Effects on male sensitivity

The agonists were found to vary considerably in their potency, with peak response in chlordimeform and XAMI treated insects occurring at 1 pg/g vs 100 pg/g for OA (Figure 2). The dose-response curves also show that males treated with chlordimeform, XAMI, lofexidine naphazoline, and synephrine exhibited levels of response to 0.01 mg pheromone that were equal to those of OA-treated (100 pg/g) males, but that clonidine, tolazoline, and tramazoline were much less effective, and that dopamine was without effect on male sensitivity. 

One of the proposed mechanisms by which OA exerts its regulatory actions is via an adenylate cyclase (12-18). In a preliminary test male CL were treated with the phosphodiesterase inhibitor 3-isobutyl-1-methylxanthine (IBMX), alone and with OA. The dose of OA (10 ug/g) was one that induced little or no effect on male sensitivity (see Figure 1). Results showed that when treated with IBMX alone (10 Ug/g) male response to a low dosage of pheromone (0.01 mg) was not significantly enhanced over that observed with controls, or OA alone (20 vs. 15% source contacts respectively). However, when treated with 10 Ug/g OA and 10 Ug/g IBMX, 78% of the males successfully reached the source. IBMX clearly potentiated the effect of a low dose of OA on male sensitivity to pheromone ... 

As to the primary developmental actions of testosterone, growth and differentiation appear to be involved. Testosterone or estradiol stimulates outgrowth of neurites from developing hypothalamic neurons that contain estrogen receptors [14, 15]. This is believed to be one of the principal aspects of testosterone action that increases the number and the size of neurons within specific hypothalamic nuclei in males, compared to females [1, 14, 15]. 5a-DHT may have a similar effect on androgen-sensitive neurons. Differentiation of target neurons also occurs in adult brain tissue, hormones like estradiol can evoke responses that differ between adult male and female rats [1,14,15],... 

Not only is it difficult to detect effects on male fertility because of group-size considerations, effects on male fertility mediated by decreased sperm production are also difficult to detect because of the normally huge excess of sperm included in a rat ejaculate. Sperm production can be decreased by up to 90% without effect on fertility (either pregnancy rate or litter size) in the rat. This is not the case for men, so the sperm excess in the rat represents a serious flaw in the rat model (see Working, 1988). To address this deficiency and improve the sensitivity of the model, it is advisable to determine the effects of the test agent on testes weights, testicular spermatid counts, and histopathology of the testes (preferably plastic sections) in the male fertility study and/or the 14-week toxicity study. In some cases, these parameters may be more predictive of possible effects on male fertility in humans than the fertility rate in rats. 

Following the hearings, work by Whorton et al. (ref. 24a) showed that reversibility of the azoospermia experienced by exposed workers was probably dose-dependent and a function of individual sensitivity. OSHA then reduced the MAC to 1 ppb (ref. 25). See table on p. 167 of ref. 47 for reproductive effects on males. All registrations of end use products except for use on pineapples in Hawaii have been cancelled (EPA, ref. 103, p. 3). 

Our agonist studies were designed to further document the effect of lower doses of OA on male sensitivity to pheromone (as shown in Figure 1), and to provide a pharmacological profile that could be compared with data from other published studies on OA receptors (12-14). The compounds included 1) the phenylethylamines synephrine and dopamine, 2) the formamidine chlordimeform, and 3) the substituted imidazolines naphazoline (2-[ 1-naphthylmethyl] imidazoline ), lofexidine (2-[ l-(2,6-dichlorophenoxy)ethyl]-2-imidazoline), XAMI (2,3-xylylaminomethyl-2-imidazoline), clonidine (2-(2,6-dichloro-anilino)-2-imidazoline), tolazoline (2-benzyl-2-imidazoline), and tramazoline (2-[5,6,7,8-tetrahydro-1-naphthyl]amino-2-imidazoline) ... 

We first determined the ability of selected agonist compounds to mimic the effect of OA on male sensitivity to the pheromone by treating males with a dose series of each compound and then testing them with the 0.01 mg dosage of pheromone, which under control conditions elicits a low level of response (Figure 2). It is important to note... 

Figure 2. Percentage of male CL making source contact (0.01 mg pheromone) 4-5 hours after injection of OA and agonist compounds ( ig/g) The curves for each compound represent the range of doses over which an effect was observed only on male sensitivity to pheromone, without a significant effect on male flight performance. N - 80 for each dose. The solid line indicates control response level (16%).

In the second series of tests the ability of several of the antagonists to block the effect of OA on male sensitivity was assessed. Data in Figure 5 show that mianserin, chlorpromazine, and yohimbine reversed the effect of OA on male sensitivity to the 1 mg dosage of pheromone, with chlorpromazine and yohimbine exhibiting greater potency than when presented alone (Figure 4). 

Male rats are sensitive to renal tubular nephropathy after exposure to hexachloroethane. The lesions observed are characteristic of hyaline droplet nephropathy. They are most likely the result of hexachloroethane or one of its metabolites binding to the excretory protein 2p-globulin, altering its kidney transport, and leading to the formation of hyaline droplets. This protein is synthesized by male rats and accounts for 26% of their urinary protein excretion (Olson et al. 1990). It is not excreted in female rats except in minimal quantities. Since some effects are also seen in kidneys of female rats and in male and female mice that do not synthesize 2p-globulin, hexachloroethane must also have milder adverse effects on the kidney through a different mechanism. 

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