Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Cyclopentanohydrophenanthrene ring system doai
Reexamination Certificate
1998-06-10
2001-04-24
Badio, Barbara P. (Department: 1616)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Cyclopentanohydrophenanthrene ring system doai
C514S178000, C514S182000
Reexamination Certificate
active
06221857
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to methods of altering sex ratios in mammalian populations by treating pregnant female mammals (P generation) with hormones or anti-hormones. The sex ratio of the F1 generation born to treated mammals exhibits a normal sex ratio, but the sex ratio of the F2 generation is altered depending on the active agent given to the pregnant dam. Administration of androgens to the P generation dam results in an P2 generation with more males than would be expected in the absence of treatment; administration of an anti-androgen results in more females.
BACKGROUND OF THE INVENTION
The expected sex ratio for a given population of mammals is approximately 50% males. Attempts to alter this ratio by genetic selection in mice and fruit flies have been unsuccessful (see, e.g., Falconer,
Am. Nat.
88:385 (1954); Laurie,
Proc. R. Soc. London
133:248 (1946)). However, alterations of the sex ratio have been described in several wild and laboratory populations of mammals. Sex ratio alterations have been ascribed to a number of environmental factors including food supply (see, e.g., Austad and Sunquist,
Nature
324:58 (1986); McClure,
Science
211:1058 (1981); Meikle and Drickamer,
J. Repro. Fert.
78:587 (1986)); timing of mating (see, e.g., Hendricks and McClintock,
Physiol. Behav.
48:625 (1990); Horning and McClintock,
Anim. Behav.
47:1224 (1994); Huck et al.,
Behav. Ecol. Sociobiol.
26:99 (1990)); social dominance status (see, e.g., Meikle et al.,
Anim. Behav.
46:79 (1993)); and intrauterine position of the fetus (see, e.g., Clark et al.,
Nature
364:712 (1993); Vandenbergh and Huggett,
PNAS
(
USA
) 91:11055 (1994); Clark and Galef,
Physiol. Behav.
57:297 (1995)).
Further, some alterations in sex ratio have been made in domestic farm animals by taking advantage of differential characteristics of the Y- and X-bearing sperm. To date, no controlled physiological manipulation of the pregnant female has been reported to alter sex ratio in naturally conceived mammalian populations.
SUMMARY OF THE INVENTION
A first aspect of the present invention is a method of treating a pregnant mammal to alter the sex ratio of the F2 generation. The pregnant mammal (P generation) is treated with an active agent with hormonal effects, with the active agent being administered to the P generation dam prior to the end of sexual differentiation of F1 female embryos. An F1 female is allowed to mature and mated, and the resulting F2 generation exhibits an altered sex ratio (more males or more females, depending on the active agent administered) than would expected in the absence of said treatment.
A further aspect of the present invention is a method of treating a pregnant mammal with an androgen, to increase the ratio of males in the F2 generation. The pregnant mammal (P generation) is treated with an androgen, the androgen being administered to the P generation dam prior to the end of sexual differentiation of F1 female embryos. An F1 female is allowed to mature and mated, and the resulting F2 generation contains more males than would expected in the absence of said treatment.
A further aspect of the present invention is a method of treating a pregnant mammal with an anti-androgen, to increase the ratio of females in the F2 generation. The pregnant mammal (P generation) is treated with an anti-androgen, the anti-androgen being administered to the P generation dam prior to the end of sexual differentiation of F1 female embryos. An F1 female is allowed to mature and mated, and the resulting F2 generation contains more females than would expected in the absence of said treatment.
A further aspect of the present invention is a method of treating a pregnant mammal with an estrogen, to increase the ratio of females in the F2 generation. The pregnant mammal (P generation) is treated with an estrogen, the estrogen being administered to the P generation dam prior to the end of sexual differentiation of F1 female embryos. An F1 female is allowed to mature and mated, and the resulting F2 generation contains more females than would expected in the absence of said treatment.
DETAILED DESCRIPTION OF THE INVENTION
Four mechanisms have been proposed to result in alteration of sex ratios: asynchronous breeding, sperm selection, sex specific embryonic mortality, and concentration of gonadotropins and gonadal steroids at conception. Asynchronous breeding relates to the time of insemination relative to the stage of the estrus cycle.
Females who are fertilized near the time of ovulation produce more females than those who are fertilized either before or after ovulation. Sperm selection operates either by favoring the survival or fertilizing ability of either the X- or Y-bearing sperm. Sex-specific embryonic mortality may occur by favoring the survival of one gonotype over another; this may result from differences in male and female responses to sub-optimal gestational conditions. James (
J. Theor. Biol.
143:555 (1990)) theorized that, in humans, parental hormone levels at the time of conception affect the sex of offspring, with high levels of gonadotropin favoring production of males and high levels of androgen or estrogen favoring the production of females. However, only correlational evidence is available to support this theory. Similarly, no physiological mechanism(s) have been experimentally confirmed as underlying any of the above mechanisms of sex ratio alteration.
The intrauterine position (IUP) of a female rodent has been shown to influence the sex ratio of litters produced by that rodent. Clark et al.,
Nature
364:712 (1993); Vandenbergh and Huggett,
PNAS
(
USA
) 91:11055 (1994); Clark and Galef,
Physiol. Behav.
57:297 (1995). Vandenbergh and Huggett (
PNAS
(
USA
) 91:11055 (1994)) reported that female mice gestated between two males produced 61.2% males; females gestated with one male adjacent produced 52.9% males; and females gestated without adjacent males produced 42.4% males. In addition to altering sex ratio, intrauterine position has been reported to masculinize the anatomy, physiology and behavior of offspring (vom Saal,
J. Animal Sci.
67:1824 (1989)). The sex of the immediate neighbors of a developing fetus determines the relative testosterone exposure of that fetus in utero (Clark et al.,
Physiol. Behav.
49:239 (1991)). The more males adjacent to a female fetus, the higher the testosterone exposure and the greater the degree of masculinization.
The present inventors have determined that hormonal active agents administered to pregnant female mice results in an alteration (from the expected 50:50 ratio) of sex ratio in the subsequent F2 generation. Where the hormone administered to the parental dam is an androgen, the F1 daughters produce male-biased litters. Where an anti-androgen is administered to the parental dam, the F1 daughters produce female-biased litters.
While not wishing to be held to a particular theory of action, the present inventors believe that hormonal changes occurring in utero preset developing females to subsequently produce litters biased toward a specific sex. The altered sex ratios in litters may result from the preferential loss of zygotes of a particular sex. Alternatively, females exposed to hormones in utero may engage in breeding that is asynchronous with the estrous cycle.
Asynchronous breeding may occur due to physiological changes (irregular estrous cycles) or to behavioral effects (mating behavior asynchronous with estrous). Previous studies have reported that animals exposed in utero to elevated physiological levels of testosterone exhibit increased occurrence of abnormal estrus cycles (vom Saal,
J. Anim. Aci.
67:1824 (1989); Hotchkiss and Vandenbergh, unpublished data). Differences in female mating behavior due to prenatal endocrine exposure have also been documented (Rines and vom Saal,
Horm. Behav.
18:117 (1984)), and might lead to significant discrepancy between coitus and endocrine status of the female.
The present inventors have determined that hormones or antihormones administered to pregnant female (P
Hotchkiss Andrew K.
Konzelmann Jacob A.
Vandenbergh John G.
Badio Barbara P.
Myers Bigel & Sibley & Sajovec
North Carolina State University
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