfere with endogenous hormones has been reported to adversely affect male reproductive health, increasing the incidence of reproductive tract abnormalities and reducing sperm production
Germ cell transplantation experiments demonstrated that the meiotic phenotype was due to alterations in the spermatogonial stem cells (SSCs) of the testis, a lineage thought to be determined during the window of exposure used in the study [38,39,40]
Summary
Data from human populations around the world provide evidence of a marked decline in male fertility during the past several decades. A comprehensive analysis in 2000 of data from more than 100 studies in Western countries provided evidence of a decline in human spermatogenesis during the preceding 50 years [1]. Subsequent experimental data, have provided evidence that male reproductive abnormalities can be induced by developmental exposure to different types of endocrine disrupting chemicals (EDCs; reviewed in [10,11]). Given the rapid increase in the variety and ubiquity of EDCs in our environment and the adverse reproductive effects ascribed to some of these chemicals, the implications for humans are significant
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